The electrophysiology of the atrioventricular node in normal and failing rabbit hearts

Conduction abnormalities affect prognosis in chronic heart failure (CHF). Previous investigators have observed abnormal delay in atrioventricular (AV) conduction in a rabbit model of left ventricular dysfunction (LVD) due to apical myocardial infarction. In this model, AV conduction time increased with increasing pacing rates, suggesting the most likely site of delay is the AV node. The mechanisms by which this occurs are not fully understood. The purpose of this thesis was to confirm that the abnormal prolongation of AV conduction time originates at the AV node in a rabbit model of LVD due to apical myocardial infarction, and explore possible mechanisms underlying the observation. Using surface electrogram recording and standardised pacing techniques in an isolated AV node tissue preparation I confirmed that there is abnormal prolongation of AV nodal conduction in this rabbit model of LVD, as evidenced by prolongation of atrio-hisian (AH) interval and Wenckebach cycle length (WCL) in LVD compared to control. Furthermore, using optical mapping of electrical activation using voltage sensitive dye I observed that the prolongation of the AH interval is predominantly a consequence of conduction delay between the inputs of the AV node and the compact nodal region. Neuro-hormonal derangement in chronic heart failure has a central role in the pathogenesis of the disease, with evidence of downregulation of beta ()-adrenoceptors in the left ventricular myocardium. I therefore explored the possibility of β-adrenoceptor downregulation in the AV node as a mechanism underlying the abnormal AH interval prolongation in LVD. There was no evidence of β-adrenoceptor downregulation in the AV node in LVD compared to control to account for the observed abnormal conduction delay. Adenosine is known to have profound effects on AV nodal conduction and the possibility of tonic excess of adenosine in LVD was explored as a possible mechanism for the prolonged conduction delay. Using an exogenously applied adenosine A1 receptor antagonist there was no evidence of excess endogenous adenosine in LVD compared to control. There was, however, an increase in the sensitivity of the LVD samples compared to control to exogenous adenosine, with a significant increase in AH interval and WCL with increasing concentrations. This thesis also investigates the effect of acidosis on AV nodal conduction. There was significant prolongation of the spontaneous sinus cycle length, AH interval and WCL, as well as the AV nodal functional and effective refractory periods, proportional to the degree of acidosis. These effects were reversible with return to normal pH. Optical mapping studies showed that the spatiotemporal pattern of AV nodal delay during acidosis was similar to that observed in LVD, with the predominant delay in conduction between the AV nodal inputs and the compact AV node. In summary this thesis has confirmed that even in the absence of a direct ischaemic insult to the AV junction, conduction abnormalities in the AV node may still occur as a pathophysiological response to a myocardial infarction resulting in LVD. The mechanisms underlying this response are likely to be complex and multiple, and are not yet clear. Establishing the electrophysiological basis and the effects of neuro-hormonal modulators of atrioventricular nodal function may lead to development of targeted therapeutic strategies to improve overall survival and improve symptom control for patients with CHF

Acidosis slows electrical conduction through the atrio-ventricular node

Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO2, pH 6.7) increased the time of earliest activation (Tact) from 100.5 ± 7.9 to 166.1 ± 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37°C). Tact increased at shorter PCL, and the hypercapnic solution prolonged Tact further: at 150 ms PCL, Tact was prolonged from 131.0 ± 5.2 to 174.9 ± 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis

Detection of Highly Pathogenic Avian Influenza Virus H5N1 Clade 2.3.4.4b in Great Skuas:A Species of Conservation Concern in Great Britain

The UK and Europe have seen successive outbreaks of highly pathogenic avian influenza across the 2020/21 and 2021/22 autumn/winter seasons. Understanding both the epidemiology and transmission of these viruses in different species is critical to aid mitigating measures where outbreaks cause extensive mortalities in both land- and waterfowl. Infection of different species can result in mild or asymptomatic outcomes, or acute infections that result in high morbidity and mortality levels. Definition of disease outcome in different species is of great importance to understanding the role different species play in the maintenance and transmission of these pathogens. Further, the infection of species that have conservation value is also important to recognise and characterise to understand the impact on what might be limited wild populations. Highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b has been detected in great skuas (Stercorarius skua) across different colonies on islands off the shore of Scotland, Great Britain during summer 2021. A large number of great skuas were observed as developing severe clinical disease and dying during the epizootic and mortalities were estimated to be high where monitored. Of eight skuas submitted for post-mortem examination, seven were confirmed as being infected with this virus using a range of diagnostic assays. Here we overview the outbreak event that occurred in this species, listed as species of conservation concern in Great Britain and outline the importance of this finding with respect to virus transmission and maintenance

Diversity of Phylogenetic Information According to the Locus and the Taxonomic Level: An Example from a Parasitic Mesostigmatid Mite Genus

Molecular markers for cladistic analyses may perform differently according to the taxonomic group considered and the historical level under investigation. Here we evaluate the phylogenetic potential of five different markers for resolving evolutionary relationships within the ectoparasitic genus Dermanyssus at the species level, and their ability to address questions about the evolution of specialization. COI provided 9–18% divergence between species (up to 9% within species), 16S rRNA 10–16% (up to 4% within species), ITS1 and 2 2–9% (up to 1% within species) and Tropomyosin intron n 8–20% (up to 6% within species). EF-1α revealed different non-orthologous copies within individuals of Dermanyssus and Ornithonyssus. Tropomyosin intron n was shown containing consistent phylogenetic signal at the specific level within Dermanyssus and represents a promising marker for future prospects in phylogenetics of Acari. Phylogenetic analyses revealed that the generalist condition is apomorphic and D. gallinae might represent a complex of hybridized lineages. The split into hirsutus-group and gallinae-group in Dermanyssus does not seem to be appropriate based upon these results and D. longipes appears to be composed of two different entities

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Catheter ablation for supraventricular arrhythmias in adults with congenital heart disease: Recurrence rates and predictors of acute procedural success

Aims: To define the cohort of adult congenital heart disease (ACHD) patients undergoing catheter ablation for supraventricular arrhythmia in a large tertiary centre, characterise outcomes, and determine factors associated with arrhythmia recurrence. Methods: Single centre retrospective study of all catheter ablations for atrial arrhythmias in ACHD patients between September 2014 and October 2021. Patients were identified using a field search through a centralised database. Pre-specified clinical and procedural data of interest, and time from ablation to recurrence, were determined. Cox regression analyses were used to determine potential predictors of acute procedural success and arrhythmia recurrence. Results: Cardiac ablation for supraventricular arrhythmia was undertaken in 142 cases across 100 unique patients (median age 41, interquartile range 31–52), with 70 (49%) cases treated for macro-reentrant atrial tachycardia, 16 (11%) for focal atrial tachycardia, 19 (13%) for multifocal atrial tachycardia, 17 (12%) for atrial fibrillation, 7 (5%) for atrioventricular nodal reentrant tachycardia, and 8 (6%) for atrioventricular reentrant tachycardia; and 68 cases (48%) had recurrent arrhythmia with a median time to recurrence of 800 days. Multivariable analysis identified acute procedural success as an independent predictor of freedom from arrhythmia, and ablation for persistent atrial fibrillation as an independent predictor for recurrence of arrhythmia. Conclusion: Catheter ablation for supraventricular arrhythmia in ACHD patients is safe and effective, with most patients achieving multiple arrhythmia-free months. Procedural success and arrhythmia mechanism are important predictors of recurrence

The effect of a superhydrophobic coating on moisture absorption and tensile strength of 3D-printed carbon-fibre/polyamide

This work investigates the effectiveness of fluorinated silica-based superhydrophobic coatings to protect 3Dprinted carbon-fibre/polyamide composites against moisture-induced degradation. Increasing exposure time in wet and humid environments led to a reduction of tensile strength and an increase in experienced strain. However, the coated PA demonstrated 6.7-12.4% higher tensile yield strength than the uncoated PA. Highresolution X-ray micro computed tomography (uCT) was used to image the microstructure and revealed that the superhydrophobic coating effectively prevented liquid water penetration into 3D-printed polyamide and delayed water vapour-driven mechanical degradation. The presence of the superhydrophobic coating eliminated the liquid water presence in the surface features of the PA matrix and reduced the moisture-induced swelling of the polyamide matrix by about 53% after 168 h under water. Further optimisation of these coatings may provide a solution to enhance the performance of PA composites in humid and wet environments

The eternal divide?: history and international relations

On one level, history is used by all parts of the International Relations (IR) discipline. But lurking beneath the surface of IR’s approach to history lies a well-entrenched binary. Whereas mainstream positions use history as a means to fill in their theoretical frames (seeing history as a kind of ‘scripture’ of abstract lessons), many post-positivists reduce history to a pick-and-mix of contingent hiccups (a ‘butterfly’ of what-ifs and maybes). Interestingly enough, this binary is one reproduced throughout the social sciences. As such, there is a bigger story to the apparently ‘eternal divide’ between history and social science than first meets the eye. This article uses the various ways in which history is used — and abused — in IR to probe more deeply into the relationship between history and social science as a whole. This exploration reveals four frameworks, two drawn from history (context and narrative) and two drawn from social science (eventfulness and ideal-typification) which illustrate the necessary co-implication of the two enterprises. The article employs these tools as a means of re-imagining the relationship between history and social science (including IR), conceiving this as a single intellectual journey in which both are permanently in view