Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease.

The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic heart has been investigated for over a century, initially focusing on the chick embryo due to the opportunity to isolate and investigate myocardial electromechanical maturation, the ability to directly instrument and measure normal cardiac function, intervene to alter ventricular loading conditions, and then investigate changes in functional and structural maturation to deduce mechanism. The paradigm of "Develop and validate quantitative techniques, describe normal, perturb the system, describe abnormal, then deduce mechanisms" was taught to many young investigators by Dr.

Chronic optical pacing conditioning of h-iPSC engineered cardiac tissues.

The immaturity of human induced pluripotent stem cell derived engineered cardiac tissues limits their ability to regenerate damaged myocardium and to serve as robust models for human disease and drug toxicity studies. Several chronic biomimetic conditioning protocols, including mechanical stretch, perfusion, and/or electrical stimulation promote engineered cardiac tissue maturation but have significant technical limitations. Non-contacting chronic optical stimulation using heterologously expressed channelrhodopsin light-gated ion channels, termed optogenetics, may be an advantageous alternative to chronic invasive electrical stimulation for engineered cardiac tissue conditioning.

Utilizing Contrast-Enhanced Ultrasound Imaging for Evaluating Fatty Liver Disease Progression in Pre-clinical Mouse Models.

We developed a protocol to investigate and optimize the application of contrast-enhanced ultrasound (CEUS) to non-invasive diagnosis of progressing fatty liver disease in mouse models. Eighteen 4-wk-old male C57 L/J mice were randomly assigned to one of the three groups and placed on a control diet, high-fat diet or non-alcoholic steatohepatitis diet for the next 10 wk. After 14 wk, B-mode imaging and CEUS imaging using a VisualSonics Vevo2100 system were performed.

Interpreter-mediated Cognitive Assessments: Who Wins and Who Loses?

Objectives: The number of people with dementia from culturally and linguistically diverse (CALD) backgrounds is increasing dramatically in Australia. Accurate cognitive assessments of people from CALD backgrounds can be achieved with the use of skilled interpreters. This study aimed to explore the experience of interpreter-mediated assessments from the perspectives of clinicians, interpreters and carers.

Quantification of Cardiomyocyte Alignment from Three-Dimensional (3D) Confocal Microscopy of Engineered Tissue.

Biological tissues have complex, three-dimensional (3D) organizations of cells and matrix factors that provide the architecture necessary to meet morphogenic and functional demands. Disordered cell alignment is associated with congenital heart disease, cardiomyopathy, and neurodegenerative diseases and repairing or replacing these tissues using engineered constructs may improve regenerative capacity. However, optimizing cell alignment within engineered tissues requires quantitative 3D data on cell orientations and both efficient and validated processing algorithms.

Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue.

The current study describes a scalable, porous large-format engineered cardiac tissue (LF-ECT) composed of human induced pluripotent stem cells (hiPSCs) derived multiple lineage cardiac cells with varied 3D geometries and cell densities developed towards the goal of scale-up for large animal pre-clinical studies. We explored multiple 15 × 15 mm ECT geometries using molds with rectangular internal staggered posts (mesh, ME), without posts (plain sheet, PS), or long parallel posts (multiple linear bundles, ML) and a gel matrix containing hiPSC-derived cardiomyocytes, endothelial, and vascular mural cells matured in vitro for 14 days. ME-ECTs displayed the lowest dead cell ratio (p < 0.

"": Insights on the Uptake of Falls Prevention Strategies from People with Dementia and Their Caregivers.

Strong evidence exists for effective falls prevention strategies for community-dwelling older people. Understanding the translation of these strategies into practice for people with dementia has had limited research focus. People with dementia desire to have their voice heard, to engage meaningfully in the health-care decision-making process, making it a priority for researchers and practitioners to better understand how to engage them in this process.

The myocardial regenerative potential of three-dimensional engineered cardiac tissues composed of multiple human iPS cell-derived cardiovascular cell lineages.

Human induced pluripotent stem cells (hiPSCs) are a robust source for cardiac regenerative therapy due to their potential to support autologous and allogeneic transplant paradigms. The in vitro generation of three-dimensional myocardial tissue constructs using biomaterials as an implantable hiPSC-derived myocardium provides a path to realize sustainable myocardial regeneration. We generated engineered cardiac tissues (ECTs) from three cellular compositions of cardiomyocytes (CMs), endothelial cells (ECs), and vascular mural cells (MCs) differentiated from hiPSCs.

Mental health issues and discrimination among older LGBTI people.

LGBT is an acronym used to describe people from diverse sexual orientation or gender identity, people that are gay, lesbian, bisexual, or transgender. LGBT people do not constitute a single group nor does each individual "group" constitute a homogeneous unity. However, as higher rates of depression and/or anxiety have been observed in older LGBT people, compared to their heterosexual counterparts (Guasp, 2011) there is a need to raise the profile of mental health issues amongst these groups.

Effects of physiologic mechanical stimulation on embryonic chick cardiomyocytes using a microfluidic cardiac cell culture model.

Hemodynamic mechanical cues play a critical role in the early development and functional maturation of cardiomyocytes (CM). Therefore, tissue engineering approaches that incorporate immature CM into functional cardiac tissues capable of recovering or replacing damaged cardiac muscle require physiologically relevant environments to provide the appropriate mechanical cues. The goal of this work is to better understand the subcellular responses of immature cardiomyocytes using an in vitro cardiac cell culture model that realistically mimics in vivo mechanical conditions, including cyclical fluid flows, chamber pressures, and tissue strains that could be experienced by implanted cardiac tissues.

Investigating developmental cardiovascular biomechanics and the origins of congenital heart defects.

Innovative research on the interactions between biomechanical load and cardiovascular (CV) morphogenesis by multiple investigators over the past 3 decades, including the application of bioengineering approaches, has shown that the embryonic heart adapts both structure and function in order to maintain cardiac output to the rapidly growing embryo. Acute adaptive hemodynamic mechanisms in the embryo include the redistribution of blood flow within the heart, dynamic adjustments in heart rate and developed pressure, and beat to beat variations in blood flow and vascular resistance. These biomechanically relevant events occur coincident with adaptive changes in gene expression and trigger adaptive mechanisms that include alterations in myocardial cell growth and death, regional and global changes in myocardial architecture, and alterations in central vascular morphogenesis and remodeling.

Left atrial ligation alters intracardiac flow patterns and the biomechanical landscape in the chick embryo.

Background: Hypoplastic left heart syndrome (HLHS) is a major human congenital heart defect that results in single ventricle physiology and high mortality. Clinical data indicate that intracardiac blood flow patterns during cardiac morphogenesis are a significant etiology. We used the left atrial ligation (LAL) model in the chick embryo to test the hypothesis that LAL immediately alters intracardiac flow streams and the biomechanical environment, preceding morphologic and structural defects observed in HLHS.

Help seeking in older Asian people with dementia in Melbourne: using the Cultural Exchange Model to explore barriers and enablers.

The prevalence of dementia is increasing in Australia. Limited research is available on access to Cognitive Dementia and Memory Services (CDAMS) for people with dementia from Culturally and Linguistically Diverse (CALD) communities. This study aimed to determine the barriers and enablers to accessing CDAMS for people with dementia and their families of Chinese and Vietnamese backgrounds.

Gene expression profiles in engineered cardiac tissues respond to mechanical loading and inhibition of tyrosine kinases.

Engineered cardiac tissues (ECTs) are platforms to investigate cardiomyocyte maturation and functional integration, the feasibility of generating tissues for cardiac repair, and as models for pharmacology and toxicology bioassays. ECTs rapidly mature in vitro to acquire the features of functional cardiac muscle and respond to mechanical load with increased proliferation and maturation. ECTs are now being investigated as platforms for in vitro models for human diseases and for pharmacologic screening for drug toxicities.

Cardiac cell culture model as a left ventricle mimic for cardiac tissue generation.

A major challenge in cardiac tissue engineering is the delivery of hemodynamic mechanical cues that play a critical role in the early development and maturation of cardiomyocytes. Generation of functional cardiac tissue capable of replacing or augmenting cardiac function therefore requires physiologically relevant environments that can deliver complex mechanical cues for cardiomyocyte functional maturation. The goal of this work is the development and validation of a cardiac cell culture model (CCCM) microenvironment that accurately mimics pressure-volume changes seen in the left ventricle and to use this system to achieve cardiac cell maturation under conditions where mechanical loads such as pressure and stretch are gradually increased from the unloaded state to conditions seen in vivo.

Development and initial testing of the Person-Centred Health Care for Older Adults Survey.

Background: Health services are encouraged to adopt a strong person-centered approach to the provision of care and services for older people. The aim of this project was to establish a user-friendly, psychometrically valid, and reliable measure of healthcare staff's practice, attitudes, and beliefs regarding person-centered healthcare.

Methods: Item reduction (factor analysis) of a previously developed "benchmarking person-centred care" survey, followed by psychometric evaluations of the internal consistency reliability and construct validity, was conducted.

Critical transitions in early embryonic aortic arch patterning and hemodynamics.

Transformation from the bilaterally symmetric embryonic aortic arches to the mature great vessels is a complex morphogenetic process, requiring both vasculogenic and angiogenic mechanisms. Early aortic arch development occurs simultaneously with rapid changes in pulsatile blood flow, ventricular function, and downstream impedance in both invertebrate and vertebrate species. These dynamic biomechanical environmental landscapes provide critical epigenetic cues for vascular growth and remodeling.

Maternal hypoxia and caffeine exposure depress fetal cardiovascular function during primary organogenesis.

Aims: Hypoxia is known to influence cardiovascular (CV) function, in part, through adenosine receptor activation. We have shown in a mouse model that during primary cardiac morphogenesis, acute maternal hypoxia negatively affects fetal heart rate, and recurrent maternal caffeine exposure reduces fetal cardiac output (CO) and downregulates fetal adenosine A(2A) receptor gene expression. In the present study, we investigated whether maternal caffeine dosing exacerbates the fetal CV response to acute maternal hypoxia during the primary morphogenesis period.

Engineered fetal cardiac graft preserves its cardiomyocyte proliferation within postinfarcted myocardium and sustains cardiac function.

The goal of cellular cardiomyoplasty is to replace damaged myocardium by healthy myocardium achieved by host myocardial regeneration and/or transplantation of donor cardiomyocytes (CMs). In the case of CM transplantation, studies suggest that immature CMs may be the optimal cell type to survive and functionally integrate into damaged myocardium. In the present study, we tested the hypothesis that active proliferation of immature CMs contributes graft survival and functional recovery of recipient myocardium.

A three-dimensional gel bioreactor for assessment of cardiomyocyte induction in skeletal muscle-derived stem cells.

Skeletal muscle-derived stem cells (MDSCs) are able to differentiate into cardiomyocytes (CMs). However, it remains to be investigated whether differentiated CMs contract similar to native CMs. Here, we developed a three-dimensional collagen gel bioreactor (3DGB) that induces a working CM phenotype from MDSCs, and the contractile properties are directly measured as an engineered cardiac tissue.

Aortic arch morphogenesis and flow modeling in the chick embryo.

Morphogenesis of the "immature symmetric embryonic aortic arches" into the "mature and asymmetric aortic arches" involves a delicate sequence of cell and tissue migration, proliferation, and remodeling within an active biomechanical environment. Both patient-derived and experimental animal model data support a significant role for biomechanical forces during arch development. The objective of the present study is to quantify changes in geometry, blood flow, and shear stress patterns (WSS) during a period of normal arch morphogenesis.

Engineered early embryonic cardiac tissue increases cardiomyocyte proliferation by cyclic mechanical stretch via p38-MAP kinase phosphorylation.

Cardiomyocyte (CM) transplantation is one therapeutic option for cardiac repair. Studies suggest that fetal CMs display the best cell type for cardiac repair, which can finitely proliferate, integrate with injured host myocardium, and restore cardiac function. We have recently developed an engineered early embryonic cardiac tissue (EEECT) using embryonic cardiac cells and have shown that EEECT contractile properties and cellular proliferative response to cyclic mechanical stretch stimulation mimic developing fetal myocardium.

The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy.

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca(2+) desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis.

Methods And Findings: We ablated Tnnt2 to produce heterozygous Tnnt2(+/-) mice, and crossbreeding produced homozygous null Tnnt2(-/-) embryos.