Avalanches in the lung: A statistical mechanical model

We study a statistical mechanical model for the dynamics of lung inflation which incorporates recent experimental observations on the opening of individual airways by a cascade or avalanche mechanism. Using an exact mapping of the avalanche problem onto percolation on a Cayley tree, we analytically derive the exponents describing the size distribution of the first avalanches and test the analytical solution by numerical simulations. We find that the tree-like structure of the airways together with the simplest assumptions concerning opening threshold pressures of each airway, is sufficient to explain the existence of power-law distributions observed experimentally.Comment: 4 pages, Figures avaliable by mail from [email protected], REVTE

A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis.

In scleroderma (systemic sclerosis, SSc), persistent activation of myofibroblast leads to severe skin and organ fibrosis resistant to therapy. Increased mechanical stiffness in the involved fibrotic tissues is a hallmark clinical feature and a cause of disabling symptoms. Myocardin Related Transcription Factor-A (MRTF-A) is a transcriptional co-activator that is sequestered in the cytoplasm and translocates to the nucleus under mechanical stress or growth factor stimulation. Our objective was to determine if MRTF-A is activated in the disease microenvironment to produce more extracellular matrix in progressive SSc. Immunohistochemistry studies demonstrate that nuclear translocation of MRTF-A in scleroderma tissues occurs in keratinocytes, endothelial cells, infiltrating inflammatory cells, and dermal fibroblasts, consistent with enhanced signaling in multiple cell lineages exposed to the stiff extracellular matrix. Inhibition of MRTF-A nuclear translocation or knockdown of MRTF-A synthesis abolishes the SSc myofibroblast enhanced basal contractility and synthesis of type I collagen and inhibits the matricellular profibrotic protein, connective tissue growth factor (CCN2/CTGF). In MRTF-A null mice, basal skin and lung stiffness was abnormally reduced and associated with altered fibrillar collagen. MRTF-A has a role in SSc fibrosis acting as a central regulator linking mechanical cues to adverse remodeling of the extracellular matrix

The natural history of EGFR and EGFRvIII in glioblastoma patients

BACKGROUND: The epidermal growth factor receptor (EGFR) is over expressed in approximately 50–60% of glioblastoma (GBM) tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24–67% of cases. This study was designed to address whether over expressed EGFR or EGFRvIII is an actual independent prognostic indicator of overall survival in a uniform body of patients in whom gross total surgical resection (GTR; ≥ 95% resection) was not attempted or achieved. METHODS: Biopsed or partially/subtotally resected GBM patients (N = 54) underwent adjuvant conformal radiation and chemotherapy. Their EGFR and EGFRvIII status was determined by immunohistochemistry and Kaplan-Meier estimates of overall survival were obtained. RESULTS: In our study of GBM patients with less than GTR, 42.6% (n = 23) failed to express EGFR, 25.9% (n = 14) had over expression of the wild-type EGFR only and 31.5 % (n = 17) expressed the EGFRvIII. Patients within groups expressing the EGFR, EGFRvIII, or lacking EGFR expression did not differ in age, Karnofsky Performance Scale (KPS) score, extent of tumor resection. They all had received postoperative radiation and chemotherapy. The median overall survival times for patients with tumors having no EGFR expression, over expressed EGFR only, or EGFRvIII were 12.3 (95% CI, 8.04–16.56), 11.03 (95% CI, 10.18–11.89) and 14.07 (95% CI, 7.39–20.74) months, respectively, log rank test p > 0.05). Patients with tumors that over expressed the EGFR and EGFRvIII were more likely to present with ependymal spread, 21.4% and 35.3% respectively, compared to those patients whose GBM failed to express either marker, 13.0%, although the difference was not statistically significant. There was no significant difference in multifocal disease or gliomatosis cerebri among EGFR expression groups. CONCLUSION: The over expressed wild-type EGFR and EGFRvIII are not independent predictors of median overall survival in the cohort of patients who did not undergo extensive tumor resection

Innate immune functions of microglia isolated from human glioma patients

BACKGROUND: Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM). METHODS: GIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells. RESULTS: GIM expressed significant levels of Toll-like receptors (TLRs), however they do not secrete any of the cytokines (IL-1β, IL-6, TNF-α) critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL) was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia. CONCLUSION: We show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas

The Potential for Ontogenetic Vertical Migration by Larvae of Bathyal Echinoderms

Planktotrophy is a relatively common developmental mode among bathyal and abyssal echinoderms, but the sources of food used by deep-sea planktotrophic larvae remain generally unknown. Very few deep-sea echinoderm larvae have been collected in plankton samples, so we do not know whether larvae migrate to the euphotic zone to feed or if they rely on bacteria or detritus at greater depths. We approached this question indirectly by investigating whether larvae of bathyal echinoids can tolerate the temperatures they would encounter in the euphotic zone and whether they possess sufficient energy stores to migrate to the euphotic zone without feeding. Twenty-four hour survival at 20 and 24 °C was always much lower than survival at colder temperatures, but there were species-specific and stage-specific differences in temperature tolerances. A numerical model of the energy consumed by migrating larvae predicted that larvae should be able to reach adequate phytoplankton concentrations before exhausting parental reserves, unless they swim very slowly and have very high metabolic rates. These results suggest that long vertical migrations are more likely to be limited by physiological tolerances than by energy stores

Interplay between geometry and flow distribution in an airway tree

Uniform fluid flow distribution in a symmetric volume can be realized through a symmetric branched tree. It is shown here, however, that the flow partitioning can be highly sensitive to deviations from exact symmetry if inertial effects are present. This is found by direct numerical simulation of the Navier-Stokes equations in a 3D tree geometry. The flow asymmetry is quantified and found to depend on the Reynolds number. Moreover, for a given Reynolds number, we show that the flow distribution depends on the aspect ratio of the branching elements as well as their angular arrangement. Our results indicate that physiological variability should be severely restricted in order to ensure uniform fluid distribution in a tree. This study suggests that any non-uniformity in the air flow distribution in human lungs should be influenced by the respiratory conditions, rest or hard exercise

On the behaviour of lung tissue under tension and compression

Lung injuries are common among those who suffer an impact or trauma. The relative severity of injuries up to physical tearing of tissue have been documented in clinical studies. However, the specific details of energy required to cause visible damage to the lung parenchyma are lacking. Furthermore, the limitations of lung tissue under simple mechanical loading are also not well documented. This study aimed to collect mechanical test data from freshly excised lung, obtained from both Sprague-Dawley rats and New Zealand White rabbits. Compression and tension tests were conducted at three different strain rates: 0.25, 2.5 and 25 min−1. This study aimed to characterise the quasi-static behaviour of the bulk tissue prior to extending to higher rates. A nonlinear viscoelastic analytical model was applied to the data to describe their behaviour. Results exhibited asymmetry in terms of differences between tension and compression. The rabbit tissue also appeared to exhibit stronger viscous behaviour than the rat tissue. As a narrow strain rate band is explored here, no conclusions are being drawn currently regarding the rate sensitivity of rat tissue. However, this study does highlight both the clear differences between the two tissue types and the important role that composition and microstructure can play in mechanical response

Avalanches in Breakdown and Fracture Processes

We investigate the breakdown of disordered networks under the action of an increasing external---mechanical or electrical---force. We perform a mean-field analysis and estimate scaling exponents for the approach to the instability. By simulating two-dimensional models of electric breakdown and fracture we observe that the breakdown is preceded by avalanche events. The avalanches can be described by scaling laws, and the estimated values of the exponents are consistent with those found in mean-field theory. The breakdown point is characterized by a discontinuity in the macroscopic properties of the material, such as conductivity or elasticity, indicative of a first order transition. The scaling laws suggest an analogy with the behavior expected in spinodal nucleation.Comment: 15 pages, 12 figures, submitted to Phys. Rev. E, corrected typo in authors name, no changes to the pape

A comprehensive computational model of sound transmission through the porcine lung

A comprehensive computational simulation model of sound transmission through the porcine lung is introduced and experimentally evaluated. This subject-specific model utilizes parenchymal and major airway geometry derived from x-ray CT images. The lung parenchyma is modeled as a poroviscoelastic material using Biot theory. A finite element (FE) mesh of the lung that includes airway detail is created and used in COMSOL FE software to simulate the vibroacoustic response of the lung to sound input at the trachea. The FE simulation model is validated by comparing simulation results to experimental measurements using scanning laser Doppler vibrometry on the surface of an excised, preserved lung. The FE model can also be used to calculate and visualize vibroacoustic pressure and motion inside the lung and its airways caused by the acoustic input. The effect of diffuse lung fibrosis and of a local tumor on the lung acoustic response is simulated and visualized using the FE model. In the future, this type of visualization can be compared and matched with experimentally obtained elastographic images to better quantify regional lung material properties to noninvasively diagnose and stage disease and response to treatment

Volume Distributions of Avalanches in Lung Inflation: a statistical mechanical approach

To study the dynamics of lung inflation, we introduce a statistical mechanical model that incorporates experimental observations that, during lung inflation from low volumes, (i) each individual airway segment opens when the external inflation pressure reaches a critical opening threshold corresponding to that segment and (ii) airway opening in the lung occurs in cascades or by avalanches. The model includes realistic asymmetry of the bronchial tree, tissue elasticity, and airway and alveolar dimensions. We perform numerical simulations of lung inflation to study the effects of these attributes on the volume distributions of both the first and all avalanches for three different distributions of critical opening threshold pressures: (a) a generation-independent, (b) a slightly generation-dependent, and (c) a highly generation-dependent distribution. For both the first and all avalanches we find that the volume distribution is a power law, except for the highly generation-dependent threshold distribution. Asymmetry and realistic airway and alveolar dimensions slightly modify the scaling region, but retain a power-law behavior as long as the distribution of threshold pressures is generation independent or slightly generation dependent. Also, for such a distribution of threshold pressures, the scaling exponent of the most realistic model (the asymmetric tree with realistic airway and alveolar dimensions and tissue elasticity) is 2, which is the value obtained both analytically using percolation theory and from simulations on a Cayley tree. Thus the power-law behavior and the scaling exponents are a consequence of finite-size effects and a distribution of threshold pressures that is generation independent or slightly generation dependent. We also predict the pressure-volume relationship of the model, which is easily and noninvasively accessible in clinical settings. The results of the avalanche size distributions and pressure-volume curves support the notion that at low lung volumes, the distribution of the critical opening threshold pressures in the normal lung is most likely wide with negligible generational dependence