Computer Diagnosis of Congenital Heart Disease

book chapterBiomedical Informatic

Subcellular calcium patterns in ventricular myocytes

Understanding the biology and mechanisms as to how the heart contracts has long been a point of interest for biologists and mathematicians alike. Since inconsistent beating of the heart has been linked to multiple pathological conditions, research into this area has been extensive but we still only have some of the answers. One of the key findings over the last century has been the role of calcium in activating the machinery within the heart that drives contraction. Further studies have shown that when calcium is mishandled by the heart's myocytes, it can lead to some of these pathological conditions. Since such discoveries a major point of research into the heart has focused on the possible avenues that calcium mishandling can occur. This thesis explores some of these avenues using a mathematical model of the ventricular myocyte developed by Thul and Coombes in their 2010 paper 'Understanding cardiac alternans: A piecewise linear modeling framework'. The chosen model contains key components involved in the movement of calcium within the myocyte. Moreover, the model used is piecewise linear and the stability of some important behaviours can be studied exactly without the need for approximations and reductions. This is often an issue in many other models used to study the calcium dynamics within a ventricular myocyte. The avenue towards calcium mishandling that this thesis predominantly focuses on is that of intracellular calcium diffusion between the building blocks of ventricular myocytes known as sarcomeres. Our research extends previous research into how strong diffusion between sarcomeres can cause unwanted calcium dynamics. Further to this, we explore how the balance in the strength of different forms of calcium diffusion between sarcomeres can drive a variety of spatial patterns in terms of how the calcium is distributed throughout the cell. Throughout these studies we also investigate the role of other parts of the myocyte, particularly the sarcoplasmic reticulum Calcium-ATPase pumps and sarcoplasmic reticulum release in relation to diffusion driven instabilities. As well as intracellular diffusion of calcium, this thesis considers the role of intercellular diffusion of calcium through gap junctions. This form of diffusion has historically been considered to a lesser extent than intracellular diffusion. As such this thesis introduces new ideas concerning gap junctions. These include a role in driving the mishandling of calcium as well as altering behaviours driven by intracellular diffusion. An important message is that calcium diffusion within the myocyte is far more important in terms of how unwanted behaviours can appear than previous studies suggest

Subcellular calcium patterns in ventricular myocytes

Understanding the biology and mechanisms as to how the heart contracts has long been a point of interest for biologists and mathematicians alike. Since inconsistent beating of the heart has been linked to multiple pathological conditions, research into this area has been extensive but we still only have some of the answers. One of the key findings over the last century has been the role of calcium in activating the machinery within the heart that drives contraction. Further studies have shown that when calcium is mishandled by the heart's myocytes, it can lead to some of these pathological conditions. Since such discoveries a major point of research into the heart has focused on the possible avenues that calcium mishandling can occur. This thesis explores some of these avenues using a mathematical model of the ventricular myocyte developed by Thul and Coombes in their 2010 paper 'Understanding cardiac alternans: A piecewise linear modeling framework'. The chosen model contains key components involved in the movement of calcium within the myocyte. Moreover, the model used is piecewise linear and the stability of some important behaviours can be studied exactly without the need for approximations and reductions. This is often an issue in many other models used to study the calcium dynamics within a ventricular myocyte. The avenue towards calcium mishandling that this thesis predominantly focuses on is that of intracellular calcium diffusion between the building blocks of ventricular myocytes known as sarcomeres. Our research extends previous research into how strong diffusion between sarcomeres can cause unwanted calcium dynamics. Further to this, we explore how the balance in the strength of different forms of calcium diffusion between sarcomeres can drive a variety of spatial patterns in terms of how the calcium is distributed throughout the cell. Throughout these studies we also investigate the role of other parts of the myocyte, particularly the sarcoplasmic reticulum Calcium-ATPase pumps and sarcoplasmic reticulum release in relation to diffusion driven instabilities. As well as intracellular diffusion of calcium, this thesis considers the role of intercellular diffusion of calcium through gap junctions. This form of diffusion has historically been considered to a lesser extent than intracellular diffusion. As such this thesis introduces new ideas concerning gap junctions. These include a role in driving the mishandling of calcium as well as altering behaviours driven by intracellular diffusion. An important message is that calcium diffusion within the myocyte is far more important in terms of how unwanted behaviours can appear than previous studies suggest

Complex patterns of subcellular cardiac alternans

Cardiac alternans, in which the membrane potential and the intracellular calcium concentration exhibit alternating durations and peak amplitudes at consecutive beats, constitute a precursor to fatal cardiac arrhythmia such as sudden cardiac death. A crucial question therefore concerns the onset of cardiac alternans. Typically, alternans are only reported when they are fully developed. Here, we present a modelling approach to explore recently discovered microscopic alternans, which represent one of the earliest manifestations of cardiac alternans. In this case, the regular periodic dynamics of the local intracellular calcium concentration is already unstable, while the whole-cell behaviour suggests a healthy cell state. In particular, we use our model to investigate the impact of calcium diffusion in both the cytosol and the sarcoplasmic reticulum on the formation of microscopic calcium alternans. We find that for dominant cytosolic coupling, calcium alternans emerge via the traditional period doubling bifurcation. In contrast, dominant luminal coupling leads to a novel route to calcium alternans through a saddle-node bifurcation at the network level. Combining semi-analytical and computational approaches, we compute areas of stability in parameter space and find that as we cross from stable to unstable regions, the emergent patterns of the intracellular calcium concentration change abruptly in a fashion that is highly dependent upon position along the stability boundary. Our results demonstrate that microscopic calcium alternans may possess a much richer dynamical repertoire than previously thought and further strengthen the role of luminal calcium in shaping cardiac calcium dynamics

A master stability function approach to cardiac alternans

During a single heartbeat, muscle cells in the heart contract and relax. Under healthy conditions, the behaviour of these muscle cells is almost identical from one beat to the next. However, this regular rhythm can be disturbed giving rise to a variety of cardiac arrhythmias including cardiac alternans. Here, we focus on so-called microscopic calcium alternans and show how their complex spatial patterns can be understood with the help of the master stability function. Our work makes use of the fact that cardiac muscle cells can be conceptualised as a network of networks, and that calcium alternans correspond to an instability of the synchronous network state. In particular, we demonstrate how small changes in the coupling strength between network nodes can give rise to drastically different activity patterns in the network

Domesticated horses differ in their behavioural and physiological responses to isolated and group housing

The predominant housing system used for domestic horses is individual stabling however, housing that limits social interaction and requires the horse to live in semi-isolation has been reported to be a concern for equine welfare. The aim of the current study was to compare behavioural and physiological responses of domestic horses in different types of housing design that provided varying levels of social contact. Horses (n = 16) were divided equally into four groups and exposed to each of four housing treatments for a period of five days per treatment in a randomized block design. The four housing treatments used were single housed no physical contact (SHNC), single housed semi contact (SHSC), paired housed full contact (PHFC) and group housed full contact (GHFC). During each housing treatment, adrenal activity was recorded using non-invasive faecal corticosterone metabolite analysis (fGC). Thermal images of the eye were captured and eye temperature assessed as a non-invasive measure of the stress response. Behavioural analysis of time budget was carried out and an ease of handling score was assigned to each horse in each treatment using video footage. SHNC horses had significantly higher (p = 0.01) concentrations of fGC and were significantly (p = 0.003) more difficult to handle compared to the other housing types. GHFC horses, although not significantly different, had numerically lower concentrations of fGC and were more compliant to handling when compared to all other housing treatments. Eye temperature was significantly (p = 0.0001) lower in the group housed treatment when compared to all other treatments. These results indicate that based on physiological and behavioural measures incorporating social contact into the housing design of domestic horses could improve the standard of domestic equine welfare

Spread of a highly mucoid Streptococcus pyogenes emm3/ST15 clone

<p>Abstract</p> <p>Background</p> <p>Hyaluronic acid capsule plays a key role in <it>Streptococcus pyogenes </it>virulence. Circulation of mucoid or highly encapsulated strains has been related to rheumatic fever epidemics and invasive disease in several countries. In 2009, an outbreak of mucoid <it>S. pyogenes </it>isolates was detected in northern Spain. The aim of the study was to describe clinical and molecular characteristics of mucoid strains causing this outbreak and to compare them with a sample of non-mucoid <it>S. pyogenes </it>isolates obtained during the same period of time.</p> <p>Methods</p> <p>All <it>S. pyogenes </it>isolates with a mucoid colony morphology (n = 132), 10% of non-mucoid (n = 144) and all invasive <it>S. pyogenes </it>isolates (n = 7) obtained in 2009 were included. Characterization was performed by T-agglutination, <it>emm </it>typing, pulsed field gel electrophoresis and multilocus sequence typing.</p> <p>Results</p> <p>One clone characterized as <it>emm</it>3.1/ST15 comprised 98.5% (n = 130) of all mucoid isolates. Subjects of all ages were affected. Main clinical manifestations were pharyngitis and scarlet fever, but this clone also caused invasive disease: two cases of streptococcal toxic shock syndrome, one arthritis, and one celullitis with a fatal outcome. Mucoid isolates were more prone to cause invasive disease than non-mucoid isolates (p = 0.001).</p> <p>Conclusions</p> <p>Although no acute rheumatic fever cases were detected, the most worrisome characteristics of this clone were the success for causing invasive disease and the merge of two virulent features: the serotype, <it>emm</it>3, and capsule hyper-production, expressed as a mucoid morphology.</p

Antibiotics for the primary prevention of acute rheumatic fever: a meta-analysis

BACKGROUND: Rheumatic fever continues to put a significant burden on the health of low socio-economic populations in low and middle-income countries despite the near disappearance of the disease in the developed world over the past century. Antibiotics have long been thought of as an effective method for preventing the onset of acute rheumatic fever following a Group-A streptococcal (GAS) throat infection; however, their use has not been widely adopted in developing countries for the treatment of sore throats. We have used the tools of systematic review and meta-analysis to quantify the effectiveness of antibiotic treatment for sore throat, with symptoms suggestive of group A streptococcal (GAS) infection, for the primary prevention of acute rheumatic fever. METHODS: Trials were identified through a systematic search of titles and abstracts found in the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 4, 2003), MEDLINE (1966–2003), EMBASE (1966–2003), and the reference lists of identified studies. The selection criteria included randomised or quasi-randomised controlled trials comparing the effectiveness of antibiotics versus no antibiotics for the prevention of rheumatic fever in patients presenting with a sore throat, with or without confirmation of GAS infection, and no history of rheumatic fever. RESULTS: Ten trials (n = 7665) were eligible for inclusion in this review. The methodological quality of the studies, in general, was poor. All of the included trials were conducted during the period of 1950 and 1961 and in 8 of the 10 trials the study population consisted of young adult males living on United States military bases. Fixed effects, meta-analysis revealed an overall protective effect for the use of antibiotics against acute rheumatic fever of 70% (RR = 0.32; 95% CI = 0.21–0.48). The absolute risk reduction was 1.67% with an NNT of 53. When meta-analysis was restricted to include only trials evaluating penicillin, a protective effect of 80% was found (Fixed effect RR = 0.20, 95% CI = 0.11–0.36) with an NNT of 60. The marginal cost of preventing one case of rheumatic fever by a single intramuscular injection of penicillin is approximately US$46 in South Africa. CONCLUSION: Antibiotics appear to be effective in reducing the incidence of acute rheumatic fever following an episode of suspected GAS pharyngitis. This effect may be achieved at relatively low cost if a single intramuscular penicillin injection is administered

Respiratory diseases among U.S. military personnel: countering emerging threats.

Emerging respiratory disease agents, increased antibiotic resistance, and the loss of effective vaccines threaten to increase the incidence of respiratory disease in military personnel. We examine six respiratory pathogens (adenoviruses, influenza viruses, Streptococcus pneumoniae, Streptococcus pyogenes, Mycoplasma pneumoniae, and Bordetella pertussis) and review the impact of the diseases they cause, past efforts to control these diseases in U.S. military personnel, as well as current treatment and surveillance strategies, limitations in diagnostic testing, and vaccine needs

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons