Simulation of human atherosclerotic femoral plaque tissue: the influence of plaque material model on numerical results

Background

Due to the limited number of experimental studies that mechanically characterise human atherosclerotic plaque tissue from the femoral arteries, a recent trend has emerged in current literature whereby one set of material data based on aortic plaque tissue is employed to numerically represent diseased femoral artery tissue. This study aims to generate novel vessel-appropriate material models for femoral plaque tissue and assess the influence of using material models based on experimental data generated from aortic plaque testing to represent diseased femoral arterial tissue.

Methods

Novel material models based on experimental data generated from testing of atherosclerotic femoral artery tissue are developed and a computational analysis of the revascularisation of a quarter model idealised diseased femoral artery from a 90% diameter stenosis to a 10% diameter stenosis is performed using these novel material models. The simulation is also performed using material models based on experimental data obtained from aortic plaque testing in order to examine the effect of employing vessel appropriate material models versus those currently employed in literature to represent femoral plaque tissue.

Results

Simulations that employ material models based on atherosclerotic aortic tissue exhibit much higher maximum principal stresses within the plaque than simulations that employ material models based on atherosclerotic femoral tissue. Specifically, employing a material model based on calcified aortic tissue, instead of one based on heavily calcified femoral tissue, to represent diseased femoral arterial vessels results in a 487 fold increase in maximum principal stress within the plaque at a depth of 0.8 mm from the lumen.

Conclusions

Large differences are induced on numerical results as a consequence of employing material models based on aortic plaque, in place of material models based on femoral plaque, to represent a diseased femoral vessel. Due to these large discrepancies, future studies should seek to employ vessel-appropriate material models to simulate the response of diseased femoral tissue in order to obtain the most accurate numerical results.

     

Oxidative stress and the etiology of insulin resistance and type 2 diabetes

The condition of oxidative stress arises when oxidant production exceeds antioxidant activity in cells and plasma. The overabundance of oxidants is mechanistically connected to the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue, and the subsequent development of type 2 diabetes. Two important mechanisms for this oxidant excess are (1) the mitochondrial overproduction of hydrogen peroxide and superoxide ion under conditions of energy surplus and (2) the enhanced activation of cellular NADPH oxidase via angiotensin II receptors. Several recent studies are reviewed that support the concept that direct exposure of mammalian skeletal muscle to an oxidant stress (including hydrogen peroxide) results in stimulation of the serine kinase p38 mitogen-activated protein kinase (p38 MAPK), and that the engagement of this stress-activated p38 MAPK signaling is mechanistically associated with diminished insulin-dependent stimulation of insulin signaling elements and glucose transport activity. The beneficial interactions between the antioxidant α-lipoic acid and the advanced glycation end-product inhibitor pyridoxamine that ameliorate oxidant stress-associated defects in whole-body and skeletal-muscle insulin action in the obese Zucker rat, a model of prediabetes, are also addressed. Overall, this review highlights the importance of oxidative stress in the development of insulin resistance in mammalian skeletal muscle tissue, at least in part via a p38-MAPK-dependent mechanism, and indicates that interventions that reduce this oxidative stress and oxidative damage can improve insulin action in insulin-resistant animal models. Strategies to prevent and ameliorate oxidative stress remain important in the overall treatment of insulin resistance and type 2 diabetes.     

Design, synthesis and biological activity of novel peptidyl benzyl ketone FVIIa inhibitors

Herein is described the synthesis of a novel class of peptidyl FVIIa inhibitors having a C-terminal benzyl ketone group. This class is designed to be potentially suitable as stabilization agents of liquid formulations of rFVIIa, which is a serine protease used for the treatment of hemophilia A and B inhibitor patients. A library of compounds was synthesized with different tripeptide sequences, N-terminals and d-amino acids in the P3 position. Cbz-d-Phe-Phe-Arg-bk (33) was found to be the best candidate with a potency of K_i = 8 μM and no substantial inhibition of related blood coagulation factors (thrombin and FXa). Computational studies revealed that 33 has a very stable binding conformation due to intramolecular hydrogen bonds, which cannot be formed with l-Phe in the P3 position. Nonpolar amino acids were found to be superior, probably due to a minimization of the cost of desolvation upon binding to FVIIa.     

Thermodynamic and biological evaluation of a thrombin binding aptamer modified with several unlocked nucleic acid (UNA) monomers and a 2'-C-piperazino-UNA monomer

Thrombin binding aptamer is a DNA 15-mer which forms a G-quadruplex structure and possess promising anticoagulant properties due to specific interactions with thrombin. Herein we present the influence of a single 2'-C-piperazino-UNA residue and UNA residues incorporated in several positions on thermodynamics, kinetics and biological properties of the aptamer. 2'-C-Piperazino-UNA is characterized by more efficient stabilization of quadruplex structure in comparison to regular UNA and increases thermodynamic stability of TBA by 0.28-0.44 kcal/mol in a position depending manner with retained quadruplex topology and molecularity. The presence of UNA-U in positions U3, U7, and U12 results in the highest stabilization of G-quadruplex structure (ΔΔG(37)(°)=-1.03kcal/mol). On the contrary, the largest destabilization mounting to 1.79 kcal/mol was observed when UNA residues were placed in positions U7, G8, and U9. Kinetic studies indicate no strict correlation between thermodynamic stability of modified variants and their binding affinity to thrombin. Most of the studied variants bind thrombin, albeit with decreased affinity in reference to unmodified TBA. Thrombin time assay studies indicate three variants as being as potent as TBA in fibrin clotting inhibition.     

The Physiology undergraduate major in the University of Arizona College of Medicine: past, present, and future

The American Physiological Society (APS) and APS Council encourage the teaching of physiology at the undergraduate, graduate, and medical school levels to support the continued prominence of this area of science. One area identified by the APS Council that is of particular importance for the development of future physiologists (the "physiology pipeline") is the teaching of physiology and physiology-related topics at the undergraduate level. In this article, we describe the historical development and implementation of an undergraduate program offered through the Department of Physiology, a basic science department in the College of Medicine at the University of Arizona, culminating in a Bachelor of Science in Health Sciences degree with a major in Physiology. Moreover, we discuss the current Physiology curriculum offered at our institution and explain how this program prepares our students for successful entry into a variety of postbaccalaureate professional programs, including medical school and numerous other programs in health professions, and in graduate study in the Masters and Doctoral programs in biomedical sciences. Finally, we cover the considerable challenges that we have faced, and continue to face, in developing and sustaining a successful physiology undergraduate major in a college of medicine. We hope that the information provided on the Physiology major offered by the Department of Physiology in the College of Medicine at the University of Arizona will be helpful for individuals at other institutions who may be contemplating the development and implementation of an undergraduate program in Physiology.     

Review and classification of variability analysis techniques with clinical applications

Background

Representation of independent biophysical sources using Fourier analysis can be inefficient because the basis is sinusoidal and general. When complex fractionated atrial electrograms (CFAE) are acquired during atrial fibrillation (AF), the electrogram morphology depends on the mix of distinct nonsinusoidal generators. Identification of these generators using efficient methods of representation and comparison would be useful for targeting catheter ablation sites to prevent arrhythmia reinduction.

Method

A data-driven basis and transform is described which utilizes the ensemble average of signal segments to identify and distinguish CFAE morphologic components and frequencies. Calculation of the dominant frequency (DF) of actual CFAE, and identification of simulated independent generator frequencies and morphologies embedded in CFAE, is done using a total of 216 recordings from 10 paroxysmal and 10 persistent AF patients. The transform is tested versus Fourier analysis to detect spectral components in the presence of phase noise and interference. Correspondence is shown between ensemble basis vectors of highest power and corresponding synthetic drivers embedded in CFAE.

Results

The ensemble basis is orthogonal, and efficient for representation of CFAE components as compared with Fourier analysis (p ≤ 0.002). When three synthetic drivers with additive phase noise and interference were decomposed, the top three peaks in the ensemble power spectrum corresponded to the driver frequencies more closely as compared with top Fourier power spectrum peaks (p ≤ 0.005). The synthesized drivers with phase noise and interference were extractable from their corresponding ensemble basis with a mean error of less than 10%.

Conclusions

The new transform is able to efficiently identify CFAE features using DF calculation and by discerning morphologic differences. Unlike the Fourier transform method, it does not distort CFAE signals prior to analysis, and is relatively robust to jitter in periodic events. Thus the ensemble method can provide a useful alternative for quantitative characterization of CFAE during clinical study.     

Biochemical markers of ongoing joint damage in rheumatoid arthritis - current and future applications, limitations and opportunities

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond.     

Adaptations in the gait pattern with experimental hamstring pain

Pain changes movement but most studies have focused on basic physiological adaptations during non-functional movement tasks. The existing studies on how pain affects lower extremity gross movement biomechanics have primarily involved movements in which the quadriceps is the primary muscle and little attention has been given to how pain in other muscles affects functional movement. The purpose of this study was to investigate the changes in the gait patterns of healthy subjects that occur during experimental muscle pain in the biceps femoris.In a cross-over study design, 14 healthy volunteers underwent EMG assisted 3D gait analyses before, during and after experimental biceps femoris pain induced by intramuscular injections of hypertonic saline. Isotonic saline injections were administered as a non-painful control.The experimental biceps femoris pain led to reductions in hip extensor moments, knee flexor and lateral rotator moments. No changes in lower extremity kinematics and EMG activity in any of the recorded muscles were observed.It is concluded that experimental muscle pain in the biceps femoris leads to changes in the gait pattern in agreement with unloading of the painful muscle. The changes are specific to the painful muscle. The present study provides support to the theory that musculoskeletal pain is a protective signal leading to changes in movement patterns that serve to unload the painful tissue.     

Screening assay for oxidative stress in a feline astrocyte cell line, G355-5

An often-suggested mechanism of virus induced neuronal damage is oxidative stress. Astrocytes have an important role in controlling oxidative stress of the Central Nervous System (CNS). Astrocytes help maintain a homeostatic environment for neurons as well as protecting neurons from Reactive Oxygen Species (ROS). CM-H2DCFDA is a cell-permeable indicator for the presence of ROS. CM-H(2)DCFDA enters the cell as a non-fluorescent compound, and becomes fluorescent after cellular esterases remove the acetate groups, and the compound is oxidized. The number of cells, measured by flow cytometry, that are found to be green fluorescing is an indication of the number of cells that are in an oxidative state. CM-H(2)DCFDA is susceptible to oxidation by a large number of different ROS. This lack of specificity, regarding which ROS can oxidize CM-H(2)DCFDA, makes this compound a valuable regent for use in the early stages of a pathogenesis investigation, as this assay can be used to screen for an oxidative cellular environment regardless of which oxygen radical or combination of ROS are responsible for the cellular conditions. Once it has been established that ROS are present by oxidation of CM-H(2)DCFDA, then additional experiments can be performed to determine which ROS or combination of ROSs are involved in the particular pathogenesis process. The results of this study demonstrate that with the addition of hydrogen peroxide an increase in CM-H(2)DCFDA fluorescence was detected relative to the saline controls, indicating that this assay is a valuable test for detecting an oxidative environment within G355-5 cells, a feline astrocyte cell line.