771-3 Direct Characterization of F1ecalnide Binding Rates from Use-Dependent Conduction Delay In Canine Purkinje Fibers

To quantitatively characterize flecainide-induced channel blockade from usedependent conduction delay (CD), 12 canine purkinje fibers were studied using a dual microelectrode technique. During 60 sec of pacing at interstimulus intervals (ISI) of 1.25–0.4 sec with 2μM flecainide (FLEC), incremental CD followed a monoexponential time course, the rates of which were linearly related to the interpulse recovery interval (tr=ISI — action potential duration). Steady state block was an exponential function of the recovery rates. Use-dependent block derived from incremental CD and decremental squared conduction velocity (θ2) was characterized by the forward (k) and reverse (I) rate constants for the activated (a) and resting (r) states:ka (× 106) (mol-1 s-1)la (s-1)kr (× 102) (mol-1 s-1)Ir (s-1)CD7.0±2.612.0±4.40.6±1.74.01±1.63θ210.0±3.414.7±2.52.8±5.73.66±1.40Vmax(prox)6.8±2.315.9±5.05.1±10.34.22±1.11These rates reflect marked open state Na+ channel block and closed channel trapping at resting membrane potentials with FLEC. The addition of 1μM isoproterenol (ISO) to FLEC-superfused fibers reversed the FLEC-induced reduction of θ2 from 1.79±0.7 to 1.89±0.89 (m/s)2 (p=0.017) without changing V˙max. The rate constants for FLEC binding and unbinding were not altered by ISO. Thus FLEC's apparent binding rates can be quantified from its use-{jependent effects on conduction. Both ISO's selective reversal of FLEC effect on θ2 but not V˙max and the absence of changes in the rate constants suggest that the modulation of FLEC effect is due to an alteration in passive membrane properties. These characterizations will facilitate subsequent comparisons of FLEC interactions in pathologic and hyperadrenergic states in vivo

Construction of Parseval wavelets from redundant filter systems

We consider wavelets in L^2(R^d) which have generalized multiresolutions. This means that the initial resolution subspace V_0 in L^2(R^d) is not singly generated. As a result, the representation of the integer lattice Z^d restricted to V_0 has a nontrivial multiplicity function. We show how the corresponding analysis and synthesis for these wavelets can be understood in terms of unitary-matrix-valued functions on a torus acting on a certain vector bundle. Specifically, we show how the wavelet functions on R^d can be constructed directly from the generalized wavelet filters.Comment: 34 pages, AMS-LaTeX ("amsproc" document class) v2 changes minor typos in Sections 1 and 4, v3 adds a number of references on GMRA theory and wavelet multiplicity analysis; v4 adds material on pages 2, 3, 5 and 10, and two more reference

Moving from information and collaboration to action: report from the 3rd International Dog Health Workshop, Paris in April 2017

Abstract Background Breed-related health problems in dogs have received increased focus over the last decade. Responsibility for causing and/or solving these problems has been variously directed towards dog breeders and kennel clubs, the veterinary profession, welfare scientists, owners, regulators, insurance companies and the media. In reality, all these stakeholders are likely to share some responsibility and optimal progress on resolving these challenges requires all key stakeholders to work together. The International Partnership for Dogs (IPFD), together with an alternating host organization, holds biennial meetings called the International Dog Health Workshops (IDHW). The Société Centrale Canine (French Kennel Club) hosted the 3rd IDHW, in Paris, in April, 2017. These meetings bring together a wide range of stakeholders in dog health, science and welfare to improve international sharing of information and resources, to provide a forum for ongoing collaboration, and to identify specific needs and actions to improve health, well-being and welfare in dogs. Results The workshop included 140 participants from 23 countries and was structured around six important issues facing those who work to improve dog health. These included individualized breed-specific strategies for health and breeding, extreme conformations, education and communication in relation to antimicrobial resistance, behavior and welfare, genetic testing and population-based evidence. A number of exciting actions were agreed during the meeting. These included setting up working groups to create tools to help breed clubs accelerate the implementation of breed-health strategies, review aspects of extreme conformation and share useful information on behavior. The meeting also heralded the development of an online resource of relevant information describing quality measures for DNA testing. A demand for more and better data and evidence was a recurring message stressed across all themes. Conclusions The meeting confirmed the benefits from inclusion of a diverse range of stakeholders who all play relevant and collaborative parts to improve future canine health. Firm actions were set for progress towards improving breed-related welfare. The next international workshop will be in the UK in 2019 and will be organized by the UK Kennel Club

Mapping quantitative trait loci in Gallus gallus using principal components.

Projeto/Plano de Ação: 01.06.10.602-03

Type of atrial fibrillation and clinical outcomes in patients with heart failure and reduced ejection fraction

Background: Atrial fibrillation (AF) is common in heart failure (HF), but the outcome by type of AF is largely unknown. Objectives: This study investigated outcomes related to type of AF (paroxysmal, persistent or permanent, or new onset) in 2 recent large trials in patients with HF with reduced ejection fraction. Methods: The study analyzed patients in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for outcomes related to AF type. Results: Of 15,415 patients, 5,481 (35.6%) had a history of AF at randomization, and of these, 1,645 (30.0%) had paroxysmal AF. Compared with patients without AF, patients with paroxysmal AF at randomization had a higher risk of the primary composite endpoint of cardiovascular death or HF hospitalization (HR: 1.20; 95% confidence interval [CI]: 1.09 to 1.32; p < 0.001), HF hospitalization (HR: 1.34; 95% CI: 1.19 to 1.51; < 0.001), and stroke (HR: 1.34; 95% CI: 1.02 to 1.76; p = 0.037), whereas the corresponding risks in patients with persistent or permanent AF were not elevated. Neither type of AF was associated with higher mortality. New onset AF was associated with the greatest risk of adverse outcomes: primary endpoint (HR: 2.21; 95% CI: 1.80 to 2.71), HF hospitalization (HR: 2.11; 95% CI: 1.58 to 2.81), stroke (HR: 2.20; 95% CI: 1.25 to 3.88), and all-cause mortality (HR: 2.26; 95% CI: 1.86 to 2.74), all p values < 0.001, compared with patients without AF. Anticoagulants were used less often in patients with paroxysmal (53%) and new onset (16%) AF than in patients with persistent or permanent AF (71%). Conclusions: Among HF patients with a history of AF, those with paroxysmal AF were at greater risk of HF hospitalization and stroke than were patients with persistent or permanent AF, underlining the importance of anticoagulant therapy. New onset AF was associated with increased risk of all outcomes. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255) (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure [ATMOSPHERE]; NCT00853658

Fast non-negative deconvolution for spike train inference from population calcium imaging

Calcium imaging for observing spiking activity from large populations of neurons are quickly gaining popularity. While the raw data are fluorescence movies, the underlying spike trains are of interest. This work presents a fast non-negative deconvolution filter to infer the approximately most likely spike train for each neuron, given the fluorescence observations. This algorithm outperforms optimal linear deconvolution (Wiener filtering) on both simulated and biological data. The performance gains come from restricting the inferred spike trains to be positive (using an interior-point method), unlike the Wiener filter. The algorithm is fast enough that even when imaging over 100 neurons, inference can be performed on the set of all observed traces faster than real-time. Performing optimal spatial filtering on the images further refines the estimates. Importantly, all the parameters required to perform the inference can be estimated using only the fluorescence data, obviating the need to perform joint electrophysiological and imaging calibration experiments.Comment: 22 pages, 10 figure

Impact of facial conformation on canine health: Brachycephalic Obstructive Airway Syndrome

The domestic dog may be the most morphologically diverse terrestrial mammalian species known to man; pedigree dogs are artificially selected for extreme aesthetics dictated by formal Breed Standards, and breed-related disorders linked to conformation are ubiquitous and diverse. Brachycephaly–foreshortening of the facial skeleton–is a discrete mutation that has been selected for in many popular dog breeds e.g. the Bulldog, Pug, and French Bulldog. A chronic, debilitating respiratory syndrome, whereby soft tissue blocks the airways, predominantly affects dogs with this conformation, and thus is labelled Brachycephalic Obstructive Airway Syndrome (BOAS). Despite the name of the syndrome, scientific evidence quantitatively linking brachycephaly with BOAS is lacking, but it could aid efforts to select for healthier conformations. Here we show, in (1) an exploratory study of 700 dogs of diverse breeds and conformations, and (2) a confirmatory study of 154 brachycephalic dogs, that BOAS risk increases sharply in a non-linear manner as relative muzzle length shortens. BOAS only occurred in dogs whose muzzles comprised less than half their cranial lengths. Thicker neck girths also increased BOAS risk in both populations: a risk factor for human sleep apnoea and not previously realised in dogs; and obesity was found to further increase BOAS risk. This study provides evidence that breeding for brachycephaly leads to an increased risk of BOAS in dogs, with risk increasing as the morphology becomes more exaggerated. As such, dog breeders and buyers should be aware of this risk when selecting dogs, and breeding organisations should actively discourage exaggeration of this high-risk conformation in breed standards and the show ring

Automated parametric neutronics analysis of the Helium Cooled Pebble Bed breeder blanket with Be₁₂Ti

The Helium Cooled Pebble Bed (HCPB) breeder blanket is being developed as part of the European Fusion Programme. Part of the programme is to investigate blanket designs relevant for future demonstration fusion power plants. This paper presents neutronics analyses of the HCPB with an alternative neutron multiplier, Be12Ti which is incorporated into the design, replacing the current Be multiplier. A parameter study was performed for a range of geometries to identify the optimal heights of the lithium ceramic and neutron multiplier pebble beds. Automated creation of CAD models followed by conversion to constructive solid geometry (CSG) and unstructured mesh (UM) geometry allows the models to be useful for both neutronics simulations and engineering simulations. In this neutronics study simulations were performed using MCNP 6.1 to find the tritium breeding ratio, energy multiplication and the volumetric heat loads of different blanket designs. Combinations of geometry parameters and material choices that resulted in adequate TBR values were identified and will be further investigated with automated engineering simulations. This paper provides insight, supported by neutronics analysis, on the validity of the design and comments on some of the potential advantages and disadvantages of using Be12Ti in the Helium Cooled Pebble Bed (HCPB) breeder blanket. Blankets with Be12Ti neutron multiplier were found to produce less tritium but higher energy multiplication when compared to blankets with Be neutron multiplier

Impact of canine epilepsy on judgement and attention biases

Idiopathic epilepsy (IE) is the most common chronic neurological condition in dogs, characterised by recurrent seizure activity and associated with negative behavioural and cognitive changes. We hypothesised that IE would negatively impact putative affective state, with dogs with IE exhibiting a more pessimistic judgement bias and more negative attention bias than controls. Dogs were tested in a previously-validated spatial judgement bias task, and a novel auditory attention bias task testing attention to sounds with different valence or salience (neutral, novel pre-habituated, threatening). Sixty-eight dogs (IE = 33, Control = 35) were tested, of which n = 37 acquired the spatial discrimination and responses to judgement bias probes were tested (IE = 19, Control = 18), and n = 36 were tested for responses to sounds (IE = 20, Control = 16). Study groups did not significantly differ by age, sex, breed or neuter-status (p > 0.05). Main effects of study group were not significant in judgement bias (F1,102 = 0.20, p = 0.658) or attention bias tasks (F3,102 = 1.64, p = 0.184). In contrast with our hypotheses, there was no evidence that IE altered cognitive biases in this study population; however, dogs with IE were significantly more likely to be unable to learn the spatial discrimination task (p = 0.019), which may reflect IE-related cognitive deficits. Developing methods to test affective state without excluding cognitively impaired individuals is a future challenge for animal welfare science