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1.
BMC Vet Res ; 19(1): 201, 2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37821927

RESUMO

BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.


Assuntos
Doenças do Cão , Prolapso da Valva Mitral , Cães , Animais , Furosemida/farmacologia , Furosemida/uso terapêutico , Enalapril/farmacologia , Enalapril/uso terapêutico , Frequência Cardíaca , Valva Mitral , Cardiotônicos/farmacologia , Prolapso da Valva Mitral/veterinária , Diuréticos , Doenças do Cão/tratamento farmacológico
2.
Health Serv Manage Res ; 36(2): 89-101, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-35485323

RESUMO

Much management and leadership development provision for healthcare professionals has been the subject of considerable criticism, and there have been numerous calls for training programmes explicitly focused on the specific managerial (manager/leader) behaviours healthcare managers, physician leaders and nurse managers need to exhibit to be perceived effective. The aim of our multiple cross-case/cross-nation comparative study has been to: i) identify similarities and differences between the findings of published qualitative critical incident studies of effective and ineffective managerial behaviour observed within British, Egyptian, Mexican and Romanian public hospitals, respectively, and ii) if possible, deduce from the identified commonalities a healthcare-related behavioural model of perceived managerial and leadership effectiveness. Adopting a philosophical stance informed by pragmatism, epistemological instrumentalism and abduction, we used realist qualitative analytic methods to code and classify into a maximum number of discrete behavioural categories empirical source data obtained from five previous studies. We found high degrees of empirical generalization which resulted in the identification of five positive (effective) and four negative (ineffective) behavioural dimensions (BDs) derived, respectively, from 14 positive and 9 negative deduced behavioural categories (BCs). These BDs and underpinning BCs are expressed in the form of an emergent two-factor universalistic behavioural model of perceived managerial and leadership effectiveness. We suggest the model could be used to critically evaluate the relevance and appropriateness of existing training provision for physician leaders, nurse managers and other healthcare managers/leaders in public hospitals or to design new explicit training programmes informed and shaped by healthcare-specific management research, as called for in the literature.


Assuntos
Pessoal de Saúde , Liderança , Humanos , Pesquisa Qualitativa , Atenção à Saúde , Serviços de Saúde
3.
Sci Rep ; 12(1): 20789, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456663

RESUMO

Centell-S is a water-soluble extract of Centella asiatica containing more than 80% w/w triterpenoid glycosides. Madecassoside and asiaticoside are two major components of the extract and can be converted into active metabolites, triterpenic acids in large mammal species. In this study, the pharmacokinetic profiles and metabolomic changes generated by the bioactive triterpenoids of Centell-S alone, and in combination with the bioenhancers piperine and curcumin, were investigated in beagle dogs. The test substances were orally administered over multiple doses for 7 consecutive days. At day 1 and 7 after receiving the test compounds, the level of major bioactive triterpenoids and related metabolites were measured using triple quadrupole and high-resolution accurate mass orbitrap models of LCMS to determine pharmacokinetic and metabolomic profiles, respectively. Centell-S was well tolerated, alone and in all combination groups. The combination of Centell-S and piperine significantly increased (p < 0.05) the systemic exposure of madecassoside on day 1 and asiatic acid on day 7, by approximately 1.5 to 3.0-fold of Cmax and AUC values as compared to the Centell-S alone, while the addition of curcumin did not provide a significant improvement. Several metabolomic changes were observed from pre-dose to 4 h post-dose, with some biomarkers of neurodegenerative diseases including L-glutamine, lysophosphatidylcholine (17:0), taurochenodeoxycholic acid, uric acid, stearic acid, palmitic acid, and lactic acid showing good correlation with the systemic exposure of the bioactive triterpenoids (asiatic acid). Thus, the combining of piperine to Centell-S exhibits the improvement of bioactive triterpenoids which are related to the biomarkers of neurodegenerative diseases. These promising results might be useful for the development of this standardised extract to become a more effective phytomedicine for neurodegenerative diseases.


Assuntos
Curcumina , Triterpenos , Cães , Animais , Curcumina/farmacologia , Triterpenos/farmacologia , Metaboloma , Extratos Vegetais/farmacologia , Mamíferos
4.
Nutrients ; 14(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36364910

RESUMO

The main barrier to the publication of observational research is a perceived inferiority to randomised designs with regard to the reliability of their conclusions. This commentary addresses this issue and makes a set of recommendations. It analyses the issue of research reliability in detail and fully describes the three sources of research unreliability (certainty, risk and uncertainty). Two of these (certainty and uncertainty) are not adequately addressed in most research texts. It establishes that randomised designs are vulnerable as observation studies to these two sources of unreliability, and are therefore not automatically superior to observational research in all research situations. Two key principles for reducing research unreliability are taken from R.A. Fisher's early work on agricultural research. These principles and their application are described in detail. The principles are then developed into four key principles that observational researchers should follow when they are designing observational research exercises in nutrition. It notes that there is an optimal sample size for any particular research exercise that should not be exceeded. It concludes that best practice in observational research is to replicate this optimal sized observational exercise multiple times in order to establish reliability and credibility.


Assuntos
Projetos de Pesquisa , Reprodutibilidade dos Testes , Tamanho da Amostra , Incerteza
5.
Meat Sci ; 194: 108964, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36115255

RESUMO

This study focuses on the details of consumer response to lab grown 'cultured meat (CM)', compared to meat derived from insects, plants and animals. A sample of 254 New Zealanders were interviewed. A word association exercise revealed that consumer reaction to CM was dominated by affective, rather than cognitive factors. The linkages between a general food neophobia scale, a specific CM evaluation scale and purchase intent were studied. The general neophobia scale performed poorly as a predictor, while the 19-point CM evaluation scale performed well. Reducing this scale to its seven affective components, and then to just the two key affective components did not significantly reduce the scale's predictive performance. Overall, the results of this research reveal very significant differences in preference for meat products based upon their origins. Insect protein was strongly disfavoured over all alternatives, while cultured meat was significantly disfavoured compared to more established alternatives. The implications of this for the commercialisation of CM are discussed.


Assuntos
Transtorno Alimentar Restritivo Evitativo , Produtos da Carne , Humanos , Animais , Carne , Preferências Alimentares/psicologia , Intenção , Comportamento do Consumidor
6.
Sci Adv ; 8(1): eabj5473, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34985951

RESUMO

Myocardial ischemia is spontaneous, frequently asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, myocardial sensory networks cannot reliably detect and correct myocardial ischemia on their own. Here, we demonstrate an artificially intelligent and responsive bioelectronic medicine, where an artificial neural network (ANN) supplements myocardial sensory networks, enabling reliable detection and correction of myocardial ischemia. ANNs were first trained to decode spontaneous cardiovascular stress and myocardial ischemia with an overall accuracy of ~92%. ANN-controlled vagus nerve stimulation (VNS) significantly mitigated major physiological features of myocardial ischemia, including ST depression and arrhythmias. In contrast, open-loop VNS or ANN-controlled VNS following a caudal vagotomy essentially failed to reverse cardiovascular pathophysiology. Last, variants of ANNs were used to meet clinically relevant needs, including interpretable visualizations and unsupervised detection of emerging cardiovascular stress. Overall, these preclinical results suggest that ANNs can potentially supplement deficient myocardial sensory networks via an artificially intelligent bioelectronic medicine system.

7.
JACC Basic Transl Sci ; 6(11): 872-881, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34869951

RESUMO

Removal of excess fluid in acute decompensated heart failure (ADHF) targets the intravascular space, whereas most fluid resides in the interstitial space. The authors evaluated an approach to interstitial decongestion using a device to enhance lymph flow. The device was deployed in sheep with induced heart failure (HF) and acute volume overload to create a low-pressure zone at the thoracic duct outlet. Treatment decreased extravascular lung water (EVLW) volume (mL/kg) (-32% ± 9%, P = 0.029) compared to controls (+46% ± 9%, P = 0.003). Device-mediated thoracic duct decompression effectively reduced EVLW. Human studies may establish device-based interstitial decongestion as a new ADHF treatment.

8.
Front Vet Sci ; 8: 646437, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34277749

RESUMO

Background: Pimobendan provides a significant survival benefit in dogs with cardiac disease, including degenerative mitral valve disease and dilated cardiomyopathy (DCM). Its positive inotropic effect is well-known, however, it has complex effects and the mechanisms behind the survival benefit are not fully characterized. Secondary hemodynamic effects may decrease mitral regurgitation (MR) in DCM, and the benefits of pimobendan may extend to improved cardiac relaxation and improved atrial function. Hypothesis/Objectives: Our objective was to investigate the acute cardiac effects of pimobendan in dogs with a DCM phenotype. We hypothesized that pimobendan would increase left atrial (LA) contractility, reduce mitral regurgitation, improve diastolic function, and lower circulating NT-ProBNP levels. Animals: Seven purpose-bred Beagles were studied from a research colony with tachycardia induced DCM phenotype. Methods: The effects of pimobendan were studied under a placebo-controlled single-blinded cross-over design. In short, dogs underwent baseline and 3 h post-dose examinations 7 days apart with echocardiography and a blood draw. Dogs were randomized to receive oral placebo or 0.25 mg/kg pimobendan after their baseline exam. Investigators were blinded to treatments until all measurements were compiled. Results: When treated with pimobendan, the dogs had significant increases in systolic function and decreases in MR, compared to when treated with placebo. There were no detectable differences in left atrial measures, including LA size, LA emptying fraction, LA functional index or mitral A wave velocity. Heart rate decreased significantly with pimobendan compared to placebo. There was also a decrease in isovolumetric relaxation time normalized to heart rate. NT-proBNP levels had a high degree of variability. Conclusions: Improved mitral regurgitation severity and improved lusitropic function may contribute to the reported survival benefit for dogs with cardiac disease administered pimobendan. Pimobendan did not overtly improve LA function as assessed by echocardiography, and NT-proBNP was not significantly changed with a single dose of this medication. Further studies are needed to better characterize LA effects with other imaging modalities, to better quantify the total improvement of MR severity, and to assess chronic use of pimobendan on diastolic function in DCM.

10.
N Engl J Med ; 383(24): 2307-2319, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33196153

RESUMO

BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).


Assuntos
Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adulto , Proteína 3 Semelhante a Angiopoietina , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/sangue , Método Duplo-Cego , Esquema de Medicação , Resistência a Medicamentos , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade
11.
Nutrients ; 12(6)2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32466408

RESUMO

This research investigated the performance of the red, octagonal Vienna Convention traffic 'STOP' sign as a front of pack (FoP) warning nutritional label. While the Vienna Convention traffic light system is an established FoP label, the potential of the 'STOP' sign in the role has not been investigated. The performance of the 'STOP' label was compared with that of a single star (low nutritional value) Australasian Health Star Rating (HSR) label using a fractionally replicated Latin square design. The labels were presented on choice diads of cold breakfast cereal packets. The sample of 240 adolescents aged 16-18 was drawn from a secondary school in the South Island of New Zealand. A large and significant main effect was observed at the p < 0.01 level for the difference between the 'STOP' sign and the control condition (no nutritional FoP label), and at p < 0.05 for the difference between the HSR and the 'STOP' label. There was no significant difference between the HSR FoP and the control condition. A significant non-additivity (interaction) (p < 0.01) was also observed via the fractional replication. The results indicate that the Vienna Convention 'STOP' sign is worthy of further research with regard to its potential as an FoP nutritional label.


Assuntos
Desjejum , Comportamento de Escolha , Comportamento do Consumidor , Grão Comestível , Rotulagem de Alimentos/métodos , Adolescente , Feminino , Preferências Alimentares , Saúde , Humanos , Masculino , Nova Zelândia , Valor Nutritivo , Obesidade
12.
Front Physiol ; 11: 222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32296340

RESUMO

The term myocardial contractility is thought to have originated more than 125 years ago and has remained and enigma ever since. Although the term is frequently used in textbooks, editorials and contemporary manuscripts its definition remains illusive often being conflated with cardiac performance or inotropy. The absence of a universally accepted definition has led to confusion, disagreement and misconceptions among physiologists, cardiologists and safety pharmacologists regarding its definition particularly in light of new discoveries regarding the load dependent kinetics of cardiac contraction and their translation to cardiac force-velocity and ventricular pressure-volume measurements. Importantly, the Starling interpretation of force development is length-dependent while contractility is length independent. Most historical definitions employ an operational approach and define cardiac contractility in terms of the hearts mechanical properties independent of loading conditions. Literally defined the term contract infers that something has become smaller, shrunk or shortened. The addition of the suffix "ility" implies the quality of this process. The discovery and clinical investigation of small molecules that bind to sarcomeric proteins independently altering force or velocity requires that a modern definition of the term myocardial contractility be developed if the term is to persist. This review reconsiders the historical and contemporary interpretations of the terms cardiac performance and inotropy and recommends a modern definition of myocardial contractility as the preload, afterload and length-independent intrinsic kinetically controlled, chemo-mechanical processes responsible for the development of force and velocity.

13.
Nutrients ; 10(7)2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012941

RESUMO

Front-of-pack (FoP) nutrition labels are a widely deployed tool in public good marketing. This article reports on a field experimental test of the impact of one of these systems, the Australasian Health Star Rating system (HSR), on consumer choice in the breakfast cereals category in New Zealand. This study forms part of a time-series replication stream of research on this topic. The research applied a 2 × 2 factorial design with multiple replications to retail food consumers exiting from supermarkets in New Zealand. The first part of the time series, undertaken shortly after the HSR's initiation in 2014, indicated that the HSR was ineffective. Between 2014 and 2016, commercial brands in the category within New Zealand massively promoted the HSR as a basis for consumer choice. The research presented in this article forms part of the second part of the series, undertaken in 2016, using an identical experimental methodology to the 2014 study. The results indicate that the HSR may be beginning to influence consumer choice as it was predicted to, but the impact of the system is still small, and statistically sub-significant, relative to other consumer decision inputs presented on the package.


Assuntos
Comportamento de Escolha , Comportamento do Consumidor , Dieta Saudável , Rotulagem de Alimentos , Promoção da Saúde , Política Nutricional , Valor Nutritivo , Recomendações Nutricionais , Rotulagem de Alimentos/legislação & jurisprudência , Promoção da Saúde/legislação & jurisprudência , Humanos , Legislação sobre Alimentos , Estudos Longitudinais , Nova Zelândia , Política Nutricional/legislação & jurisprudência , Recomendações Nutricionais/legislação & jurisprudência , Fatores de Tempo , Percepção Visual
14.
Artigo em Inglês | MEDLINE | ID: mdl-29704608

RESUMO

INTRODUCTION: FDA has established initiatives to characterize clinical and non-clinical biomarkers to enable more precise prediction of proarrhythmia risk based upon knowledge of drug effect on multiple cardiac ion channels (Colatsky et al., 2016). The FDA has recently demonstrated superiority of early ventricular repolarization interval (JTp) in differentiating pure hERG block from multi-channel block in human subjects. Preclinical studies often acquire a single lead ECG, whereas FDA measurements of JTp were derived ​from a spatial vectorcardiogram computed using multiple leads. This study compares QT subintervals derived from single lead vs. spatial magnitude (SM) ECG and contrasts information obtained from multilead and single lead ECGs in the canine model. METHODS: Four beagle dogs were instrumented with 3-lead Holter monitors to acquire continuous surface ECG recordings for three consecutive days. A 24-h baseline recording was obtained on day 1 followed by administration of dofetilide on day 2 and atropine and dofetilide on day 3. Lead II and SM ECGs were automatically analyzed using the AE-1010 Rhythm Express™ (RE) software (VivaQuant, St. Paul, MN USA) without manual intervention or editing of the results (auto). Five-minute averages of beat-to-beat intervals measured on each lead were compared for agreement assessed by Bland-Altman (BA) statistics and consistency measured as the repeatability standard deviation (SD) from 5-min intervals. The fully automated results were screened by an operator (semi-automated) and compared to automated results. RESULTS: JTp and TpTe measured using SM lead are less sensitive to changes in posture and respiration related changes in T-wave morphology. The 24-h repeatability SD of 5-min subintervals for JTp and TpTe over the three days was improved by 15.4% and 15.5% respectively with the highest improvements of 23.3% for JTp on day 2 and 25.3% for TpTe on day 3. Drug induced changes in QTcV, QRS, RR, and PR intervals were qualitatively similar between the SM lead and Lead II and in close agreement based on BA statistics. Semi-automated and automated measurements from SM Lead were in close agreement based on BA statistics. DISCUSSION: Single lead ECG is adequate for PR, RR, QRS, and QT, but produces different and more variable results when assessing QT subintervals relative to the SM lead. Close agreement between automated and semi-automated measurements demonstrates Rhythm Express accuracy and the potential to streamline interval analysis.


Assuntos
Eletrocardiografia/instrumentação , Eletrocardiografia/métodos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Cães , Eletrocardiografia/normas , Eletrocardiografia Ambulatorial/instrumentação , Eletrocardiografia Ambulatorial/métodos , Eletrocardiografia Ambulatorial/normas , Eletrodos , Feminino , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiologia , Masculino
15.
Exp Anim ; 67(2): 175-183, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29162767

RESUMO

The QTc interval is widely used in Safety Pharmacological studies to predict arrhythmia risk, and the electromechanical window (EMW) and short-term variability of QT intervals (STVQT) have been studied as new biomarkers for drug-induced Torsades de Pointes (TdP). However, the use of EMW and STVQT to predict ventricular fibrillation (VF) has not been elucidated. This study aimed to evaluate EMW and STVQT to predict VF in anesthetized rabbit model of VF. VF was induced by ligation of the left anterior descending and a descending branch of the left circumflex coronary arteries in a sample population of rabbits (n=18). VF was developed 55.6% (10/18). In rabbit with VF, the EMW was significantly higher than in rabbits without VF (96.3 ± 15.6 ms and 49.5 ± 5.6 ms, respectively, P<0.05). STVQT had significantly increased before the onset of VF in rabbits that experienced VF, but not in rabbits that did not experience VF (11.7 ± 1.8 ms and 3.7 ± 0.4 ms, respectively, P<0.05). The EMW and STVQT had better predictive power for VF with higher sensitivity and specificity than the QTc measure. The result suggested that the increasing of EMW, as well as the elevation of STVQT, can potentially be used as biomarkers for predicting of VF.


Assuntos
Anestesia , Eletrocardiografia , Isquemia Miocárdica/complicações , Fibrilação Ventricular/diagnóstico , Animais , Biomarcadores , Vasos Coronários , Modelos Animais de Doenças , Feminino , Ligadura , Masculino , Valor Preditivo dos Testes , Coelhos , Sensibilidade e Especificidade , Fibrilação Ventricular/etiologia
16.
Front Physiol ; 8: 894, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29209225

RESUMO

The nitroxyl (HNO) prodrug, CXL-1020, induces vasorelaxation and improves cardiac function in canine models and patients with systolic heart failure (HF). HNO's unique mechanism of action may be applicable to a broader subset of cardiac patients. This study investigated the load-independent safety and efficacy of CXL-1020 in two rodent (rat) models of diastolic heart failure and explored potential drug interactions with common HF background therapies. In vivo left-ventricular hemodynamics/pressure-volume relationships assessed before/during a 30 min IV infusion of CXL-1020 demonstrated acute load-independent positive inotropic, lusitropic, and vasodilatory effects in normal rats. In rats with only diastolic dysfunction due to bilateral renal wrapping (RW) or pronounced diastolic and mild systolic dysfunction due to 4 weeks of chronic isoproterenol exposure (ISO), CXL-1020 attenuated the elevated LV filling pressures, improved the end diastolic pressure volume relationship, and accelerated relaxation. CXL-1020 facilitated Ca2+ re-uptake and enhanced myocyte relaxation in isolated cardiomyocytes from ISO rats. Compared to milrinone, CXL-1020 more effectively improved Ca2+ reuptake in ISO rats without concomitant chronotropy, and did not enhance Ca2+ entry via L-type Ca2+ channels nor increase myocardial arrhythmias/ectopic activity. Acute-therapy with CXL-1020 improved ventricular relaxation and Ca2+ cycling, in the setting of chronic induced diastolic dysfunction. CXL-1020's lusitropic effects were greater than those seen with the cAMP-dependent agent milrinone, and unlike milrinone it did not produce chronotropy or increased ectopy. HNO is a promising new potential therapy for both systolic and diastolic heart failure.

17.
J Toxicol Sci ; 42(5): 579-587, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28904293

RESUMO

The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.


Assuntos
Arritmias Cardíacas/fisiopatologia , Eletrocardiografia , Síndrome do QT Longo/fisiopatologia , Sístole , Pressão Ventricular , Anestesia , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/diagnóstico , Benzopiranos , Biomarcadores , Biomarcadores Farmacológicos , Cromakalim , Modelos Animais de Doenças , Isoflurano , Síndrome do QT Longo/induzido quimicamente , Fenetilaminas , Pinacidil , Quinidina , Coelhos , Risco , Sulfonamidas , Torsades de Pointes/diagnóstico
18.
Exp Anim ; 66(3): 251-258, 2017 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381818

RESUMO

Atrial fibrillation (AF) is a supraventricular arrhythmia that leads to a decrease in cardiac output and impairs cardiac function and quality of life. Dronedarone has an atrial-selective property and has been used for management of AF in humans, but limited information is available in dogs. This study was designed to evaluate efficacy of dronedarone in attenuating the duration of AF in dog model of sustained AF. Six beagle dogs were anesthetized with isoflurane and instrumented to measure atrial action potential duration (aAPD) and atrial effective refractory period (AERP). Then AF was induced by rapid right atrial pacing (20 V, 40 Hz) simultaneously with infusion of phenylephrine (2 µg/kg/min, intravenously) for 20 min. The duration of sustained AF was recorded, and the animals were allowed to recover. Dronedarone was given at a dose of 20 mg/kg, BID, orally for 7 days. On the last day, the dogs were anesthetized again to record aAPD and AERP, and AF was induced with the same procedure as described above. The results showed that after dronedarone administration the aAPD was lengthened significantly from 76.4 ± 4.2 ms to 91.2 ± 3.9 ms (P<0.05) and AERP was prolonged significantly from 97.5 ± 2.8 ms to 120 ± 4.8 ms (P<0.05). The duration of sustained AF was also significantly attenuated after receipt of dronedarone (P<0.05). It can be suggested that oral dronedarone attenuates the duration of sustained AF in a dog model of AF by extending the AERP more than the aAPD, causing post-repolarization refractoriness. Hence, dronedarone may be useful for management of AF in dogs.


Assuntos
Amiodarona/análogos & derivados , Fibrilação Atrial/tratamento farmacológico , Modelos Animais de Doenças , Cães , Potenciais de Ação/efeitos dos fármacos , Administração Oral , Amiodarona/administração & dosagem , Amiodarona/farmacologia , Animais , Fibrilação Atrial/fisiopatologia , Dronedarona , Átrios do Coração/fisiopatologia , Humanos , Período Refratário Eletrofisiológico/efeitos dos fármacos , Fatores de Tempo
19.
Top Cogn Sci ; 9(2): 264-288, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28220988

RESUMO

This article is a case study that describes the natural and human history of the gaze heuristic. The gaze heuristic is an interception heuristic that utilizes a single input (deviation from a constant angle of approach) repeatedly as a task is performed. Its architecture, advantages, and limitations are described in detail. A history of the gaze heuristic is then presented. In natural history, the gaze heuristic is the only known technique used by predators to intercept prey. In human history the gaze heuristic was discovered accidentally by Royal Air Force (RAF) fighter command just prior to World War II. As it was never discovered by the Luftwaffe, the technique conferred a decisive advantage upon the RAF throughout the war. After the end of the war in America, German technology was combined with the British heuristic to create the Sidewinder AIM9 missile, the most successful autonomous weapon ever built. There are no plans to withdraw it or replace its guiding gaze heuristic. The case study demonstrates that the gaze heuristic is a specific heuristic type that takes a single best input at the best time (take the best2 ). Its use is an adaptively rational response to specific, rapidly evolving decision environments that has allowed those animals/humans/machines who use it to survive, prosper, and multiply relative to those who do not.


Assuntos
Heurística , Animais , Humanos , Análise e Desempenho de Tarefas
20.
Nutrients ; 8(6)2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27258305

RESUMO

This article describes an experiment to measure the impact of the Australasian "Health Star Rating" front of pack nutritional label system on consumer choice behaviour. This system presents a one-half to five star rating of nutritional quality via the front facings of food product packages. While this system has been recently rolled out across Australasia, no test of its impact on food choice has been conducted. A sample of 1200 consumers was recruited on exit from supermarkets in New Zealand. A 2 × 2 factorial design was used with two levels of cold cereal product nutritional status (high, five star/low, two star) and two levels of the Health Star Rating label (present/absent). The dependent variable was revealed choice behaviour. The results indicated that the presence of the label had a significant depressive effect on consumer preference, but that this impact was not moderated in any way by the nutritional status expressed by the label. The result represents a significant functional failure of the Health Star Rating label in this research environment. The nature of the failure is consistent with the consumers processing the label in much the same way as the nominal brand cues that dominate the retail food packaging.


Assuntos
Rotulagem de Alimentos/normas , Alimentos/classificação , Valor Nutritivo , Austrália , Comportamento de Escolha , Comportamento do Consumidor , Preferências Alimentares , Comportamentos Relacionados com a Saúde , Humanos , Nova Zelândia , Política Nutricional
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