The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3.

Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p = 0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fibrosis (both: p < 0.001). Ventricles also showed increased fibrosis with age (p < 0.001). Age and Scn5a+/ΔKPQ interacted in increasing incidences of repolarisation alternans (p = 0.02). Dobutamine increased ventricular rate (p < 0.001) and reduced both atrioventricular conduction (PR segment-p = 0.02; PR interval-p = 0.02) and incidences of repolarisation alternans (p < 0.001) in all mice. However, in Scn5a+/ΔKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present findings implicate interactions between age and Scn5a+/ΔKPQ in prolonging ventricular activation, correlating them with fibrotic change for the first time, adding activation abnormalities to established recovery abnormalities in LQTS3. These findings, together with dynamic electrophysiological responses to β-adrenergic challenge, have therapeutic implications for ageing LQTS patients

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multicountry study

Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named ‘bovine neonatal pancytopenia’ (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0–280.1). This was also the case for the practices of feeding calves colostrum from the calf’s own dam (OR 2.0; 95% CI: 1.1–3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9–8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves

Selective ETA vs. Dual ETA/B receptor blockade for the prevention of sunitinib-induced hypertension and albuminuria in WKY rats

Aims Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro-or antihypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria. Methods and results Male Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of-25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib-than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan. Conclusions Our results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury

External validation of a collar-mounted triaxial accelerometer for second-by-second monitoring of eight behavioural states in dogs

Early detection of disease by an animal owner may motivate them to seek early veterinary advice. Presentation before a more advanced clinical manifestation is evident could lead to more effective treatment and thus benefit the animal's health and welfare. Accelerometers are able to detect changes in specific activities or behaviours, thus indicating early signs of possible adverse health events. The objective of this validation study was to determine whether the detection of eight behavioural states: walk, trot, canter/gallop, sleep, static/inactive, eat, drink, and headshake, by an accelerometer device was sufficiently accurate to be useful in a clinical setting. This fully independent external validation estimated the accuracy of a specific triaxial, collar-mounted accelerometer on a second-by second basis in 51 healthy dogs of different breeds, aged between 6 months and 13 years, weighing >10 kg. The overall diagnostic effectiveness was estimated as:%record correctly classified of > 95% in walk, trot, canter/gallop, eat, drink and headshake and >90% in sleep and static/inactive. The positive predictive values ranged from 93±100%, while the negative predictive values ranged from 96±100%, with exception of static/inactive (86%).This was probably because dogs were placed in unfamiliar kennels where they did not exhibit their typical resting behaviour. The device is worn on a collar, making its use feasible for anyone wanting to monitor their dog's behaviour. The high accuracy in detecting various kinds of behaviour appears promising in assessing canine health and welfare states

The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3

Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased agedependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting efects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fbrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p=0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fbrosis (both: p<0.001). Ventricles also showed increased fbrosis with age (p<0.001). Age and Scn5a+/ΔKPQ interacted in increasing incidences of repolarisation alternans (p=0.02). Dobutamine increased ventricular rate (p<0.001) and reduced both atrioventricular conduction (PR segment-p=0.02; PR interval-p=0.02) and incidences of repolarisation alternans (p<0.001) in all mice. However, in Scn5a+/ΔKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present fndings implicate interactions between age and Scn5a+/ΔKPQ in prolonging ventricular activation, correlating them with fbrotic change for the frst time, adding activation abnormalities to established recovery abnormalities in LQTS3. These fndings, together with dynamic electrophysiological responses to β-adrenergic challenge, have therapeutic implications for ageing LQTS patients

Dog wearing the triaxial accelerometer on its collar.

<p>Dog wearing the triaxial accelerometer on its collar.</p

Description of eight behavioural states predicted based on data collected from the triaxial accelerometer.

<p>Description of eight behavioural states predicted based on data collected from the triaxial accelerometer.</p

External validation of a triaxial accelerometer in dogs

These are the characteristics of the dogs participating in the external validation of a triaxial accelerometer and the data from the validation. the column tag represents the tagged catgeory and the rtc is the device classification

Dog wearing the triaxial accelerometer on its collar.

<p>Dog wearing the triaxial accelerometer on its collar.</p