3,198 research outputs found
Medication nonadherence and psychiatry.
Nonadherence to appropriately prescribed medication for psychiatric disorders prevents patients from realizing the full benefits of their treatment and negatively impacts on individuals, their families and the healthcare system. Understanding and reducing nonadherence is therefore a key challenge to quality care for patients with psychiatric disorders. This review highlights findings regarding the prevalence and consequence of nonadherence, barriers to adherence and new intervention methods from 2012 onwards
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
Erratum to: 25 Years of Self-organized Criticality: Concepts and Controversies
Introduced by the late Per Bak and his colleagues, self-organized criticality (SOC) has been one of the most stimulating concepts to come out of statistical mechanics and condensed matter theory in the last few decades, and has played a significant role in the development of complexity science. SOC, and more generally fractals and power laws, have attracted much comment, ranging from the very positive to the polemical. The other papers (Aschwanden et al. in Space Sci. Rev., 2014, this issue; McAteer et al. in Space Sci. Rev., 2015, this issue; Sharma et al. in Space Sci. Rev. 2015, in preparation) in this special issue showcase the considerable body of observations in solar, magnetospheric and fusion plasma inspired by the SOC idea, and expose the fertile role the new paradigm has played in approaches to modeling and understanding multiscale plasma instabilities. This very broad impact, and the necessary process of adapting a scientific hypothesis to the conditions of a given physical system, has meant that SOC as studied in these fields has sometimes differed significantly from the definition originally given by its creators. In Bakâs own field of theoretical physics there are significant observational and theoretical open questions, even 25 years on (Pruessner 2012). One aim of the present review is to address the dichotomy between the great reception SOC has received in some areas, and its shortcomings, as they became manifest in the controversies it triggered. Our article tries to clear up what we think are misunderstandings of SOC in fields more remote from its origins in statistical mechanics, condensed matter and dynamical systems by revisiting Bak, Tang and Wiesenfeldâs original papers
Size matters in quantitative radar monitoring of animal migration: estimating monitored volume from wingbeat frequency
This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Quantitative radar studies are an important component of studying the movements of birds. Whether a bird, at a certain distance from the radar, is detected or not depends on its size. The volume monitored by the radar is therefore different for birds of different sizes. Consequently, an accurate quantification of bird movements recorded by small-scale radar requires an accurate determination of the monitored volume for the objects in question, although this has tended to be ignored. Here, we demonstrate the importance of sensitivity settings for echo detection on the estimated movement intensities of birds of different sizes. The amount of energy reflected from a bird and detected by the radar receiver (echo power) depends not only on the bird's size and on the distance from the radar antenna, but also on the beam shape and the bird's position within this beam. We propose a method to estimate the size of a bird based on the wingbeat frequency, retrieved from the echo-signal, independent of the absolute echo power. The estimated bird-size allows calculation of size-specific monitored volumes, allowing accurate quantification of movement intensities. We further investigate the importance of applying size-specific monitored volumes to quantify avian movements instead of using echo counts. We also highlight the importance of accounting for size-specific monitored volume of small scale radar systems, and the necessity of reporting technical information on radar parameters. Applying this framework will increase the quality and validity of quantitative radar monitoring.COST â European Cooperation in Science and Technolog
Beliefs about medication predict the misattribution of a common symptom as a medication side effect - Evidence from an analogue online study.
OBJECTIVE: Some perceived medication side effects may be 'normal' symptoms that patients misattribute to the medication. Using an analogue approach, we tested if medication beliefs predict whether participants misattribute a headache as a side effect and subsequently intend to stop medication. METHODS: We recruited 690 participants, 223 reporting a past asthma diagnosis. They received information about asthma and Molair, a fictitious asthma treatment modeled on a licensed treatment (montelukast). We varied the description of efficacy and side effects (which did not include headache). Pre-exposure to this information, participants completed the Beliefs about Medicine Questionnaire (BMQ)-General and the Perceived Sensitivity to Medicines Scale (PSM), post-exposure they completed the BMQ-Specific. Participants were asked to imagine they experienced a headache while taking Molair. Finally, they rated whether the headache was a side effect (misattribution) and if they would stop taking Molair (behavioral intention). RESULTS: Nearly a quarter (170) of participants misattributed the headache to Molair and 69 (10%) subsequently intended to stop Molair. Both outcomes were predicted by general and specific medication beliefs. Odds of misattribution (m) and behavioral intention (i) increased with higher General Harm (ORm=1.90, ORi=2.72), General Overuse (ORm=1.74, ORi=1.56) and Molair Concern beliefs (ORm=1.52, ORi=1.78, all p<.01), but decreased with General Benefit (ORm=0.72, ORi=0.53) and Molair Necessity beliefs (ORm=0.72, ORi=0.70, all p<.05). CONCLUSION: Symptom misattribution and subsequent intentions to stop Molair were predicted by pre-exposure beliefs about medicines in general and post-exposure beliefs about Molair. Patients with negative medication beliefs may be prone to misattribute symptoms and subsequently stop medication
The Galaxy Structure-Redshift Relationship
There exists a gradual, but persistent, evolutionary effect in the galaxy
population such that galaxy structure and morphology change with redshift. This
galaxy structure-redshift relationship is such that an increasingly large
fraction of all bright and massive galaxies at redshifts 2 < z < 3 are
morphologically peculiar at wavelengths from rest-frame ultraviolet to
rest-frame optical. There are however examples of morphologically selected
spirals and ellipticals at all redshifts up to z ~ 3. At lower redshift, the
bright galaxy population smoothly transforms into normal ellipticals and
spirals. The rate of this transformation strongly depends on redshift, with the
swiftest evolution occurring between 1 < z < 2. This review characterizes the
galaxy structure-redshift relationship, discusses its various physical causes,
and how these are revealing the mechanisms responsible for galaxy formation.Comment: 20 pages, 8 figures. Invited Review to appear in "Penetrating Bars
Through Masks of Cosmic Dust: The Hubble Tuning Fork Strikes A New Note", ed.
D. Block et a
Evaluation of the vector competence of a native UK mosquito Ochlerotatus detritus (Aedes detritus) for dengue, chikungunya and West Nile viruses
BACKGROUND: To date there has been no evidence of mosquito-borne virus transmission of public health concern in the UK, despite the occurrence of more than 30 species of mosquito, including putative vectors of arboviruses. The saltmarsh mosquito Ochlerotatus detritus [syn. Aedes (Ochlerotatus) detritus] is locally common in parts of the UK where it can be a voracious feeder on people. METHODS: Here, we assess the competence of O. detritus for three major arboviruses: dengue virus (DENV), chikungunya virus (CHIKV) and West Nile virus (WNV) using adult mosquitoes reared from wild, field-obtained immatures. RESULTS: We demonstrate laboratory competence for WNV at 21 °C, with viral RNA detected in the mosquitoâs saliva 17 days after oral inoculation. By contrast, there was no evidence of laboratory competence of O. detritus for either DENV or CHIKV. CONCLUSIONS: To our knowledge, this is the first study to demonstrate competence of a UK mosquito for WNV and confirms that O. detritus may present a potential risk for arbovirus transmission in the UK and that further investigation of its vector role in the wild is required
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