Edward Henry Mathews

The mechanism by which moderate alcohol consumption influences coronary heart disease

BackgroundModerate alcohol consumption is associated with a lower risk for coronary heart disease (CHD). A suitably integrated view of the CHD pathogenesis pathway will help to elucidate how moderate alcohol consumption could reduce CHD risk.MethodsA comprehensive literature review was conducted focusing on the pathogenesis of CHD. Biomarker data were further systematically analysed from 294 cohort studies, comprising 1 161 560 subjects. From the above a suitably integrated CHD pathogenetic system for the purpose of this study was developed.ResultsThe resulting integrated system now provides insight into the integrated higher-order interactions underlying CHD and moderate alcohol consumption. A novel ‘connection graph’ further simplifies these interactions by illustrating the relationship between moderate alcohol consumption and the relative risks (RR) attributed to various measureable CHD serological biomarkers. Thus, the possible reasons for the reduced RR for CHD with moderate alcohol consumption become clear at a glance.ConclusionsAn integrated high-level model of CHD, its pathogenesis, biomarkers, and moderate alcohol consumption provides a summary of the evidence that a causal relationship between CHD risk and moderate alcohol consumption may exist. It also shows the importance of each CHD pathway that moderate alcohol consumption influences.

A practical quantification of blood glucose production due to high-level chronic stress.

Blood glucose (BG) is the primary metabolic fuel for, among others, cancer cell progression, cardiovascular disease and inflammation. Stress is an important contributor to the amount of BG produced especially by the liver. In this paper, we attempt to quantify the BG production due to chronic (in the order of weeks) high-level psychological stress in a manner that a lay person will understand. Three independent approaches were used. The first approach was based on a literature survey of stress hormone data from healthy individuals and its subsequent mathematical manipulation. The next approach was a deductive process where BG levels could be deduced from published stress data of large cardiovascular clinical trials. The third approach used empirical BG data and a BG simulation model. The three different methods produced an average BG increase of 2.2-fold above basal for high levels of stress over a period of more than a day. The standard deviation normalized to the average value was 4.5%.

How do high glycemic load diets influence coronary heart disease

BackgroundDiet has a significant relationship with the risk of coronary heart disease (CHD). Traditionally the effect of diet on CHD was measured with the biomarker for low-density lipoprotein (LDL) cholesterol. However, LDL is not the only or even the most important biomarker for CHD risk. A suitably integrated view of the mechanism by which diet influences the detailed CHD pathogenetic pathways is therefore needed in order to better understand CHD risk factors and help with better holistic CHD prevention and treatment decisions.MethodsA systematic review of the existing literature was conducted. From this an integrated CHD pathogenetic pathway system was constructed. CHD biomarkers, which are found on these pathways, are the only measurable data to link diet with these CHD pathways. They were thus used to simplify the link between diet and the CHD mechanism. Data were systematically analysed from 294 cohort studies of CHD biomarkers constituting 1 187 350 patients.Results and discussionThe resulting integrated analysis provides insight into the higher-order interactions underlying CHD and high-glycemic load (HGL) diets. A novel “connection graph” illustrates the measurable relationship between HGL diets and the relative risks attributed to the important CHD serological biomarkers.The “connection graph” vividly shows that HGL diets not only influence the lipid and metabolic biomarkers, but also the inflammation, coagulation and vascular function biomarkers in an important way.ConclusionA focus primarily on the low density lipoprotein cholesterol biomarker for CHD risk has led to the traditional guidelines of CHD dietary recommendations. This has however inadvertently led to HGL diets. The influence of HGL diets on the other CHD biomarkers is not always fully appreciated. Thus, new diets or other interventions which address the full integrated CHD impact, as shown in this paper, are required.

A new model to estimate Bolus Insulin Need

BACKGROUND Patients with type 1 diabetes usually use the carbohydrate (CHO) counting method to establish their bolus insulin need. However, most still struggle with blood glucose control. We believe that for good control their insulin requirements should strive to mimic the insulin secretion of those without diabetes. The objective here is to develop, from first principles, a better model than the CHO counting model for calculating the bolus insulin need of subjects without diabetes. Such a model may also provide better blood glucose control for patients with type 1 diabetes. This will be investigated in a future article. METHODS Equations for metabolism of CHO and for insulin response were derived from first principles. Clinical trials were used to verify these models. The final results--namely, the new bolus insulin requirement equations--were verified using clinical trials by other researchers (Wolever and co-workers). Their methods used are described in their articles given in the list of references. RESULTS The postprandial insulin secretion relationships resulted in an average Pearson R(2) of 0.807 (for the new method) versus the old methods R(2) of 0.562 (CHO counting). CONCLUSIONS The newly derived equation provides a better approximation than the CHO counting method of insulin secretion due to metabolized blood glucose energy from ingested carbohydrates for those without diabetes. We believe that insulin dosage requirements for a patient with type 1 diabetes should mimic the insulin secretion of those without diabetes. If this is true, it means that the new equation should also estimate bolus insulin need for a patient with type 1 diabetes more accurately than before. This will be investigated in a future article.

Oral health and coronary heart disease

BackgroundIt is well documented that there is some correlation between poor oral health in the form of periodontal disease and coronary heart disease (CHD). It is unclear whether this correlation is due to a causal relationship or shared underlying disorder such as inflammation. A suitable integrated model of the CHD pathogenetic pathways relevant to periodontal disease may help to elucidate the association. Such a model is currently not available in literature.MethodsA previously developed integrated model of CHD was used to investigate potential pathogenetic pathways linking periodontal disease to CHD biomarkers.ResultsThe integrated model was created to provide insight into possible higher-order biological interactions underlying CHD and periodontal disease. In order to simplify these interactions a novel ‘connection graph’ was developed. It quantitatively illustrates the relationship between periodontal disease and various serological biomarkers of CHD. The pathogenesis of periodontitis shows various possible pathways which could link periodontitis to CHD pathogenesis.ConclusionAn integrated model of CHD was developed which provides a summary of the potential CHD effects of periodontal disease. Further research must refine and validate the model.

Complexity of metabolic cancer control: Can we exploit the superior metabolic position of glucose?

We respond to a paper by Ko and colleagues (“Glutamine fuels a vicious cycle of autophagy...”). They hypothesize that tumor stroma are the central fuel generators for cancer growth, the so-called “reverse Warburg effect.” Irrespective of whether this mechanism or the extensively quoted “Warburg effect” accounts for energy production and biosynthesis, we propose (based on recent findings) that all cancer cell metabolites are either glucose-dependent or glucose-derived. We ask whether metabolic cancer control may be simpler than expected. Ko and colleagues show that neighboring cancer-associated fibroblasts are stimulated to convert to glycolytic metabolism through cancer cell-initiated oxidative stress. The fibroblasts thus become glucose dependent. This is the reason why the FDG-PET image of fibroblasts may be even larger than that of the primary tumors. Complexity of metabolic cancer control Can we exploit the superior metabolic position of glucose?

Development of a motion platform for an educational flight simulator

Flight simulators are regularly used in the undergraduate and postgraduate training of mechanical and aeronautical engineers. Due to advances in computing technology, several flight simulation-related tasks can now be accomplished in real-time using low-cost PC platforms and inexpensive commercial software. The difficulty in realising an educational flight simulator system with motion platform therefore lies with the design and construction of an effective motion platform. Costs become exorbitant when simulation platforms of more than two degrees of freedom (i.e. pitch and roll) are attempted. This paper describes the development of a drive system for a motion platform with two degrees of freedom (pitch and roll) for use in undergraduate engineering training. Use was made of off-the-shelf PC equipment and flight simulation software and hardware, together with commercial actuators and drive systems. The motion platform was manufactured from square tubing and consisted of three frames: the stationary main frame and, rotating inside this, the roll frame and pitch frame. These rotated relative to each other and were actuated by two similar-sized DC motors and gearbox/chain transmissions. The system effectively simulated the pitch and roll motions of commercial airliners, using a low-cost, easily maintainable motion platform. The educational value of the simulator was twofold: first, it was to be displayed in the science exploratorium (SciEnza) of the University of Pretoria; and second, it provided a platform on which mechanical (as well as electrical, electronic and computer) engineering students could conduct practical work in courses such as dynamics and control, and on which final-year and postgraduate students could conduct research.

Is knowledge of brain metabolism the key to treating highly glycolytic cancers and metastases

In their recent article, Weller et al1 delineate the minor improvement in survival rates among patients with glioblastoma treated with various chemotherapeutic strategies. Malignant gliomas resort in the group of highly glycolytic cancers and metastases (HGCM) responsible for 90% of cancer-associated deaths.2 Is it possible to improve the outcome in these patients by considering the brains strong metabolic regulation? The brain is the healthy bodys most glycolytic organ, with a typical 18fluorodeoxyglucose (FDG) PET-derived standard uptake value of 8.22.3 Of interest, this is close to the mean standard uptake value of 9.25 (variance, 5–22) for the HGCM that we investigated previously.3 This means that the level of cerebral blood glucose (BG) metabolism is similar to that of the mean HGCM. Therefore, the brain with its strong energy regulation should provide the ideal microenvironment for highly glycolytic metastasis. This is indeed what is found in practice (US data), with 40% of all metastases also occupying the brain.4 With the high BG microenvironment, brain metastases are also lethal within months.1,4 Because brain BG needs are similar to those of HGCM, any aggressive antiglycolytic treatment must account for the brains BG needs. This is indeed what is starting to emerge in practice. Before entering phase II clinical trials, the glycolytic inhibitor 2DG showed brain toxicity.5 Should we not devise methods to harm HGCM in a controlled manner while still satisfying the brains minimum metabolic needs?3 In vivo data 6,7 suggest that such an approach (via extracorporeal glucose deprivation)3 could potentially work. Furthermore, the latest BG control technology may make such an approach practical.8 When devising clinical trials for antiglycolytic treatments, it should be borne in mind that rodent models will not manifest the key invasive properties of malignant gliomas.9 This is attributable to the vastly different regulation strengths that the rodent and the human brains have on their respective BG environments.10 There is an urgent need to more fully explore antiglycolytic treatments for patients with glioblastoma. We hypothesize that the human brain metabolism may be the limiting factor for any aggressive antiglycolytic HGCM treatment. Exploiting such a fact could result in more successful therapies targeting this tumor-protective niche. We believe that this merits further investigation.

The design and development of a stented tissue mitral and aortic heart valve replacement for human implantation

Abstract A study was conducted into the development of a mitral and aortic heart valve replacement that caters for patients having suffered valve damage due to stenosis or rheumatic fever. The appeal of the valve is that it is constituted from a solid frame housing pericardial tissue leaflets, and allows the patient freedom from post-operative blood-thinning medication. The valve is designed to appeal to patients in developing areas of the world, as it features a clip-in mechanism to secure the valve assembly into the sewing ring, which is stitched in independently of the frame and leaflets. Re-operative valve replacement would then be made possible when the pericardial leaflets began to calcify. Novel aspects of the design added value to the science of heart valve replacements, through the use of sintered chrome cobalt in the valve components, the insights gained into mechanical testing of pericardium, and the patient benefits offered by the complete design. Further work is planned to fatigue test the assembly, undergo animal trials and make the valve available for commercial use.

Household photovoltaics — A worthwhile investment?

A combination of factors, including recent advances in Small-Scale Energy Generation (SSEG) legislation as well as decreases in the cost of photovoltaic cells and batteries, have recently made investment in Solar Photovoltaic energy for a consumers household more appealing. In order to quantify the benefits of investing in such an installation a simulation model was created to test the financial feasibility of different configurations of such an installation. This model was then used to simulate several different configurations of battery and photovoltaic installations for a medium- and high-income urban household. From these simulations it was found that a household pure photovoltaic installation is economically feasible, with payback periods for medium- and high income households being 7.52 and 6.94 years respectively. SSEG contracts with the municipality were also found to increase the economic benefits to the consumer. This was largely due to the consumers ability to use the municipal grid as a ‘battery’ and offset power generation to peak-use times with an SSEG contract.