Integrated method for quantitative morphometry and oxygen transport modelling in striated muscle

Identifying structural limitations in O2 transport is primarily restricted by current methods employed to characterise the nature of physiological remodelling. Inadequate resolution or breadth of available data has impaired development of routine diagnostic protocols and effective therapeutic strategies. Understanding O2 transport within striated muscle faces major challenges, most notably in quantifying how well individual fibres are supplied by the microcirculation, which has necessitated exploring tissue O2 supply using theoretical modelling of diffusive exchange. Having identified capillary domains as a suitable model for the description of local O2 supply, and requiring less computation than numerically calculating the trapping regions that are supplied by each capillary via biophysical transport models, we sought to design a high throughput method for histological analysis. We present an integrated package that identifies optimal protocols for identification of important input elements, processing of digitised images with semi-automated routines, and incorporation of these data into a mathematical modelling framework with computed output visualised as the tissue partial pressure of O2 (PO2) distribution across a biopsy sample. Worked examples are provided using muscle samples from experiments involving rats and humans

Maternal hypoxia decreases capillary supply and increases metabolic inefficiency leading to divergence in myocardial oxygen supply and demand

Maternal hypoxia is associated with a decrease in left ventricular capillary density while cardiac performance is preserved, implying a mismatch between metabolism and diffusive exchange. We hypothesised this requires a switch in substrate metabolism to maximise efficiency of ATP production from limited oxygen availability. Rat pups from pregnant females exposed to hypoxia (FIO2=0.12) at days 10-20 of pregnancy were grown to adulthood and working hearts perfused ex vivo. 14 C-labelled glucose and 3 H-palmitate were provided as substrates and metabolism quantified from recovery of 14CO2 and 3 H2O, respectively. Hearts of male offspring subjected to Maternal Hypoxia showed a 20% decrease in cardiac output (P<0.05), despite recording a 2-fold increase in glucose oxidation (P<0.01) and 2.5-fold increase (P<0.01) in palmitate oxidation. Addition of insulin to Maternal Hypoxic hearts, further increased glucose oxidation (P<0.01) and suppressed palmitate oxidation (P<0.05), suggesting preservation in insulin signalling in the heart. In vitro enzyme activity measurements showed that Maternal Hypoxia increased both total and the active component of cardiac pyruvate dehydrogenase (both P<0.01), although pyruvate dehydrogenase sensitivity to insulin was lost (NS), while citrate synthase activity declined by 30% (P<0.001) and acetyl-CoA carboxylase activity was unchanged by Maternal Hypoxia, indicating realignment of the metabolic machinery to optimise oxygen utilisation. Capillary density was quantified and oxygen diffusion characteristics examined, with calculated capillary domain area increased by 30% (P<0.001). Calculated metabolic efficiency decreased 4-fold (P<0.01) for Maternal Hypoxia hearts. Paradoxically, the decline in citrate synthase activity and increased metabolism suggest that the scope of individual mitochondria had declined, rendering the myocardium potentially more sensitive to metabolic stress. However, decreasing citrate synthase may be essential to preserve local PO2, minimising regions of hypoxia and hence maximising the area of myocardium able to preserve cardiac output following maternal hypoxia

The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co-expression Networks

Regular endurance training improves muscle oxidative capacity and reduces the risk of age-related disorders. Understanding the molecular networks underlying this phenomenon is crucial. Here, by exploiting the power of computational modeling, we show that endurance training induces profound changes in gene regulatory networks linking signaling and selective control of translation to energy metabolism and tissue remodeling. We discovered that knockdown of the mTOR-independent factor Eif6, which we predicted to be a key regulator of this process, affects mitochondrial respiration efficiency, ROS production, and exercise performance. Our work demonstrates the validity of a data-driven approach to understanding muscle homeostasis

Effect of Information and Telephone-Guided Access to Community Support for People with Chronic Kidney Disease: Randomised Controlled Trial

Background: Implementation of self-management support in traditional primary care settings has proved difficult, encouraging the development of alternative models which actively link to community resources. Chronic kidney disease (CKD) is a common condition usually diagnosed in the presence of other co-morbidities. This trial aimed to determine the effectiveness of an intervention to provide information and telephone-guided access to community support versus usual care for patients with stage 3 CKD. Methods and Findings: In a pragmatic, two-arm, patient level randomised controlled trial 436 patients with a diagnosis of stage 3 CKD were recruited from 24 general practices in Greater Manchester. Patients were randomised to intervention (215) or usual care (221). Primary outcome measures were health related quality of life (EQ-5D health questionnaire), blood pressure control, and positive and active engagement in life (heiQ) at 6 months. At 6 months, mean health related quality of life was significantly higher for the intervention group (adjusted mean difference = 0.05; 95% CI = 0.01, 0.08) and blood pressure was controlled for a significantly greater proportion of patients in the intervention group (adjusted odds ratio = 1.85; 95% CI = 1.25, 2.72). Patients did not differ significantly in positive and active engagement in life. The intervention group reported a reduction in costs compared with control. Conclusions: An intervention to provide tailored information and telephone-guided access to community resources was associated with modest but significant improvements in health related quality of life and better maintenance of blood pressure control for patients with stage 3 CKD compared with usual care. However, further research is required to identify the mechanisms of action of the intervention

A Novel Role for PECAM-1 (CD31) in Regulating Haematopoietic Progenitor Cell Compartmentalization between the Peripheral Blood and Bone Marrow

Abstract Although the expression of PECAM-1 (CD31) on vascular and haematopoietic cells within the bone marrow microenvironment has been recognized for some time, its physiological role within this niche remains unexplored. In this study we show that PECAM-1 influences steady state hematopoietic stem cell (HSC) progenitor numbers in the peripheral blood but not the bone marrow compartment. PECAM-1 2/2 mice have higher levels of HSC progenitors in the blood compared to their littermate controls. We show that PECAM-1 is required on both progenitors and bone marrow vascular cells in order for efficient transition between the blood and bone marrow to occur. We have identified key roles for PECAM-1 in both the regulation of HSC migration to the chemokine CXCL12, as well as maintaining levels of the matrix degrading enzyme MMP-9 in the bone marrow vascular niche. Using intravital microscopy and adoptive transfer of either wild type (WT) or PECAM-1 2/2 bone marrow precursors, we demonstrate that the increase in HSC progenitors in the blood is due in part to a reduced ability to migrate from blood to the bone marrow vascular niche. These findings suggest a novel role for PECAM-1 as a regulator of resting homeostatic progenitor cell numbers in the bloo

Module-based multiscale simulation of angiogenesis in skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem.</p> <p>Results</p> <p>We present an object-oriented module-based computational integration strategy to build a multiscale model of angiogenesis that links currently available models. As an example case, we use this approach to integrate modules representing microvascular blood flow, oxygen transport, vascular endothelial growth factor transport and endothelial cell behavior (sensing, migration and proliferation). Modeling methodologies in these modules include algebraic equations, partial differential equations and agent-based models with complex logical rules. We apply this integrated model to simulate exercise-induced angiogenesis in skeletal muscle. The simulation results compare capillary growth patterns between different exercise conditions for a single bout of exercise. Results demonstrate how the computational infrastructure can effectively integrate multiple modules by coordinating their connectivity and data exchange. Model parameterization offers simulation flexibility and a platform for performing sensitivity analysis.</p> <p>Conclusions</p> <p>This systems biology strategy can be applied to larger scale integration of computational models of angiogenesis in skeletal muscle, or other complex processes in other tissues under physiological and pathological conditions.</p

3D finite element electrical model of larval zebrafish ECG signals

Assessment of heart function in zebrafish larvae using electrocardiography (ECG) is a potentially useful tool in developing cardiac treatments and the assessment of drug therapies. In order to better understand how a measured ECG waveform is related to the structure of the heart, its position within the larva and the position of the electrodes, a 3D model of a 3 days post fertilisation (dpf) larval zebrafish was developed to simulate cardiac electrical activity and investigate the voltage distribution throughout the body. The geometry consisted of two main components; the zebrafish body was modelled as a homogeneous volume, while the heart was split into five distinct regions (sinoatrial region, atrial wall, atrioventricular band, ventricular wall and heart chambers). Similarly, the electrical model consisted of two parts with the body described by Laplace’s equation and the heart using a bidomain ionic model based upon the Fitzhugh-Nagumo equations. Each region of the heart was differentiated by action potential (AP) parameters and activation wave conduction velocities, which were fitted and scaled based on previously published experimental results. ECG measurements in vivo at different electrode recording positions were then compared to the model results. The model was able to simulate action potentials, wave propagation and all the major features (P wave, R wave, T wave) of the ECG, as well as polarity of the peaks observed at each position. This model was based upon our current understanding of the structure of the normal zebrafish larval heart. Further development would enable us to incorporate features associated with the diseased heart and hence assist in the interpretation of larval zebrafish ECGs in these conditions

Barriers and facilitators of effective self-management in asthma: systematic review and thematic synthesis of patient and healthcare professional views

Self-management is an established, effective approach to controlling asthma, recommended in guidelines. However, promotion, uptake and use among patients and health-care professionals remain low. Many barriers and facilitators to effective self-management have 25 been reported, and views and beliefs of patients and health care professionals have been explored in qualitative studies. We conducted a systematic review and thematic synthesis of qualitative research into self-management in patients, carers and health care professionals regarding self-management of asthma, to identify perceived barriers and facilitators associated with reduced effectiveness of asthma self-management interventions. Electronic databases and guidelines were searched systematically for qualitative literature that explored factors relevant to facilitators and barriers to uptake, adherence, or outcomes of self-management in patients with asthma. Thematic synthesis of the 56 included studies identified 11 themes: 1) partnership between patient and health care professional; 2) issues around medication; 3) education about asthma and its management; 4) health beliefs; 5) self-management interventions; 6) co-morbidities 7) mood disorders and anxiety; 8) social support; 9) non-pharmacological methods; 10) access to healthcare; 11) professional factors. From this, perceived barriers and facilitators were identified at the level of individuals with asthma (and carers), and health-care professionals. Future work addressing the concerns and beliefs of adults, adolescents and children (and carers) with asthma, effective communication and partnership, tailored support and education (including for ethnic minorities and at risk groups), and telehealthcare may improve how self-management is recommended by professionals and used by patients. Ultimately, this may achieve better outcomes for people with asthma

A Novel Role for PECAM-1 (CD31) in Regulating Haematopoietic Progenitor Cell Compartmentalization between the Peripheral Blood and Bone Marrow

Although the expression of PECAM-1 (CD31) on vascular and haematopoietic cells within the bone marrow microenvironment has been recognized for some time, its physiological role within this niche remains unexplored. In this study we show that PECAM-1 influences steady state hematopoietic stem cell (HSC) progenitor numbers in the peripheral blood but not the bone marrow compartment. PECAM-1−/− mice have higher levels of HSC progenitors in the blood compared to their littermate controls. We show that PECAM-1 is required on both progenitors and bone marrow vascular cells in order for efficient transition between the blood and bone marrow to occur. We have identified key roles for PECAM-1 in both the regulation of HSC migration to the chemokine CXCL12, as well as maintaining levels of the matrix degrading enzyme MMP-9 in the bone marrow vascular niche. Using intravital microscopy and adoptive transfer of either wild type (WT) or PECAM-1−/− bone marrow precursors, we demonstrate that the increase in HSC progenitors in the blood is due in part to a reduced ability to migrate from blood to the bone marrow vascular niche. These findings suggest a novel role for PECAM-1 as a regulator of resting homeostatic progenitor cell numbers in the bloo