2,488 research outputs found
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 BiociĂȘncias, ramo de especialização em Toxicologia, apresentada Ă Faculdade de CiĂȘncias e Tecnologia da Universidade de CoimbraDoxorubicin (DOX) is one of the most potent antineoplastic drugs. Although
possessing a superior anti-Âââcancer activity, a broader clinical use of DOX is limited by
a dose-Âââdependent, 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-Âââinduced
cardiotoxicity, mitochondrial disruption has been observed in different models. This
alteration of mitochondrial function is often sub-Âââclinical 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-Âââ
treated rats in order to identify metabolic alterations caused by an acute and sub-Âââ
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).
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For the acute treatment protocol, sixteen week-Âââold male Wistar rats were i.p. injected
with 20mg/Kg DOX or 1mg/Kg 0.9%NaCl and sacrificed 24 hours later. For sub-Âââ
chronic protocol, eight weeks-Âââold 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 -Âââ GG or octanoate plus malate â
OM). Glycolytic (iodoacetate) and oxidative phosphorylation (rotenone-Âââ Rot or
cyanide-Âââ KCN) inhibitors were separately added to the different metabolic
perfusates, aiming to detect undercover mitochondrial defects in the DOX-Âââtreated
group. In non-Âââperfused hearts, or hearts perfused in the absence (time controls, TC)
or presence of inhibitors, selected metabolic and mitochondrial proteins were semi-Âââ
quantified by Western blotting, and mRNA levels were quantified by RT-ÂââPCR.
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-Âââquantified 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-Âââtreated 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-Âââchronic model and using glucose as substrate, the DOX-Âââtreated 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-Âââquantification 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-Âââchronic DOX-Âââtreated 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-Âââ
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) Ă© um dos fĂĄrmacos antineoplĂĄsicos mais potentes. Apesar de
possuir uma actividade anti-Âââcancro superior, uma mais ampla utilização clĂnica da
DOX Ă© limitada por uma dose-Âââdependente, 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 crĂłnicos resultam muitas vezes numa
cardiotoxicidade persistente, incluindo a deterioração progressiva do metabolismo
mitocondrial, o desenvolvimento de cardiomiopatia e por fim insuficiĂȘncia cardĂaca
congestiva. Importante no contexto da cardiotoxicidade induzida pela DOX,
perturbação mitocondrial foi observada em diferentes modelos. Esta alteração da
função mitocondrial Ă© muitas vezes sub-ÂââclĂnica e sĂł se manifesta como
cardiomiopatia quando outros factores sĂŁo combinados, incluindo a idade ou
diferentes tipos de estresse cardiovascular. Além disso, ocorrem alteraçÔes
metabĂłlicas na cĂ©lula cardĂaca, o que contribui para a capacidade do coração resistir
a maior demanda. Embora a perturbação mitocondrial seja um marcador precoce e
sensĂvel de DOX cardiotoxicidade, como o stress metabĂłlico 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 coraçÔes perfundidos de ratos tratados com uma solução
salina (SAL) e ratos tratados com DOX, a fim de identificar alteraçÔes metabólicas
causadas por um tratamento agudo e sub-ÂââcrĂŽnico.
XIX
O nosso pressuposto para esta estratégia é que uma menor susceptibilidade a um
determinado inibidor durante a perfusĂŁo, seria um sinal de uma forma mais robusta
(ou seja, mais de capacidade) da via-Âââalvo (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-ÂââcrĂŽnico, ratos machos Wistar
de oito semanas de idade, receberam sete injecçÔes s.c. semanais com DOX (2 mg /
kg) ou uma equivalente da solução SAL sendo sacrificados uma semana após a
Ășltima injecção. ApĂłs o protocolo de tratamentos, os animais foram sacrificados e os
coraçÔes foram perfundidos com um aparelho de Langendorff com substratos
cardĂacos distintos (glucose, galactose mais glutamina -Âââ GG ou octanoato mais
malato -Âââ OM). Inibidores glicolĂticos (iodoacetato) e inibidores da fosforilação
oxidativa (Rot-Âââ rotenona ou KCN-Âââ cianeto) foram adicionados separadamente nos
diferentes substratos metabĂłlicos, com o objetivo de detectar defeitos mitocondriais
no grupo tratado com DOX. Em coraçÔes não perfundidos, ou coraçÔes perfundidos
na ausĂȘncia (controlos de tempo, TC) ou na presença de inibidores, algumas
proteĂnas metabĂłlicas e proteĂnas mitocondriais foram semi-Âââquantificadas por
Western blotting, e os nĂveis de mRNA foram quantificados por RT-ÂââPCR.
No modelo de tratamento agudo DOX, coraçÔes perfundidos com glucose como
substrato sofreram um declĂnio no nĂșmero de batimentos cardĂacos e produto da
taxa de pressĂŁo (RPP), quando iodoacetato foi adicionado, ao contrĂĄrio da Rot ou
KCN, que não teve nenhum efeito. Com GG, a titulação com o inibidor diminuiu a
frequĂȘncia cardĂaca, 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
frequĂȘncia cardĂaca e do RPP na presença dos inibidores, mostrando uma resposta
igual entre os tratamentos. Quando proteĂnas glicolĂticas e mitocondriais foram semi-Âââ
quantificadas por Western blotting, alteraçÔes de proteĂnas envolvidas na biogĂȘnese
mitocondrial e autofagia foram observados em coraçÔes DOX perfundidos com
inibidores. Os dados do protocolo de estudo agudo, parecem sugerir que os coraçÔes
provenientes de animais tratados com DOX na presença de inibidores, tĂȘm a função
metabólica melhorada, indicando assim que a DOX desencadeia adaptaçÔes que
permitem que os coraçÔes sejam menos susceptĂveis Ă inibição mitocondrial e
glicolĂtica.
No modelo sub-ÂââcrĂłnica 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 cardĂaco e no
RPP em grupo DOX, quando rot ou KCN foi adicionado o nĂșmero de batimentos
cardĂacos e RPP permaneceram idĂȘnticos entre os dois grupos. A semi-Âââquantificação
de proteĂnas glicolĂticas e mitocondriais sugerem uma deficiĂȘncia da autofagia em
coraçÔes DOX perfundidos, mais evidente durante a perfusão com GG. A presença
de inibidores da perfusão geralmente também reduziu a quantidade total de
proteĂnas detectadas atravĂ©s de Western Blot, embora proteĂnas glicolĂticas
aumentaram quando os coraçÔes foram perfundidos com glucose, ao contrårio da
perfusĂŁo com GG.
Os resultados sugerem que ratos tratados sub-Âââcronicamente com DOX sofreram uma
remodelação metabĂłlica, que Ă© baseado em fluxos glicolĂticos mais fortes para
manter a contratilidade, embora nenhum defeito mitocondrial ostensivo foi
descoberto.
XXI
Um resultado surpreendente Ă© que, independentemente do tampĂŁo de perfusĂŁo
utilizado, não foram encontradas diferenças marcantes entre SAL e DOX coraçÔes em
termos de parĂąmetros hemodinĂąmicos.
O presente trabalho sugere que o remodelação metabólica durante o tratamento
agudo e sub-ÂââcrĂŽnico com DOX, mantĂ©m a função cardĂaca nos animais tratados. Esta
remodelação é, aparentemente, baseado numa contribuição mais forte da glicólise ao
metabolismo geral. Os resultados de quantidade de proteĂna 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 perĂodo de repouso tambĂ©m 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 ”-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: â17.73âh (95% CI, â21.26 to â14.19âh); p < 0.001), stool (â9.52âh (95% CI, â14.74 to â4.79âh); p < 0.001), and oral tolerance (â12.00âh (95% CI, â18.01 to â5.99âh); p < 0.001). Morphine consumption was reduced in the active groups of 4 studies (average reduction, 12.9â30.0âmg), 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 â19: Crossâsectional study
This study explores the response to COVIDâ19 from investigators, editors, and publishers and seeks to define challenges during the early stages of the pandemic. A crossâsectional bibliometric review of COVIDâ19 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 submissionâtoâacceptance time and availability of original data. Publisherâresponsiveness was assessed by measuring the acceptanceâtoâpublication time and the provision of open access. Three hundred and ninetyâeight of 2,835 COVIDâ19 and 55 of 1,513 MERS search results were eligible. Most COVIDâ19 studies were clinical reports (n =â242; 60.8%). The submissionâtoâacceptance [median: 5âdays (IQR: 3â11) versus 71.5âdays (38â106); P <â.001] and acceptanceâtoâpublication [median: 5âdays (IQR: 2â8) versus 22.5âdays (4â48·5â; P <â.001] times were strikingly shorter for COVIDâ19. Almost all COVIDâ19 (n =â396; 99.5%) and MERS (n =â55; 100%) studies were openâaccess. Data sharing was infrequent, with original data available for 104 (26.1%) COVIDâ19 and 10 (18.2%) MERS studies (P =â.203). The early academic response was characterized by investigators aiming to define the disease. Studies were made rapidly and openly available. Only oneâinâfour 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 ÎČ-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 ÎČ2-agonist and ICS treatment [3]. Although several studies have suggested that steroid signalling [4] or ÎČ2-adrenoceptor (ÎČ2AR) signalling may be abnormally regulated in severe asthma [5], it remains unknown whether impaired airway smooth muscle corticosteroid and/or ÎČ2-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 ÎČ2-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 ÎČ2-agonist treatment than those from patients without FA
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