A continuum model for the elongation and orientation of Von Willebrand factor with applications in arterial flow.

The blood protein Von Willebrand factor (VWF) is critical in facilitating arterial thrombosis. At pathologically high shear rates, the protein unfolds and binds to the arterial wall, enabling the rapid deposition of platelets from the blood. We present a novel continuum model for VWF dynamics in flow based on a modified viscoelastic fluid model that incorporates a single constitutive relation to describe the propensity of VWF to unfold as a function of the scalar shear rate. Using experimental data of VWF unfolding in pure shear flow, we fix the parameters for VWF's unfolding propensity and the maximum VWF length, so that the protein is half unfolded at a shear rate of approximately 5000 s - 1 . We then use the theoretical model to predict VWF's behaviour in two complex flows where experimental data are challenging to obtain: pure elongational flow and stenotic arterial flow. In pure elongational flow, our model predicts that VWF is 50% unfolded at approximately 2000 s - 1 , matching the established hypothesis that VWF unfolds at lower shear rates in elongational flow than in shear flow. We demonstrate the sensitivity of this elongational flow prediction to the value of maximum VWF length used in the model, which varies significantly across experimental studies, predicting that VWF can unfold between 2000 and 3200 s - 1 depending on the selected value. Finally, we examine VWF dynamics in a range of idealised arterial stenoses, predicting the relative extension of VWF in elongational flow structures in the centre of the artery compared to high shear regions near the arterial walls.

Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.

Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25R)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1+ oculomotor neurons. Furthermore, our results suggest that elevated 24(S),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development.

Challenges in progressing cell therapies to the clinic for Huntington's disease: A review of the progress made with pluripotent stem cell derived medium spiny neurons.

Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by a triad of symptoms: motor, cognitive and psychiatric. HD is caused by a genetic mutation, expansion of the CAG repeat in the huntingtin gene, which results in loss of medium spiny neurons (MSNs) of the striatum. Cell replacement therapy (CRT) has emerged as a possible therapy for HD, aiming to replace those cells lost to the disease process and alleviate its symptoms. Initial pre-clinical studies used primary fetal striatal cells to provide proof-of-principal that CRT can bring about functional recovery on some behavioral tasks following transplantation into HD models. Alternative donor cell sources are required if CRT is to become a viable therapeutic option and human pluripotent stem cell (hPSC) sources, which have undergone differentiation toward the MSNs lost to the disease process, have proved to be strong candidates. The focus of this chapter is to review work conducted on the functional assessment of animals following transplantation of hPSC-derived MSNs. We discuss different ways that graft function has been assessed, and the results that have been achieved to date. In addition, this chapter presents and discusses challenges that remain in this field.

Do foetal transplant studies continue to be justified in Huntington's disease?

Early CNS transplantation studies used foetal derived cell products to provide a foundation of evidence for functional recovery in preclinical studies and early clinical trials. However, it was soon recognised that the practical limitations of foetal tissue make it unsuitable for widespread clinical use. Considerable effort has since been directed towards producing target cell phenotypes from pluripotent stem cells (PSCs) instead, and there now exist several publications detailing the differentiation and characterisation of PSC-derived products relevant for transplantation in Huntington's disease (HD). In light of this progress, we ask if foetal tissue transplantation continues to be justified in HD research. We argue that (i) the extent to which accurately differentiated target cells can presently be produced from PSCs is still unclear, currently making them undesirable for studying wider CNS transplantation issues; (ii) foetal derived cells remain a valuable tool in preclinical research for advancing our understanding of which products produce functional striatal grafts and as a reference to further improve PSC-derived products; and (iii) until PSC-derived products are ready for human trials, it is important to continue using foetal cells to gather clinical evidence that transplantation is a viable option in HD and to use this opportunity to optimise practical parameters (such as trial design, clinical practices, and delivery strategies) to pave the way for future PSC-derived products.

Experimental and mathematical modelling of magnetically labelled mesenchymal stromal cell delivery.

A key challenge for stem cell therapies is the delivery of therapeutic cells to the repair site. Magnetic targeting has been proposed as a platform for defining clinical sites of delivery more effectively. In this paper, we use a combined in vitro experimental and mathematical modelling approach to explore the magnetic targeting of mesenchymal stromal cells (MSCs) labelled with magnetic nanoparticles using an external magnet. This study aims to (i) demonstrate the potential of magnetic tagging for MSC delivery, (ii) examine the effect of red blood cells (RBCs) on MSC capture efficacy and (iii) highlight how mathematical models can provide both insight into mechanics of therapy and predictions about cell targeting in vivo. In vitro MSCs are cultured with magnetic nanoparticles and circulated with RBCs over an external magnet. Cell capture efficacy is measured for varying magnetic field strengths and RBC percentages. We use a 2D continuum mathematical model to represent the flow of magnetically tagged MSCs with RBCs. Numerical simulations demonstrate qualitative agreement with experimental results showing better capture with stronger magnetic fields and lower levels of RBCs. We additionally exploit the mathematical model to make hypotheses about the role of extravasation and identify future in vitro experiments to quantify this effect.

Induced pluripotent stem cells derived from the developing striatum as a potential donor source for cell replacement therapy for Huntington disease.

BACKGROUND: Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells. RESULTS: We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.

PREVENTION-ACHD: PRospEctiVE study on implaNTable cardioverter-defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease; Rationale and Design.

BACKGROUND: Many adult congenital heart disease (ACHD) patients are at risk of sudden cardiac death (SCD). An implantable cardioverter-defibrillator (ICD) may prevent SCD, but the evidence for primary prevention indications is still unsatisfactory. STUDY DESIGN: PREVENTION-ACHD is a prospective study with which we aim to prospectively validate a new risk score model for primary prevention of SCD in ACHD patients, as well as the currently existing guideline recommendations. Patients are screened using a novel risk score to predict SCD as well as current ICD indications according to an international Consensus Statement. Patients are followed up for two years. The primary endpoint is the occurrence of SCD and sustained ventricular arrhythmias. The Study was registered at ClinicalTrials.gov (NCT03957824). CONCLUSION: PREVENTION-ACHD is the first prospective study on SCD in ACHD patients. In the light of a growing and aging population of patients with more severe congenital heart defects, more robust clinical evidence on primary prevention of SCD is urgently needed.

Is it always necessary to perform an axillary lymph node dissection after neoadjuvant chemotherapy for breast cancer?

INTRODUCTION: Recent prospective studies support the feasibility of performing sentinel lymph node biopsy following neoadjuvant chemotherapy in initially fine-needle aspiration cytology or ultrasound-guided biopsy-proven node-positive breast cancer. The main aid is to identify preoperative features that help us predict a complete axillary response to neoadjuvant chemotherapy in these patients and thus select the candidates for sentinel lymph node biopsy post-neoadjuvant chemotherapy to avoid unnecessary axillary lymphadenectomy. MATERIALS AND METHODS: A retrospective observational study with a total of 150 patients, biopsy-proven node-positive breast cancer who underwent neoadjuvant chemotherapy followed by breast surgery and axillary lymphadenectomy were included and retrospectively analysed. A predictive model was generated by a multivariate logistic regression analysis for pathological complete response-dependent variable. RESULTS: The response of the primary lesion to neoadjuvant chemotherapy according to post-treatment magnetic resonance imaging, Her2/neu overexpression and a low estrogen receptor expression are associated with a higher rate of nodal pathologically complete response. The multivariant model generated a receiver operating characteristic curve with an area under the curve of 0.79 and a confidence interval of 0.72-0.87 at a 95% level of significance. CONCLUSIONS: This model could be a helpful tool for the surgeon to help in predicting which cases have a higher likelihood of achieving a pathologically complete response and therefore selecting those who may benefit from a post-neoadjuvant chemotherapy sentinel lymph node biopsy and avoid unnecessary axillary lymphadenectomy.

Pattern formation in multiphase models of chemotactic cell aggregation.

We develop a continuum model for the aggregation of cells cultured in a nutrient-rich medium in a culture well. We consider a 2D geometry, representing a vertical slice through the culture well, and assume that the cell layer depth is small compared with the typical lengthscale of the culture well. We adopt a continuum mechanics approach, treating the cells and culture medium as a two-phase mixture. Specifically, the cells and culture medium are treated as fluids. Additionally, the cell phase can generate forces in response to environmental cues, which include the concentration of a chemoattractant that is produced by the cells within the culture medium. The model leads to a system of coupled nonlinear partial differential equations for the volume fraction and velocity of the cell phase, the culture medium pressure and the chemoattractant concentration, which must be solved subject to appropriate boundary and initial conditions. To gain insight into the system, we consider two model reductions, appropriate when the cell layer depth is thin compared to the typical length scale of the culture well: a (simple) 1D and a (more involved) thin-film extensional flow reduction. By investigating the resulting systems of equations analytically and numerically, we identify conditions under which small amplitude perturbations to a homogeneous steady state (corresponding to a spatially uniform cell distribution) can lead to a spatially varying steady state (pattern formation). Our analysis reveals that the simpler 1D reduction has the same qualitative features as the thin-film extensional flow reduction in the linear and weakly nonlinear regimes, motivating the use of the simpler 1D modelling approach when a qualitative understanding of the system is required. However, the thin-film extensional flow reduction may be more appropriate when detailed quantitative agreement between modelling predictions and experimental data is desired. Furthermore, full numerical simulations of the two model reductions in regions of parameter space when the system is not close to marginal stability reveal significant differences in the evolution of the volume fraction and velocity of the cell phase, and chemoattractant concentration.

Kinetic effects regularize the mass-flux singularity at the contact line of a thin evaporating drop.

We consider the transport of vapour caused by the evaporation of a thin, axisymmetric, partially wetting drop into an inert gas. We take kinetic effects into account through a linear constitutive law that states that the mass flux through the drop surface is proportional to the difference between the vapour concentration in equilibrium and that at the interface. Provided that the vapour concentration is finite, our model leads to a finite mass flux in contrast to the contact-line singularity in the mass flux that is observed in more standard models that neglect kinetic effects. We perform a local analysis near the contact line to investigate the way in which kinetic effects regularize the mass-flux singularity at the contact line. An explicit expression is derived for the mass flux through the free surface of the drop. A matched-asymptotic analysis is used to further investigate the regularization of the mass-flux singularity in the physically relevant regime in which the kinetic timescale is much smaller than the diffusive one. We find that the effect of kinetics is limited to an inner region near the contact line, in which kinetic effects enter at leading order and regularize the mass-flux singularity. The inner problem is solved explicitly using the Wiener-Hopf method and a uniformly valid composite expansion is derived for the mass flux in this asymptotic limit.

Acute Effect of Cluster and Traditional Set Configurations on Myokines Associated with Hypertrophy.

This study compared the acute cytokine response, and kinetic and kinematic profile following back squat exercise in resistance-trained men. In a randomized, cross-over design, 10 resistance-trained men (27±4 y, 1.80±0.07 m, 82.8±6.7 kg, 16.3±3.5% fat) performed the back squat exercise using traditional and cluster set configurations. Kinetic and kinematic data were sampled throughout each condition. Venous blood was sampled prior, immediately post, 30 min, 60 min, 24 h, and 48 h post-exercise for plasma interleukin-6 (IL-6) and interleukin-15 (IL-15). Cluster sets allowed for greater mean power (mean difference, 110 W; 90% confidence interval, ±63 W; benefit odds, 41 447:1), driven by higher overall mean velocities (0.053 m∙s-1; 0.039 m∙s-1; 3 105:1) as evidenced by the lack of clear contrasts for mean force. IL-15 increased post-exercise in both conditions, but increased at 24 h (0.13 pg·mL-1; ±0.11 pg·mL-1; 486:1) and 48 h (0.12 pg·mL-1; ±0.10 pg·mL-1; 667:1) in traditional sets only. IL-6 increased similarly in both conditions, post-exercise through 60 min post. Cluster set configurations allow for greater mean power, attributed to higher velocities. Despite a similar response of IL-6, traditional set configuration may provide a greater stimulus for hypertrophy as evidenced by a secondary increase in IL-15.

On a poroviscoelastic model for cell crawling.

In this paper a minimal, one-dimensional, two-phase, viscoelastic, reactive, flow model for a crawling cell is presented. Two-phase models are used with a variety of constitutive assumptions in the literature to model cell motility. We use an upper-convected Maxwell model and demonstrate that even the simplest of two-phase, viscoelastic models displays features relevant to cell motility. We also show care must be exercised in choosing parameters for such models as a poor choice can lead to an ill-posed problem. A stability analysis reveals that the initially stationary, spatially uniform strip of cytoplasm starts to crawl in response to a perturbation which breaks the symmetry of the network volume fraction or network stress. We also demonstrate numerically that there is a steady travelling-wave solution in which the crawling velocity has a bell-shaped dependence on adhesion strength, in agreement with biological observation.

Predicting skin permeability from complex chemical mixtures: incorporation of an expanded QSAR model.

Quantitative structure-activity relationship (QSAR) models have been widely used to study the permeability of chemicals or solutes through skin. Among the various QSAR models, Abraham's linear free-energy relationship (LFER) model is often employed. However, when the experimental conditions are complex, it is not always appropriate to use Abraham's LFER model with a single set of regression coefficients. In this paper, we propose an expanded model in which one set of partial slopes is defined for each experimental condition, where conditions are defined according to solvent: water, synthetic oil, semi-synthetic oil, or soluble oil. This model not only accounts for experimental conditions but also improves the ability to conduct rigorous hypothesis testing. To more adequately evaluate the predictive power of the QSAR model, we modified the usual leave-one-out internal validation strategy to employ a leave-one-solute-out strategy and accordingly adjust the Q(2) LOO statistic. Skin permeability was shown to have the rank order: water > synthetic > semi-synthetic > soluble oil. In addition, fitted relationships between permeability and solute characteristics differ according to solvents. We demonstrated that the expanded model (r(2) = 0.70) improved both the model fit and the predictive power when compared with the simple model (r(2) = 0.21).

Multiple travelling-wave solutions in a minimal model for cell motility.

Two-phase flow models have been used previously to model cell motility. In order to reduce the complexity inherent with describing the many physical processes, we formulate a minimal model. Here we demonstrate that even the simplest 1D, two-phase, poroviscous, reactive flow model displays various types of behaviour relevant to cell crawling. We present stability analyses that show that an asymmetric perturbation is required to cause a spatially uniform, stationary strip of cytoplasm to move, which is relevant to cell polarization. Our numerical simulations identify qualitatively distinct families of travelling-wave solutions that coexist at certain parameter values. Within each family, the crawling speed of the strip has a bell-shaped dependence on the adhesion strength. The model captures the experimentally observed behaviour that cells crawl quickest at intermediate adhesion strengths, when the substrate is neither too sticky nor too slippy.

Selection of appropriate training and validation set chemicals for modelling dermal permeability by U-optimal design.

Quantitative structure-activity relationship (QSAR) models are being used increasingly in skin permeation studies. The main idea of QSAR modelling is to quantify the relationship between biological activities and chemical properties, and thus to predict the activity of chemical solutes. As a key step, the selection of a representative and structurally diverse training set is critical to the prediction power of a QSAR model. Early QSAR models selected training sets in a subjective way and solutes in the training set were relatively homogenous. More recently, statistical methods such as D-optimal design or space-filling design have been applied but such methods are not always ideal. This paper describes a comprehensive procedure to select training sets from a large candidate set of 4534 solutes. A newly proposed 'Baynes' rule', which is a modification of Lipinski's 'rule of five', was used to screen out solutes that were not qualified for the study. U-optimality was used as the selection criterion. A principal component analysis showed that the selected training set was representative of the chemical space. Gas chromatograph amenability was verified. A model built using the training set was shown to have greater predictive power than a model built using a previous dataset [1].

Balancing the risks and benefits of genomic data sharing: genome research participants' perspectives.

BACKGROUND: Technological advancements are rapidly propelling the field of genome research forward, while lawmakers attempt to keep apace with the risks these advances bear. Balancing normative concerns of maximizing data utility and protecting human subjects, whose privacy is at risk due to the identifiability of DNA data, are central to policy decisions. Research on genome research participants making real-time data sharing decisions is limited; yet, these perspectives could provide critical information to ongoing deliberations. METHODS: We conducted a randomized trial of 3 consent types affording varying levels of control over data release decisions. After debriefing participants about the randomization process, we invited them to a follow-up interview to assess their attitudes toward genetic research, privacy and data sharing. RESULTS: Participants were more restrictive in their reported data sharing preferences than in their actual data sharing decisions. They saw both benefits and risks associated with sharing their genomic data, but risks were seen as less concrete or happening in the future, and were largely outweighed by purported benefits. CONCLUSION: Policymakers must respect that participants' assessment of the risks and benefits of data sharing and their privacy-utility determinations, which are associated with their final data release decisions, vary. In order to advance the ethical conduct of genome research, proposed policy changes should carefully consider these stakeholder perspectives.

[Serious complications after pulmonary radiofrequency ablation: report of 2 cases]. / Dos casos de complicaciones graves tras radiofrecuencia pulmonar.

Radiofrequency ablation can be used to treat primary or metastatic pulmonary tumors when surgery is not indicated or involves high risk. Although this technique is less invasive than surgical resection, it is not free of risk for complications and adverse events, especially when it is used in patients with serious respiratory disease in whom comorbidity is common. We report 2 cases of serious complications. One was an intractable air leak that led to death. The other was a large hemothorax that was brought under control in the radiology procedure room. We review the literature on this technique as well as recommendations that contribute to making it as safe as possible.

Acute rheumatic fever in a grown up with repaired tetralogy of Fallot: the role of acquired diseases in patients with congenital heart diseases.

We report a 20 year old patient with repaired Tetralogy of Fallot who presented with acute right side heart failure. The echocardiogram showed severe mitral regurgitation which was not present one year before. Because of mitral insufficiency, pulmonary pressure increased and it was nearby 70% systemic pressure. Pulmonary regurgitation got worse, and the patient came to the hospital in a state of anasarca. After valve replacement, histopathological study of the mitral valve and the aortic valve revealed Aschoff nodules and rheumatic fever was confirmed.

Pheochromocytoma in Eisenmenger's syndrome: a therapeutic challenge.

Surgical treatment of pheochromocytoma is associated with high hemodynamic risk, which is even higher in patients with complex congenital heart disease. Nowadays, patients with cyanotic congenital heart disease are living longer and an increased incidence of pheochromocytoma has been reported in this population. We demonstrate the feasibility and importance of minimally invasive surgery in the management of pheochromocytoma in a 45-year-old woman with complex congenital heart disease and Eisenmenger's syndrome. A successful laparoscopic resection of the tumor was performed in association with multidisciplinary management during hospitalization.