Lung injury after cigarette smoking is particle related

The specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking are yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure to and retention of particles produced during smoking and 2) the biological effects of particles associated with cigarette smoking share a single mechanism of injury with all particles. Smoking one cigarette exposes the human respiratory tract to between 15,000 and 40,000 μg particulate matter; this is a carbonaceous product of an incomplete combustion. There are numerous human exposures to other particles, and these vary widely in composition, absolute magnitude, and size of the particle. Individuals exposed to all these particles share a common clinical presentation with a loss of pulmonary function, increased bronchial hyperresponsiveness, pathologic changes of emphysema and fibrosis, and comorbidities, including cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and cancers. Mechanistically, all particle exposures produce an oxidative stress, which is associated with a series of reactions, including an activation of kinase cascades and transcription factors, release of inflammatory mediators, and apoptosis. If disease associated with cigarette smoking is recognized to be particle related, then certain aspects of the clinical presentation can be predicted; this would include worsening of pulmonary function and progression of pathological changes and comorbidity (eg, emphysema and carcinogenesis) after smoking cessation since the particle is retained in the lung and the exposure continues

Emerging Risk Profile of Lung Cancer Therapy: Diffuse Alveolar Hemorrhage from Osimertinib

Osimertinib is an oral epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used primarily in the treatment of metastatic non-small cell lung cancer. It is usually well tolerated with less than 5% of patients developing significant pulmonary toxicity from the medication, typically within the first few months after initiation. Previously reported pulmonary adverse reactions include pneumonitis (nonspecific interstitial pneumonia or other forms of acute interstitial process), fleeting asymptomatic infiltrates on imaging, and eosinophilic pneumonia. We present an interesting case of a 65-year-old female with recurrent metastatic adenocarcinoma of the lung, treated with Osimertinib for 4 months, who developed a previously unreported toxicity of diffuse alveolar hemorrhage (DAH) requiring mechanical ventilatory support

Birkman Screening and the Covariance of the Fluid Velocity of Fixed Beds

The phenomenon of Brinkman screening, whereby the fluid velocity disturbance produced by each particle in a fixed bed is attenuated by the forces that the fluid exerts on surrounding particles, plays a crucial role in limiting the range of velocity correlations in porous media and fixed beds. Koch and Brady [J. Fluid Mech. 154, 399 (1985)] showed theoretically that Brinkman screening leads to a finite hydrodynamic diffusion coefficient for fluid phase tracers in dilute fixed beds. In this Letter, we present the results of two simulation techniques (lattice-Boltzmann method and a multipole method) confirming the screening of the fluid velocity covariance that underlies the Koch and Brady theory

Identification and Modeling the Impact of Marine Shale Bedrock on Groundwater and Stream Salinity: Upper Colorado River Basin

Recent studies have shown that groundwater is a major contributor to stream salinity in the Upper Colorado River Basin. The primary salt sources are the marine shales and shale residuum that underlie the soils of much of the basin. A field site in the Price River Basin, a tributary to the Green and Colorado Rivers, was selected to study the physical and chemical factors that control the interactions between groundwater and these shales. Preliminary data were available at the site as a result of a Bureau of Reclamation study conducted by CH2M Hill. On the basis of the CH2M Hill study and the additional data collected during this study groundwater flow paths, salt transport and weathering processes were identified. Results show that the groundwater evolved from a calcium-bicarbonate water to a sodium-sulfate water with depth and distance along the flow paths. Geochemical equilibrium modeling and mass balance computations were performed using the USGS models PHREEQE and BALANCE. A preliminary saturated-unsaturated two-dimensional flow model (UNSAT) was implemented along the identified groundwater flow path. Once a satisfactory flow calibration was achieved, a solute transport model was then implemented to examine the relative importance of advective, dispersive and diffusive mixing processes along the flow profile. Preliminary management runs were made to study the effect of possible changes in land use practices. Results of these hypothetical cases suggest that water conservation methods (improved irrigation efficiency, canal lining and retiring irrigated land) will reduce return flow salt loads over the short run (about 50 years), when the transport of salts by displacement is most important. However, these salinity control alternatives are much less effective in the long range (\u3e 50 years) because the diffuse salt loading from underlying marine shales is unaffected by groundwater flow rates in the alluvium. Although additional field data must be collected for verification the proposed model is a realistic first step towards a quantitative physically based approach to land use-salinity control issues

Steady Stokes flow with long-range correlations, fractal Fourier spectrum, and anomalous transport

We consider viscous two-dimensional steady flows of incompressible fluids past doubly periodic arrays of solid obstacles. In a class of such flows, the autocorrelations for the Lagrangian observables decay in accordance with the power law, and the Fourier spectrum is neither discrete nor absolutely continuous. We demonstrate that spreading of the droplet of tracers in such flows is anomalously fast. Since the flow is equivalent to the integrable Hamiltonian system with 1 degree of freedom, this provides an example of integrable dynamics with long-range correlations, fractal power spectrum, and anomalous transport properties.Comment: 4 pages, 4 figures, published in Physical Review Letter

Far-field approximation for hydrodynamic interactions in parallel-wall geometry

A complete analysis is presented for the far-field creeping flow produced by a multipolar force distribution in a fluid confined between two parallel planar walls. We show that at distances larger than several wall separations the flow field assumes the Hele-Shaw form, i.e., it is parallel to the walls and varies quadratically in the transverse direction. The associated pressure field is a two-dimensional harmonic function that is characterized by the same multipolar number m as the original force multipole. Using these results we derive asymptotic expressions for the Green's matrix that represents Stokes flow in the wall-bounded fluid in terms of a multipolar spherical basis. This Green's matrix plays a central role in our recently proposed algorithm [Physica A xx, {\bf xxx} (2005)] for evaluating many-body hydrodynamic interactions in a suspension of spherical particles in the parallel-wall geometry. Implementation of our asymptotic expressions in this algorithm increases its efficiency substantially because the numerically expensive evaluation of the exact matrix elements is needed only for the neighboring particles. Our asymptotic analysis will also be useful in developing hydrodynamic algorithms for wall-bounded periodic systems and implementing acceleration methods by using corresponding results for the two-dimensional scalar potential.Comment: 28 pages 5 figure

Many-particle hydrodynamic interactions in parallel-wall geometry: Cartesian-representation method

This paper describes the results of our theoretical and numerical studies of hydrodynamic interactions in a suspension of spherical particles confined between two parallel planar walls, under creeping-flow conditions. We propose a novel algorithm for accurate evaluation of the many-particle friction matrix in this system--no such algorithm has been available so far. Our approach involves expanding the fluid velocity field into spherical and Cartesian fundamental sets of Stokes flows. The interaction of the fluid with the particles is described using the spherical basis fields; the flow scattered with the walls is expressed in terms of the Cartesian fundamental solutions. At the core of our method are transformation relations between the spherical and Cartesian basis sets. These transformations allow us to describe the flow field in a system that involves both the walls and particles. We used our accurate numerical results to test the single-wall superposition approximation for the hydrodynamic friction matrix. The approximation yields fair results for quantities dominated by single particle contributions, but it fails to describe collective phenomena, such as a large transverse resistance coefficient for linear arrays of spheres

Simulating Three-Dimensional Hydrodynamics on a Cellular-Automata Machine

We demonstrate how three-dimensional fluid flow simulations can be carried out on the Cellular Automata Machine 8 (CAM-8), a special-purpose computer for cellular-automata computations. The principal algorithmic innovation is the use of a lattice-gas model with a 16-bit collision operator that is specially adapted to the machine architecture. It is shown how the collision rules can be optimized to obtain a low viscosity of the fluid. Predictions of the viscosity based on a Boltzmann approximation agree well with measurements of the viscosity made on CAM-8. Several test simulations of flows in simple geometries -- channels, pipes, and a cubic array of spheres -- are carried out. Measurements of average flux in these geometries compare well with theoretical predictions.Comment: 19 pages, REVTeX and epsf macros require

Free energy of colloidal particles at the surface of sessile drops

The influence of finite system size on the free energy of a spherical particle floating at the surface of a sessile droplet is studied both analytically and numerically. In the special case that the contact angle at the substrate equals $\pi/2$ a capillary analogue of the method of images is applied in order to calculate small deformations of the droplet shape if an external force is applied to the particle. The type of boundary conditions for the droplet shape at the substrate determines the sign of the capillary monopole associated with the image particle. Therefore, the free energy of the particle, which is proportional to the interaction energy of the original particle with its image, can be of either sign, too. The analytic solutions, given by the Green's function of the capillary equation, are constructed such that the condition of the forces acting on the droplet being balanced and of the volume constraint are fulfilled. Besides the known phenomena of attraction of a particle to a free contact line and repulsion from a pinned one, we observe a local free energy minimum for the particle being located at the drop apex or at an intermediate angle, respectively. This peculiarity can be traced back to a non-monotonic behavior of the Green's function, which reflects the interplay between the deformations of the droplet shape and the volume constraint.Comment: 24 pages, 19 figure

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.Clefts of the lip and palate are common birth defects, and require long-term multidisciplinary management. Their etiology involves genetic factors and environmental influences and/or a combination of both, however, these interactions are poorly defined. Moreover, although clefts of the lip may or may not involve the palate, the determinants predisposing to specific subphenotypes are largely unknown. Here we demonstrate that variations in the non-coding region near the GREM1 gene show a highly significant association with a particular phenotype in which cleft lip and cleft palate co-occ