Two-way FSI modelling of blood flow through CCA accounting on-line medical diagnostics in hypertension

Flow parameters can induce pathological changes in the arteries. We propose a method to asses those parameters using a 3D computer model of the flow in the Common Carotid Artery. Input data was acquired using an automatic 2D ultrasound wall tracking system. This data has been used to generate a 3D geometry of the artery. The diameter and wall thickness have been assessed individually for every patient, but the artery has been taken as a 75mm straight tube. The Young’s modulus for the arterial walls was calculated using the pulse pressure, diastolic (minimal) diameter and wall thickness (IMT). Blood flow was derived from the pressure waveform using a 2-parameter Windkessel model. The blood is assumed to be non-Newtonian. The computational models were generated and calculated using commercial code. The coupling method required the use of Arbitrary Lagrangian-Euler formulation to solve Navier-Stokes and Navier-Lamè equations in a moving domain. The calculations showed that the distention of the walls in the model is not significantly different from the measurements. Results from the model have been used to locate additional risk factors, such as wall shear stress or circumferential stress, that may predict adverse hypertension complications

Observations of mineralised tissues of teeth in X-ray micro-computed tomography

Background: The one of the most recent imaging technology is X-ray microtomography which allows non-invasive three-dimensional visualisation of structures. It also offers the opportunity to conduct a comprehensive quantitative analysis of the tested objects such as measuring the shares of the various phases, determining the material density and distribution of the size of pores and particles. The aim of the paper was to present an overview on the applicability and relevance of X-ray microtomography in the study of mineralised tissues of the teeth. Materials and methods: The article is based on the most recent and significant literature and own observations. Results: The use of X-ray microtomography in dentistry has recently increased and includes, inter alia, the assessment of the density of minerals in enamel and dentin, the detection of demineralisation in an artificially and a naturally induced caries, the automatic measurement of the depth of cavities in dentin, the measurement of the amount of removed dentin in preparation of carious lesions by various methods, the assessment of microleakage around fillings and fissure sealants, cortical bone density measurement, evaluation of root canal morphology, comparison of the accuracy of root canal working and filling by various methods. Conclusions: X-ray microtomography offers within the analysis of mineralised tissues — complex structures of bone, teeth and biomedical materials, turn out to be indispensable since it opens new opportunities for cognitive and implementation research

An orifice shape-based reduced order model of patient-specific mitral valve regurgitation

Mitral valve regurgitation (MR) is one of the most prevalent valvular heart diseases. Its quantitative assessment is challenging but crucial for treatment decisions. Using computational fluid dynamics (CFD), we developed a reduced order model (ROM) describing the relationship between MR flow rates, transvalvular pressure differences, and the size and shape of the regurgitant valve orifice. Due to its low computational cost, this ROM could easily be implemented into clinical workflows to support the assessment of MR. We reconstructed mitral valves of 43 patients from 3D transesophageal echocardiographic images and estimated the 3D anatomic regurgitant orifice areas using a shrink-wrap algorithm. The orifice shapes were quantified with three dimensionless shape parameters. Steady-state CFD simulations in the reconstructed mitral valves were performed to analyse the relationship between the regurgitant orifice geometry and the regurgitant hemodynamics. Based on the results, three ROMs with increasing complexity were defined, all of which revealed very good agreement with CFD results with a mean bias below 3% for the MR flow rate. Classifying orifices into two shape groups and assigning group-specific flow coefficients in the ROM reduced the limit of agreement predicting regurgitant volumes from 9.0 ml to 5.7 ml at a mean regurgitant volume of 57 ml

Validation of a novel numerical model to predict regionalized blood flow in the coronary arteries

Aims Ischaemic heart disease results from insufficient coronary blood flow. Direct measurement of absolute flow (mL/min) is feasible, but has not entered routine clinical practice in most catheterization laboratories. Interventional cardiologists, therefore, rely on surrogate markers of flow. Recently, we described a computational fluid dynamics (CFD) method for predicting flow that differentiates inlet, side branch, and outlet flows during angiography. In the current study, we evaluate a new method that regionalizes flow along the length of the artery. Methods and results Three-dimensional coronary anatomy was reconstructed from angiograms from 20 patients with chronic coronary syndrome. All flows were computed using CFD by applying the pressure gradient to the reconstructed geometry. Side branch flow was modelled as a porous wall boundary. Side branch flow magnitude was based on morphometric scaling laws with two models: a homogeneous model with flow loss along the entire arterial length; and a regionalized model with flow proportional to local taper. Flow results were validated against invasive measurements of flow by continuous infusion thermodilution (Coroventis™, Abbott). Both methods quantified flow relative to the invasive measures: homogeneous (r 0.47, P 0.006; zero bias; 95% CI −168 to +168 mL/min); regionalized method (r 0.43, P 0.013; zero bias; 95% CI −175 to +175 mL/min). Conclusion During angiography and pressure wire assessment, coronary flow can now be regionalized and differentiated at the inlet, outlet, and side branches. The effect of epicardial disease on agreement suggests the model may be best targeted at cases with a stenosis close to side branches

Modelling the hemodynamics of coronary ischemia

Acting upon clinical patient data, acquired in the pathway of percutaneous intervention, we deploy hierarchical, multi-stage, data-handling protocols and interacting low- and high-order mathematical models (chamber elastance, state-space system and CFD models), to establish and then validate a framework to quantify the burden of ischaemia. Our core tool is a compartmental, zero-dimensional model of the coupled circulation with four heart chambers, systemic and pulmonary circulations and an optimally adapted windkessel model of the coronary arteries that reflects the diastolic dominance of coronary flow. We guide the parallel development of protocols and models by appealing to foundational physiological principles of cardiac energetics and a parameterisation (stenotic Bernoulli resistance and micro-vascular resistance) of patients’ coronary flow. We validate our process first with results which substantiate our protocols and, second, we demonstrate good correspondence between model operation and patient data. We conclude that our core model is capable of representing (patho)physiological states and discuss how it can potentially be deployed, on clinical data, to provide a quantitative assessment of the impact, on the individual, of coronary artery disease

The Anti-Apoptotic Activity of BAG3 Is Restricted by Caspases and the Proteasome

Caspase-mediated cleavage and proteasomal degradation of ubiquitinated proteins are two independent mechanisms for the regulation of protein stability and cellular function. We previously reported BAG3 overexpression protected ubiquitinated clients, such as AKT, from proteasomal degradation and conferred cytoprotection against heat shock. We hypothesized that the BAG3 protein is regulated by proteolysis. caspase-resistant mutant. Caspase and proteasome inhibition resulted in partial and independent protection of BAG3 whereas inhibitors of both blocked BAG3 degradation. STS-induced apoptosis was increased when BAG3 was silenced, and retention of BAG3 was associated with cytoprotection.BAG3 is tightly controlled by selective degradation during STS exposure. Loss of BAG3 under STS injury required sequential caspase cleavage followed by polyubiquitination and proteasomal degradation. The need for dual regulation of BAG3 in apoptosis suggests a key role for BAG3 in cancer cell resistance to apoptosis

Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors

Connexin-43 (Cx43), a gap junction protein involved in control of cell proliferation, differentiation and migration, has been suggested to have a role in hematopoiesis. Cx43 is highly expressed in osteoblasts and osteogenic progenitors (OB/P). To elucidate the biologic function of Cx43 in the hematopoietic microenvironment (HM) and its influence in hematopoietic stem cell (HSC) activity, we studied the hematopoietic function in an in vivo model of constitutive deficiency of Cx43 in OB/P. The deficiency of Cx43 in OB/P cells does not impair the steady state hematopoiesis, but disrupts the directional trafficking of HSC/progenitors (Ps) between the bone marrow (BM) and peripheral blood (PB). OB/P Cx43 is a crucial positive regulator of transstromal migration and homing of both HSCs and progenitors in an irradiated microenvironment. However, OB/P Cx43 deficiency in nonmyeloablated animals does not result in a homing defect but induces increased endosteal lodging and decreased mobilization of HSC/Ps associated with proliferation and expansion of Cxcl12-secreting mesenchymal/osteolineage cells in the BM HM in vivo. Cx43 controls the cellular content of the BM osteogenic microenvironment and is required for homing of HSC/Ps in myeloablated animal

REDD1 Protects Osteoblast Cells from Gamma Radiation-Induced Premature Senescence

Radiotherapy is commonly used for cancer treatment. However, it often results in side effects due to radiation damage in normal tissue, such as bone marrow (BM) failure. Adult hematopoietic stem and progenitor cells (HSPC) reside in BM next to the endosteal bone surface, which is lined primarily by hematopoietic niche osteoblastic cells. Osteoblasts are relatively more radiation-resistant than HSPCs, but the mechanisms are not well understood. In the present study, we demonstrated that the stress response gene REDD1 (regulated in development and DNA damage responses 1) was highly expressed in human osteoblast cell line (hFOB) cells after γ irradiation. Knockdown of REDD1 with siRNA resulted in a decrease in hFOB cell numbers, whereas transfection of PCMV6-AC-GFP-REDD1 plasmid DNA into hFOB cells inhibited mammalian target of rapamycin (mTOR) and p21 expression and protected these cells from radiation-induced premature senescence (PS). The PS in irradiated hFOB cells were characterized by significant inhibition of clonogenicity, activation of senescence biomarker SA-β-gal, and the senescence-associated cytokine secretory phenotype (SASP) after 4 or 8 Gy irradiation. Immunoprecipitation assays demonstrated that the stress response proteins p53 and nuclear factor κ B (NFkB) interacted with REDD1 in hFOB cells. Knockdown of NFkB or p53 gene dramatically suppressed REDD1 protein expression in these cells, indicating that REDD1 was regulated by both factors. Our data demonstrated that REDD1 is a protective factor in radiation-induced osteoblast cell premature senescence

Selective Enhancement of Donor Hematopoietic Cell Engraftment by the CXCR4 Antagonist AMD3100 in a Mouse Transplantation Model

The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation

The Endoplasmic Reticulum Chaperone Protein GRP94 Is Required for Maintaining Hematopoietic Stem Cell Interactions with the Adult Bone Marrow Niche

Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology