Local Identifiability Analysis, Parameter Subset Selection and Verification for a Minimal Brain PBPK Model.

Physiologically-based pharmacokinetic (PBPK) modeling is important for studying drug delivery in the central nervous system, including determining antibody exposure, predicting chemical concentrations at target locations, and ensuring accurate dosages. The complexity of PBPK models, involving many variables and parameters, requires a consideration of parameter identifiability; i.e., which parameters can be uniquely determined from data for a specified set of concentrations. We introduce the use of a local sensitivity-based parameter subset selection algorithm in the context of a minimal PBPK (mPBPK) model of the brain for antibody therapeutics. This algorithm is augmented by verification techniques, based on response distributions and energy statistics, to provide a systematic and robust technique to determine identifiable parameter subsets in a PBPK model across a specified time domain of interest. The accuracy of our approach is evaluated for three key concentrations in the mPBPK model for plasma, brain interstitial fluid and brain cerebrospinal fluid. The determination of accurate identifiable parameter subsets is important for model reduction and uncertainty quantification for PBPK models.

Application and reduction of a nonlinear hyperelastic wall model capturing ex vivo relationships between fluid pressure, area, and wall thickness in normal and hypertensive murine left pulmonary arteries.

Pulmonary hypertension is a cardiovascular disorder manifested by elevated mean arterial blood pressure (>20 mmHg) together with vessel wall stiffening and thickening due to alterations in collagen, elastin, and smooth muscle cells. Hypoxia-induced (type 3) pulmonary hypertension can be studied in animals exposed to a low oxygen environment for prolonged time periods leading to biomechanical alterations in vessel wall structure. This study introduces a novel approach to formulating a reduced order nonlinear elastic structural wall model for a large pulmonary artery. The model relating blood pressure and area is calibrated using ex vivo measurements of vessel diameter and wall thickness changes, under controlled pressure conditions, in left pulmonary arteries isolated from control and hypertensive mice. A two-layer, hyperelastic, and anisotropic model incorporating residual stresses is formulated using the Holzapfel-Gasser-Ogden model. Complex relations predicting vessel area and wall thickness with increasing blood pressure are derived and calibrated using the data. Sensitivity analysis, parameter estimation, subset selection, and physical plausibility arguments are used to systematically reduce the 16-parameter model to one in which a much smaller subset of identifiable parameters is estimated via solution of an inverse problem. Our final reduced one layer model includes a single set of three elastic moduli. Estimated ranges of these parameters demonstrate that nonlinear stiffening is dominated by elastin in the control animals and by collagen in the hypertensive animals. The pressure-area relation developed in this novel manner has potential impact on one-dimensional fluids network models of vessel wall remodeling in the presence of cardiovascular disease.

Bulk and mosaic deletions of Egfr reveal regionally defined gliogenesis in the developing mouse forebrain.

The epidermal growth factor receptor (EGFR) plays a role in cell proliferation and differentiation during healthy development and tumor growth; however, its requirement for brain development remains unclear. Here we used a conditional mouse allele for Egfr to examine its contributions to perinatal forebrain development at the tissue level. Subtractive bulk ventral and dorsal forebrain deletions of Egfr uncovered significant and permanent decreases in oligodendrogenesis and myelination in the cortex and corpus callosum. Additionally, an increase in astrogenesis or reactive astrocytes in effected regions was evident in response to cortical scarring. Sparse deletion using mosaic analysis with double markers (MADM) surprisingly revealed a regional requirement for EGFR in rostrodorsal, but not ventrocaudal glial lineages including both astrocytes and oligodendrocytes. The EGFR-independent ventral glial progenitors may compensate for the missing EGFR-dependent dorsal glia in the bulk Egfr-deleted forebrain, potentially exposing a regenerative population of gliogenic progenitors in the mouse forebrain.

Unsupervised learning methods for efficient geographic clustering and identification of disease disparities with applications to county-level colorectal cancer incidence in California.

Many public health policymaking questions involve data subsets representing application-specific attributes and geographic location. We develop and evaluate standard and tailored techniques for clustering via unsupervised learning (UL) algorithms on such amalgamated (dual-domain) data sets. The aim of the associated algorithms is to identify geographically efficient clusters that also maximize the number of statistically significant differences in disease incidence and demographic variables across top clusters. Two standard UL approaches, k means with k++ initialization (k++) and the standard self-organizing map (SSOM), are considered along with a new, tailored version of the SOM (TSOM). The TSOM algorithm involves optimization of a customized objective function with terms promoting individual geographic cluster cohesion while also maximizing the number of differences across clusters, and two hyper-parameters controlling the relative weighting of geographic and attribute subspaces in a non-Euclidean distance measure within the clustering problem. The performance of these three techniques (k++, SSOM, TSOM) is compared and evaluated in the context of a data set for colorectal cancer incidence in the state of California, at the level of individual counties. Clusters are visualized via chloropleth maps and ordered graphs are also used to illustrate disparities in disease incidence among four identity groups. While all three approaches performed well, the TSOM identified the largest number of disease and demographic disparities while also yielding more geographically efficient top clusters. Techniques presented in this study are relevant to applications including the delivery of health care resources and identifying disparities among identity groups, and to questions involving coordination between county- and state-level policymakers.

Modeling and Parameter Subset Selection for Fibrin Polymerization Kinetics with Applications to Wound Healing.

During the hemostatic phase of wound healing, vascular injury leads to endothelial cell damage, initiation of a coagulation cascade involving platelets, and formation of a fibrin-rich clot. As this cascade culminates, activation of the protease thrombin occurs and soluble fibrinogen is converted into an insoluble polymerized fibrin network. Fibrin polymerization is critical for bleeding cessation and subsequent stages of wound healing. We develop a cooperative enzyme kinetics model for in vitro fibrin matrix polymerization capturing dynamic interactions among fibrinogen, thrombin, fibrin, and intermediate complexes. A tailored parameter subset selection technique is also developed to evaluate parameter identifiability for a representative data curve for fibrin accumulation in a short-duration in vitro polymerization experiment. Our approach is based on systematic analysis of eigenvalues and eigenvectors of the classical information matrix for simulations of accumulating fibrin matrix via optimization based on a least squares objective function. Results demonstrate robustness of our approach in that a significant reduction in objective function cost is achieved relative to a more ad hoc curve-fitting procedure. Capabilities of this approach to integrate non-overlapping subsets of the data to enhance the evaluation of parameter identifiability are also demonstrated. Unidentifiable reaction rate parameters are screened to determine whether individual reactions can be eliminated from the overall system while preserving the low objective cost. These findings demonstrate the high degree of information within a single fibrin accumulation curve, and a tailored model and parameter subset selection approach for improving optimization and reducing model complexity in the context of polymerization experiments.

Clonal Analysis of Gliogenesis in the Cerebral Cortex Reveals Stochastic Expansion of Glia and Cell Autonomous Responses to Egfr Dosage.

Development of the nervous system undergoes important transitions, including one from neurogenesis to gliogenesis which occurs late during embryonic gestation. Here we report on clonal analysis of gliogenesis in mice using Mosaic Analysis with Double Markers (MADM) with quantitative and computational methods. Results reveal that developmental gliogenesis in the cerebral cortex occurs in a fraction of earlier neurogenic clones, accelerating around E16.5, and giving rise to both astrocytes and oligodendrocytes. Moreover, MADM-based genetic deletion of the epidermal growth factor receptor (Egfr) in gliogenic clones revealed that Egfr is cell autonomously required for gliogenesis in the mouse dorsolateral cortices. A broad range in the proliferation capacity, symmetry of clones, and competitive advantage of MADM cells was evident in clones that contained one cellular lineage with double dosage of Egfr relative to their environment, while their sibling Egfr-null cells failed to generate glia. Remarkably, the total numbers of glia in MADM clones balance out regardless of significant alterations in clonal symmetries. The variability in glial clones shows stochastic patterns that we define mathematically, which are different from the deterministic patterns in neuronal clones. This study sets a foundation for studying the biological significance of stochastic and deterministic clonal principles underlying tissue development, and identifying mechanisms that differentiate between neurogenesis and gliogenesis.

A computational reaction-diffusion model for biosynthesis and linking of cartilage extracellular matrix in cell-seeded scaffolds with varying porosity.

Cartilage tissue engineering is commonly initiated by seeding cells in porous materials such as hydrogels or scaffolds. Under optimal conditions, the resulting engineered construct has the potential to fill regions where native cartilage has degraded or eroded. Within a cell-seeded scaffold supplied by nutrients and growth factors, extracellular matrix accumulation should occur concurrently with scaffold degradation. At present, the interplay between cell-mediated synthesis and linking of matrix constituents and the evolving scaffold properties is not well understood. We develop a computational model of extracellular matrix accumulation in a cell-seeded scaffold based on a continuum reaction-diffusion system with inhomogeneous inclusions representing individual cells. The effects of porosity on engineered tissue outcomes is accounted for via the use of mixture variables capturing the spatiotemporal dynamics of both bound and unbound system constituents. The unbound constituents are the nutrients and unlinked extracellular matrix, while the bound constituents are the scaffold and the linked extracellular matrix. The linking model delineates binding of matrix constituents to either existing bound extracellular matrix or to scaffold. Results on a representative domain exhibit bound matrix trapping (vs spreading) around cells in scaffolds with lower (vs higher) initial porosity, similar to experimental results obtained by Erickson et al. (Osteoarthr Cartil 17:1639-1648, 2009). Significant alterations in the spatiotemporal accumulation of bound matrix are observed when, among the set of all model parameters, only the initial scaffold porosity is varied. The model presented herein proposes a methodology to investigate coupling between cell-mediated biosynthesis and linking of extracellular matrix in porous, cell-seeded scaffolds that has the potential to aid in the design of optimal tissue-engineered cartilage constructs.

Rituximab/IVIG in pemphigus - a 10-year study with a long follow-up.

BACKGROUND: Pemphigus is a chronic potentially life-threatening autoimmune blistering disease affecting the skin and/or mucous membranes. Rituximab is being increasingly used and found efficacious in the treatment of pemphigus. OBJECTIVE: To present the Middle-Eastern experience with the use of rituximab in pemphigus. METHODS: A retrospective analysis of patient files was conducted which revealed 23 patients of pemphigus who were treated with rituximab (either alone or with IVIG) in the dermatology department of a tertiary care hospital from July 2004 to December 2014. RESULTS: The mean time to disease control was 8 weeks (median 5 weeks and range 2-30 weeks). 90.9% attained early study end point with the first cycle of rituximab. The remaining 9.1% needed an additional course of rituximab + IVIG to attain disease control. 90.5% of our patients attained complete remission during the study period. The average time to attain complete remission on minimal treatment was 25.4 weeks and partial remission on minimal treatment was attained after a mean period of 18.3 weeks. Rituximab was well tolerated by our patients and the rate of adverse-effects in our cohort was comparable to the previous reports. CONCLUSIONS: Rituximab is an effective and safe treatment for pemphigus and should be considered earlier in the algorithm of pemphigus treatment.

Hemodynamic assessment of pulmonary hypertension in mice: a model-based analysis of the disease mechanism.

This study uses a one-dimensional fluid dynamics arterial network model to infer changes in hemodynamic quantities associated with pulmonary hypertension in mice. Data for this study include blood flow and pressure measurements from the main pulmonary artery for 7 control mice with normal pulmonary function and 5 mice with hypoxia-induced pulmonary hypertension. Arterial dimensions for a 21-vessel network are extracted from micro-CT images of lungs from a representative control and hypertensive mouse. Each vessel is represented by its length and radius. Fluid dynamic computations are done assuming that the flow is Newtonian, viscous, laminar, and has no swirl. The system of equations is closed by a constitutive equation relating pressure and area, using a linear model derived from stress-strain deformation in the circumferential direction assuming that the arterial walls are thin, and also an empirical nonlinear model. For each dataset, an inflow waveform is extracted from the data, and nominal parameters specifying the outflow boundary conditions are computed from mean values and characteristic timescales extracted from the data. The model is calibrated for each mouse by estimating parameters that minimize the least squares error between measured and computed waveforms. Optimized parameters are compared across the control and the hypertensive groups to characterize vascular remodeling with disease. Results show that pulmonary hypertension is associated with stiffer and less compliant proximal and distal vasculature with augmented wave reflections, and that elastic nonlinearities are insignificant in the hypertensive animal.

Characteristic impedance: frequency or time domain approach?

OBJECTIVE: Characteristic impedance (Zc) is an important component in the theory of hemodynamics. It is a commonly used metric of proximal arterial stiffness and pulse wave velocity. Calculated using simultaneously measured dynamic pressure and flow data, estimates of characteristic impedance can be obtained using methods based on frequency or time domain analysis. Applications of these methods under different physiological and pathological conditions in species with different body sizes and heart rates show that the two approaches do not always agree. In this study, we have investigated the discrepancies between frequency and time domain estimates accounting for uncertainties associated with experimental processes and physiological conditions. APPROACH: We have used published data measured in different species including humans, dogs, and mice to investigate: (a) the effects of time delay and signal noise in the pressure-flow data, (b) uncertainties about the blood flow conditions, (c) periodicity of the cardiac cycle versus the breathing cycle, on the frequency and time domain estimates of Zc, and (d) if discrepancies observed under different hemodynamic conditions can be eliminated. Main results and Significance: We have shown that the frequency and time domain estimates are not equally sensitive to certain characteristics of hemodynamic signals including phase lag between pressure and flow, signal to noise ratio and the end of systole retrograde flow. The discrepancies between two types of estimates are inherent due to their intrinsically different mathematical expressions and therefore it is impossible to define a criterion to resolve such discrepancies. Considering the interpretation and role of Zc as an important hemodynamic parameter, we suggest that the frequency and time domain estimates should be further assessed as two different hemodynamic parameters in a future study.

Hidradenitis Suppurativa in Down Syndrome: A Case Series.

BACKGROUND/OBJECTIVES: Many dermatologic and systemic diseases have been reported in association with hidradenitis suppurativa, but its association with Down syndrome is rarely mentioned in the literature. The objective of the current study was to assess the frequency of hidradenitis suppurativa in patients with Down syndrome who visited our clinic over 4 years. METHODS: We recorded the presenting complaints and dermatologic problems of patients with Down syndrome who visited our clinic from January 2011 to December 2014. Medical photographs were taken. Patients with hidradenitis suppurativa were assessed according to severity and treated with topical and systemic medications. RESULTS: Twenty-nine new patients with Down syndrome visited our clinic during this period. Eleven had hidradenitis suppurativa. Disease severity included Hurley stages I and II. CONCLUSION: The presence of hidradenitis suppurativa in 38% of patients with Down syndrome is far higher than would be expected by chance alone.

Use of hybrid discrete cellular models for identification of macroscopic nutrient loss in reaction-diffusion models of tissues.

Macroscopic models accounting for cellular effects in natural or engineered tissues may involve unknown constitutive terms that are highly dependent on interactions at the scale of individual cells. Hybrid discrete models, which represent cells individually, were used to develop and apply techniques for modeling diffusive nutrient transport and cellular uptake to identify a nonlinear nutrient loss term in a macroscopic reaction-diffusion model of the system. Flexible and robust numerical methods were used, based on discontinuous Galerkin finite elements in space and a Crank-Nicolson temporal discretization. Scales were bridged via averaging operations over a complete set of subdomains yielding data for identification of a macroscopic nutrient loss term that was accurately captured via a fifth-order polynomial. Accuracy of the identified macroscopic model was demonstrated by direct, quantitative comparisons of the tissue and cellular scale models in terms of three error norms computed on a mesoscale mesh.

Radiation- and chemotherapy-induced permanent alopecia: case series.

BACKGROUND: Radiation- and chemotherapy-induced alopecia is mostly temporary. However, permanent scalp alopecia is reported, albeit infrequently. OBJECTIVE: The objective of this observational case series was to determine the kind and doses of chemotherapeutic agents and radiation in inducing permanent alopecia of the scalp. METHODS AND RESULTS: Eleven patients referred to our department over a period of 3 years for permanent alopecia after chemotherapy/radiotherapy or combination therapy were included. A detailed medical and therapeutic history was obtained from each patient and from medical records. Photography was done, and the scalp biopsies were taken. Patients were divided into three groups according to the type of therapy. The first group received conditioning chemotherapy prior to bone marrow transplantation. The second group had radiation for brain tumors, and the third group received both. CONCLUSION: A comprehensive multicenter and multidisciplinary study is required to determine the definite causative agents, doses, and other cofactors that induce permanent alopecia following chemotherapy/radiotherapy, as well as the means to avoid this distressing outcome in surviving patients.

Lupus erythematosus-associated primary and secondary anetoderma.

BACKGROUND: Anetoderma (focal loss of dermal elastic tissue) can either be primary, which is an idiopathic occurrence of anetoderma in normal areas of the skin, or secondary, which is preceded by an inflammatory dermatosis in the same location. OBJECTIVE: Sporadic reports of lupus erythematosus-associated anetoderma have been described in the literature. All reported cases were positive for antiphospholipid antibodies. We present a patient with primary and secondary anetoderma with chronic lupus dermatitis and negative antiphospholipid antibodies. METHOD AND RESULTS: A middle-aged woman presented with a soft nodule with a wrinkled surface on her left arm and an erythematous atrophic plaque with a nodular surface on the chest. Skin biopsy from the left arm showed epidermal atrophy without inflammatory changes. Histologic findings of the lesion on the chest were consistent with chronic lupus dermatitis and secondary anetoderma. Laboratory investigations showed positive antinuclear antibody anti-double-stranded deoxyribonucleic acid (DNA) antibody but negative antiphospholipid antibodies. CONCLUSION: Primary and secondary anetodermas may occur in patients of lupus dermatitis without positive antiphospholipid antibodies.

A phenomenological mixture model for biosynthesis and linking of cartilage extracellular matrix in scaffolds seeded with chondrocytes.

A phenomenological mixture model is presented for interactions between biosynthesis of extracellular matrix (ECM) constituents and ECM linking in a scaffold seeded with chondrocytes. A system of three ordinary differential equations for average apparent densities of unlinked ECM, linked ECM and scaffold is developed along with associated initial conditions for scaffold material properties. Equations for unlinked ECM synthesis and ECM linking include an inhibitory mechanism where associated rates decrease as unlinked ECM concentration in the interstitial fluid increases. Linking rates are proposed to depend on average porosity in the evolving tissue construct. The resulting initial value problem contains nine independent parameters that account for scaffold biomaterial properties and interacting mechanisms in the engineered system. Effects of parameter variations on model variables are analyzed relative to a baseline case with emphasis on the evolution of solid phase apparent density, which is often correlated with the compressive elastic modulus of the tissue construct. The new model provides an additional quantitative framework for assessing and optimizing the design of engineered cell-scaffold systems and guiding strategies for articular cartilage tissue engineering.

Linear and nonlinear viscoelastic modeling of aorta and carotid pressure-area dynamics under in vivo and ex vivo conditions.

A better understanding of the biomechanical properties of the arterial wall provides important insight into arterial vascular biology under normal (healthy) and pathological conditions. This insight has potential to improve tracking of disease progression and to aid in vascular graft design and implementation. In this study, we use linear and nonlinear viscoelastic models to predict biomechanical properties of the thoracic descending aorta and the carotid artery under ex vivo and in vivo conditions in ovine and human arteries. Models analyzed include a four-parameter (linear) Kelvin viscoelastic model and two five-parameter nonlinear viscoelastic models (an arctangent and a sigmoid model) that relate changes in arterial blood pressure to the vessel cross-sectional area (via estimation of vessel strain). These models were developed using the framework of Quasilinear Viscoelasticity (QLV) theory and were validated using measurements from the thoracic descending aorta and the carotid artery obtained from human and ovine arteries. In vivo measurements were obtained from 10 ovine aortas and 10 human carotid arteries. Ex vivo measurements (from both locations) were made in 11 male Merino sheep. Biomechanical properties were obtained through constrained estimation of model parameters. To further investigate the parameter estimates, we computed standard errors and confidence intervals and we used analysis of variance to compare results within and between groups. Overall, our results indicate that optimal model selection depends on the artery type. Results showed that for the thoracic descending aorta (under both experimental conditions), the best predictions were obtained with the nonlinear sigmoid model, while under healthy physiological pressure loading the carotid arteries nonlinear stiffening with increasing pressure is negligible, and consequently, the linear (Kelvin) viscoelastic model better describes the pressure-area dynamics in this vessel. Results comparing biomechanical properties show that the Kelvin and sigmoid models were able to predict the zero-pressure vessel radius; that under ex vivo conditions vessels are more rigid, and comparatively, that the carotid artery is stiffer than the thoracic descending aorta; and that the viscoelastic gain and relaxation parameters do not differ significantly between vessels or experimental conditions. In conclusion, our study demonstrates that the proposed models can predict pressure-area dynamics and that model parameters can be extracted for further interpretation of biomechanical properties.

An axisymmetric boundary element model for determination of articular cartilage pericellular matrix properties in situ via inverse analysis of chondron deformation.

The pericellular matrix (PCM) is the narrow tissue region surrounding all chondrocytes in articular cartilage and, together, the chondrocyte(s) and surrounding PCM have been termed the chondron. Previous theoretical and experimental studies suggest that the structure and properties of the PCM significantly influence the biomechanical environment at the microscopic scale of the chondrocytes within cartilage. In the present study, an axisymmetric boundary element method (BEM) was developed for linear elastic domains with internal interfaces. The new BEM was employed in a multiscale continuum model to determine linear elastic properties of the PCM in situ, via inverse analysis of previously reported experimental data for the three-dimensional morphological changes of chondrons within a cartilage explant in equilibrium unconfined compression (Choi, et al., 2007, "Zonal Changes in the Three-Dimensional Morphology of the Chondron Under Compression: The Relationship Among Cellular, Pericellular, and Extracellular Deformation in Articular Cartilage," J. Biomech., 40, pp. 2596-2603). The microscale geometry of the chondron (cell and PCM) within the cartilage extracellular matrix (ECM) was represented as a three-zone equilibrated biphasic region comprised of an ellipsoidal chondrocyte with encapsulating PCM that was embedded within a spherical ECM subjected to boundary conditions for unconfined compression at its outer boundary. Accuracy of the three-zone BEM model was evaluated and compared with analytical finite element solutions. The model was then integrated with a nonlinear optimization technique (Nelder-Mead) to determine PCM elastic properties within the cartilage explant by solving an inverse problem associated with the in situ experimental data for chondron deformation. Depending on the assumed material properties of the ECM and the choice of cost function in the optimization, estimates of the PCM Young's modulus ranged from approximately 24 kPa to 59 kPa, consistent with previous measurements of PCM properties on extracted chondrons using micropipette aspiration. Taken together with previous experimental and theoretical studies of cell-matrix interactions in cartilage, these findings suggest an important role for the PCM in modulating the mechanical environment of the chondrocyte.

Acquired cutis laxa type II (Marshall syndrome) in an 18-month-old child: a case report.

Cutis laxa is a rare disorder resulting from degradation and clumping of elastic fibers in dermis. Type II acquired cutis laxa, shows only cutaneous changes without any systemic involvement. We describe an infant with acquired cutis laxa type II following a generalized inflammatory dermatitis.