Biomedical subjects

Werner Hofmann

Publications and source records attributed to Werner Hofmann.

At least 19 recordsLinked to original sources

PubMed2006

Alpha-hit, cellular dose, cell transformation and inactivation probability distributions of radon progenies in the bronchial epithelium.

A fluid dynamics based model has been used to determine the deposition patterns of inhaled radon daughters in a realistic approach of the bronchial airway geometry. The interaction of the emitted alpha particles with epithelial cells has been analyzed by applying a complex hit probability model (Bronchial Alpha Hit Model). The biological response of the hit cells has been calculated by the Probability-Per-Unit-Track-Length Model, which relates the probability of a specific biological effect to the track length of alpha particles as a function of the particles' LET. The models mentioned above form a complex lung-radon interaction description. The calculations indicate that compared to the average values the transformation and cell killing probabilities are higher at bronchial carinal ridges. In addition, a considerable number of cells possessing a not negligible transformation and cell killing probabilities can also be found in the outer sides of the central zone.

Aerosols↗

PubMed2006

CFD as a tool in risk assessment of inhaled radon progenies.

During the last decade, computational fluid dynamics techniques proved to be a powerful tool in the modelling of biological processes and the design of biomedical devices. In this work, a computational fluid dynamics method was applied to model the transport of inhaled air and radioactive particles within the human respiratory tract. A finite volume numerical approach was used to compute the flow field characteristics and particle trajectories in the lumen of the first five airway generations of the human tracheobronchial tree, leading to the right upper lobe. The computations were performed for breathing and exposure conditions characteristic of uranium mines and homes. Primary radon daughter deposition patterns and energy distributions were computed, exhibiting highly inhomogeneous particle and energy deposition patterns. The results of the present modelling effort can serve as input data in lung cancer risk analysis.

Administration, Inhalation↗

PubMed2006

Identification of members of the annexin family in the detergent-insoluble fraction of rat Morris hepatoma plasma membranes.

For proteomic analysis, plasma membranes of rat hepatocellular carcinoma Morris hepatoma 7777 were selectively solubilized according to the previously developed method [D. Josic, K. Zeilinger, Methods Enzymol. 271 (1996) 113-134]. If the Triton X100 insoluble pellet is subsequently extracted, several proteins can be solubilized. These proteins can be classified in two groups according to their molecular size. The proteins with apparent molecular weights in SDS-PAGE between 70 and 75 kDa belong to the first group. Smaller proteins, with apparent molecular weights between 30 and 45 kDa, are members of the second group. The main protein of higher molecular weight was also found in the Triton X100 insoluble extract from normal rat liver plasma membranes. This protein was identified as Annexin A6. The proteins from the second group are practically absent in the Triton X100 insoluble extract from rat liver. These proteins are present in relatively high concentrations in plasma membranes of Morris hepatoma 7777. Both groups of detergent-insoluble proteins from Morris hepatoma 7777 were further analyzed with SELDI-TOF and LC electrospray ionization mass spectrometry. From the first group, Annexin A6, together with two other integral plasma membrane proteins, was identified. In the second group of proteins with apparent molecular weights between 30 and 45kDa, further members of the annexin family, Annexins A1, A2, A4, A5 and A7 were identified. The possible role of these low molecular size annexins as potential cancer biomarkers is discussed.

Amino Acid Sequence↗

PubMed2006

Integrin alpha3beta1 interacts with I1PP2A/lanp and phosphatase PP1.

Integrin alpha3beta1 is a receptor for the extracellular matrix component laminin 5. To elucidate possible signaling pathways induced by integrin alpha3beta1, we looked for proteins that interact with the cytoplasmic part of the alpha3A integrin subunit. We identified several multifunctional proteins by affinity chromatography and subsequent MALDI-TOF-MS and focused on the inhibitor 1 of serine/threonine phosphatase PP2A (I1PP2A, synonym: lanp) which also plays a role during the development of the mouse cerebellum. I1PP2A/lanp colocalizes with the alpha3A integrin subunit in differentiated PC12 cells in the cell body and in neurites as well as in Purkinje cells of mouse cerebellum. Overexpression of GFP-I1PP2A/lanp in PC12 cells leads to markedly reduced neurite length on laminin 5 after induction with nerve growth factor. By affinity chromatography the protein phosphatase PP1 can also be identified as a alpha3A/cyto-binding protein. PP1 and integrin alpha3beta1 can be pulled down by GST-I1PP2A/lanp from cell lysates of differentiated and undifferentiated PC12 cells. The phosphatase binds to the cytoplasmic membrane-proximal conserved GFFKR motif of the alpha integrin subunit, whereas I1PP2A/lanp requires a longer sequence for binding. PP1 but not PP2A is able to dephosphorylate precipitated integrin alpha3beta1 in vitro. Furthermore, PP1 releases phosphate from T1046 of phosphopeptides that mimic the phosphorylation consensus sequence in the cytoplasmic part of the alpha3A integrin subunit. These data suggest that I1PP2A/lanp forms a complex with PP1 and the alpha3A integrin subunit and might possibly regulate the phosphorylation status of integrin alpha3beta1 and/or integrin downstream targets.

Animals↗

PubMed2006

[Stochastic model for the spatial visualization of particle-deposition patterns in the lung and their significance in lung medicine].

The present paper provides a detailed description of an extension of the Monte Carlo computer model IDEAL, which enables the generation of spatial particle deposition patterns in the human lung. Randomly determined particle trajectories are transformed to a Cartesian coordinate system within which the orientation of the trachea corresponds to the z-direction. At the same time, the determination of particle deposition sites is carried out by application of a grid composed of specific volume elements (voxel). The calculation of particle deposition are based on the physical mechanisms of Brownian diffusion, sedimentation, and inertial impaction. After their storage in a matrix, the deposition data are subject to graphical processing. This allows the presentation of spatial particle distribution patterns (3d-density plots) and of the lung surface itself as well as the generation of two-dimensional distributions by sectioning the three-dimensional structures at pre-defined positions. The results of different model simulations (variation of particle size and breathing conditions) are discussed in detail.

Computer Simulation↗

PubMed2006

The effect of morphological variability on surface deposition densities of inhaled particles in human bronchial and acinar airways.

Deposition fractions in human airway generations were computed with a stochastic deposition model, which is based on a randomly, asymmetrically dividing lung morphology, applying Monte Carlo techniques. Corresponding uncorrelated surface deposition densities were obtained by dividing the average deposition fraction in a given generation by the average total surface area of that generation. In order to consider the statistical correlation between deposition probability and linear airway dimensions in each airway, correlated surface deposition densities were calculated by dividing the deposition fraction in a randomly selected bronchial or acinar airway by the surface area of that airway and by the total number of bronchial or acinar airways in that generation. Average surface deposition densities are relatively constant throughout bronchial airway generations, while average acinar surface deposition densities exhibit a distinct decrease with rising penetration into the acinar region. Due to the correlation between deposition fraction and surface area in a given airway generation, average correlated surface deposition densities are consistently higher than average uncorrelated densities, particularly in the acinar region, where differences can be as high as a few orders of magnitude. Already significant statistical fluctuations of the deposition fractions in individual airway generations are even exacerbated for surface deposition densities, with coefficients of variation about twice as high as for correlated deposition fractions.

Aerosols↗

PubMed2006

Clusters of DNA double-strand breaks induced by different doses of nitrogen ions for various LETs: experimental measurements and theoretical analyses.

The yields and clustering of DNA double-strand breaks (DSBs) were investigated in normal human skin fibroblasts exposed to gamma rays or to a wide range of doses of nitrogen ions with various linear energy transfers (LETs). Data obtained by pulsed-field gel electrophoresis on the dose and LET dependence of DNA fragmentation were analyzed with the randomly located clusters (RLC) formalism. The formalism considers stochastic clustering of DSBs along a chromosome due to chromatin structure, particle track structure, and multitrack action. The relative biological effectiveness (RBE) for the total DSB yield did not depend strongly on LET, but particles with higher LET produced higher fractions of small DNA fragments, corresponding in the formalism to an increase in the average number of DSBs per DSB cluster. The results are consistent with the idea that DSB clustering along chromosomes is what leads to large RBEs of high-LET radiations for major biological end points. At a given dose, large fragments are less affected by the variability in LET than small fragments, suggesting that the two free ends in large fragments are often produced by two different tracks. The formalism successfully described an extra increase in small DNA fragments as dose increases and a related decrease in large fragments, mainly due to interlacing of DSB clusters produced along a chromosome by different tracks, since interlacing cuts larger DNA fragments into smaller ones.

Cell Line↗

PubMed2006

Exposure assessment of diesel bus emissions.

The goal of this study was to measure ultrafine particle concentrations with diameters less than 1 mum emitted by diesel buses and to assess resulting human exposure levels. The study was conducted at the Woolloongabba Busway station in Brisbane, Australia in the winter months of 2002 during which temperature inversions frequently occurred. Most buses that utilize the station are fuelled by diesel, the exhaust of which contains a significant quantity of particle matter. Passengers waiting at the station are exposed to these particles emitted from the buses. During the course of this study, passenger census was conducted, based on video surveillance, yielding person-by-person waiting time data. Furthermore, a bus census revealed accurate information about the total number of diesel versus Compressed Natural Gas (CNG) powered buses. Background (outside of the bus station) and platform measurements of ultrafine particulate number size distributions were made to determine ambient aerosol concentrations. Particle number exposure concentration ranges from 10 and 40 to 60% of bus related exhaust fumes. This changes dramatically when considering the particle mass exposure concentration, where most passengers are exposed to about 50 to 80% of exhaust fumes. The obtained data can be very significant for comparison with similar work of this type because it is shown in previous studies that exhaust emissions causes cancer in laboratory animals. It was assumed that significant differences between platform and background distributions were due to bus emissions which, combined with passenger waiting times, yielded an estimate of passenger exposure to ultrafine particles from diesel buses. From an exposure point of view, the Busway station analyzed resembles a street canyon. Although the detected exhaust particle concentration at the outbound platform is found to be in the picogram range, exposure increases with the time passengers spend on the platform along with their breathing frequency.

Air Pollutants↗

PubMed2006

[High utilization of health insurance services by the elderly--analysis of hospital and drug utilization data].

The present contribution discusses the utilization of the healthcare system by elderly patients in Germany. First, the paper focuses on the detailed characterization of a group of people aged 60 years or more (N = 73,454). Second, the objective is to analyze the data for high utilization of healthcare services by older men and women. The analysis is based on data regularly recorded by a German health insurance agency for the year 2000. High utilization is operationalized by a 10% cutoff for users with the highest number of treatments, highest costs and/or other criteria depending on the respective health service sector. The insured group investigated received approximately 1.4 million prescriptions, producing costs of 42 million E. High utilizers account for 32% of all prescriptions and 44% of the costs, respectively. At the same time, the age groups with the highest prescription rates do not cause the highest costs: So the relationship between age and prescription drug expenses as well as between age and prescription rates does not display an arithmetically increasing pattern. Within the timeframe investigated 26,000 hospital treatments were accounted for by 21.75% of the elderly under research. In total, they caused expenses of 88 million E. High utilization in the hospital sector was operationalized by four criteria. Sex- and age-specific analysis of high utilization of hospital treatment revealed that the four different criteria apply to different insured groups. In summary, the high utilization of healthcare services appears to be a multidimensional phenomenon.

Aged↗

PubMed2005

Simulation of fiber deposition in bronchial airways.

Penetration probabilities of inhaled man-made mineral fibers to reach central human airways were computed by a stochastic lung deposition model for different flow rates and equivalent diameters. Results indicate that even thick and long fibers can penetrate into the central airways at low flow rates. Deposition efficiencies and localized deposition patterns were then computed for man-made fibers with variable lengths in a three-dimensional physiologically realistic bifurcation model of the central human airways by computational fluid dynamics (CFD) techniques for characteristic breathing patterns. The results obtained for inspiratory flow conditions indicate that deposition efficiencies were highest for parallel orientation of the fibers, increasing with rising flow rate, branching angle, and fiber length at all orientations. Furthermore, deposition patterns were highly inhomogeneous and their localized distributions showed hot spots in the vicinity of the carinal ridge and at the inner sides of the daughter airways. Comparisons with other theoretical results demonstrate that the equivalent diameter concept, if including interception, presents a reasonable approximation for the parameter ranges employed in the present study.

Air Pollutants↗

PubMed2005

A computer program for the simulation of fiber deposition in the human respiratory tract.

As inhaled fibers may lead to a variety of lung diseases, detailed information on their deposition in the human respiratory tract is an indispensable requirement in medical science. In the work presented here, a Visual Basic((R)) computer program, termed FIBROS, is described which enables the simulation of fibrous particle deposition in both the extrathoracic region and different parts of the lung itself, including the results of published numerical studies on inertial/interceptional as well as diffusional and gravitational deposition. The input window of FIBROS includes the selection of specific breathing conditions by variation of the tidal volume and breathing cycle. Furthermore, the user is able to determine fiber properties such as diameter, aspect ratio, specific weight, and fiber orientation with respect to the air stream in the upper and lower airways of the lungs. Besides the offer of various deposition formulae for each region of the respiratory tract, thereby also allowing a distinction between mouth and nose breathing, the user may select between different morphometric datasets of the lung and respective airway scaling procedures. Analysis routines of FIBROS include the estimation of regional deposition fractions, thereby distinguishing between extrathoracic, bronchial, and acinar compartments, and a calculation of generation-by-generation deposition probabilities within tubular and alveolar structures. Preliminary results presented here should demonstrate the effects on fiber deposition due to variations of the breathing behaviour and the particle properties.

Algorithms↗

PubMed2004

Mucociliary and long-term particle clearance in the airways of healthy nonsmoker subjects.

Spherical monodisperse ferromagnetic iron oxide particles of 1.9-microm geometric and 4.2-microm aerodynamic diameter were inhaled by 13 healthy nonsmoking subjects using the shallow bolus technique. The bolus width was 100 ml, and the penetration front depth was 150 +/- 27 ml. The mean flow rate during inhalation and exhalation was 250 ml/s. The Fowler dead space and the phase 1 dead space of the airways were 282 +/- 49 and 164 +/- 34 ml, respectively. Deposition was below 20% without breath holding and 51 +/- 8% after an 8-s breath-holding time. We attempted to confine the bolus deposition to the bronchial airways by limiting the bolus front depth to the phase 1 dead space volume. Particle retention was measured by the magnetopneumographic method over a period of 9 mo. Particle clearance from the airways showed a fast and a slow phase; 49 +/- 9% followed the fast phase with a mean half-time of 3.0 +/- 1.6 h and characterized the mucociliary clearance. The remaining fraction was cleared slowly with a half-time of 109 +/- 78 days. The slow clearance phase was comparable to clearance measurements from the lung periphery of healthy nonsmokers, which allowed macrophage-dependent clearance mechanisms of the slow cleared fraction to be taken into account. Despite the fact that part of the slowly cleared particles may originate from peripheral deposition, the data demonstrate that mucociliary clearance does not remove all particles deposited in the airways and that a significant fraction undergoes long-term retention mechanisms, the origin of which is still under discussion.

Adult↗

PubMed2004

Stochastic model of particle clearance in human bronchial airways.

A stochastic bronchial clearance model, based on a stochastic morphometric model of the human bronchial tree, has been developed, which simulates the combined action of fast and slow bronchial clearance mechanisms by Monte Carlo methods. To model fast bronchial clearance, mucus velocities in individual airways were based on a correlation between mucus velocity and airway diameter, considering conservation of mucus flow. In addition, mucus transport was assumed to be delayed at bronchial bifurcation zones. The size dependence of the slow bronchial clearance phase was considered by a linear relationship between the slow bronchial clearance fraction, f(s), and the geometric particle diameter, derived from bolus inhalation experiments. Potential variations of f(s) from proximal to distal airway generations were simulated by five different scenarios, which allocated slow bronchial clearance to successively peripheral bronchial regions. Alveolar clearance, which contributes only to longterm particle retention, was modeled by transfer rates supplied by the ICRP respiratory tract model. To test the different components of the clearance model, modeling predictions were compared with experimental retention data from bolus inhalation experiments, using various particle sizes and bolus front depths, as well as from slow inhalation experiments, with a flow rate of only 0.045 L sec(-1). The overall good agreement between modeling results and experimental data indicate that the present model correctly predicts bronchial clearance, suggesting that slow bronchial clearance mechanisms are most effective in smaller bronchial airways.

Biological Transport↗

PubMed2003

The effect of lung structure on mucociliary clearance and particle retention in human and rat lungs.

Mucociliary clearance velocities in human and rat bronchial airways were calculated in asymmetric, multiple-path models of the bronchial tree by solving mass transport equations based on the assumption of conservation of mucus volume and normalized to measured tracheal mucus velocities of 5.5 mm/min for humans and 1.9 mm/min for rats. Mucus velocities in single airways of the rat lung exhibited a significant statistical relationship with airway diameters but not with generation numbers, while both parameters provided equally suitable relationships for the human lung. Retention curves reflecting the combined effects of deposition and clearance were computed for unit density particles of 0.1, 1, 2, and 7 microm for resting breathing conditions. About 10 to 15% of the particles initially deposited in the human bronchial tree were still retained after 24 h, while most of the particles deposited in the rat bronchial tree were cleared after about 6 to 8 h. Snapshots of the distributions of mass retained among human bronchial airways at different times after the end of exposure indicated that the observed slow bronchial clearance may partly be attributed to delayed mucociliary clearance from particles initially deposited in the most peripheral conductive airways. If plotted as functions of airway diameter, human and rat bronchial retention patterns exhibit very similar shapes in contrast to their dependence on airway generation number. Thus, extrapolation of toxicologic response, based on local retention patterns from rat to human exposures, should be based on airway diameter rather than on generation number.

Animals↗

PubMed2003

Local particle deposition patterns may play a key role in the development of lung cancer.

The apparent discrepancy between the reported preferential occurrence of bronchial carcinomas in central bronchial airways and current dose estimates for inhaled particles suggests that experimentally observed local accumulations of particles within bronchial airway bifurcations may play a crucial role in lung cancer induction. Here, we computed three-dimensional particle deposition patterns in lobar-segmental airway bifurcations and quantified the resulting inhomogeneous deposition patterns in terms of deposition enhancement factors, which are defined as the ratio of local to average deposition densities. Our results revealed that a small fraction of epithelial cells located at carinal ridges can receive massive doses that may be even a few hundred times higher than the average dose for the whole airway. This lends further credence to the hypothesis that the apparent site selectivity of neoplastic lesions may indeed be caused by the enhanced deposition of toxic particulate matter at bronchial airway bifurcations.

Aerosols↗

PubMed2002

Nonlinear dose-response relationships and inducible cellular defence mechanisms.

With the inclusion of inducible radioprotective mechanisms in a radiobiological state-vector model it was possible to explain plateaus in dose-response relationships for neoplastic transformation produced by in vitro irradiation of different cell lines with low-LET irradiation at high dose rates. The current study repeated the simulation of one data set that contains a plateau at mid doses. In contrast to earlier studies, the new one did not model the repair of double-strand breaks (DSBs) located in bulk DNA (likely via non-homologous end joining) as being inducible. Repair of specific DSBs located in actively transcribed genes was assumed to occur via homologous recombination and was considered to be inducible. This reduced the number of parameters that have to be determined by fitting the model to data. In addition, all types of radical scavengers were formerly considered to be inducible by radiation. This was redefined in the current work and the effectiveness of scavengers was implemented in a refined way. The current work investigated whether these and other model adjustments lead to an improved fit of the data set.

Animals↗

PubMed2002

Analysis of radon-induced lung cancer risk by a stochastic state-vector model of radiation carcinogenesis.

A biologically based state-vector model (SVM) of radiation carcinogenesis has been extended to incorporate stochasticity of cellular transitions and specific in vivo irradiation conditions in the lungs. Dose-rate-dependent cellular transitions related to the formation of double-stranded DNA breaks, repair of breaks, interactions (translocations) between breaks, fixation of breaks, cellular inactivation, stimulated mitosis and promotion through loss of intercellular communication are simulated by Monte Carlo methods. The stochastic SVM has been applied to the analysis of lung cancer incidence in uranium miners exposed to alpha-emitting radon progeny. When incorporating in vivo features of cell differentiation, stimulated cell division and heterogeneity of cellular doses into the model, excellent agreement between epidemiological data and modelling results could be obtained. At low doses, the model predicts a nonlinear dose-response relationship; e.g., computed lung cancerrisk at 20WLM is about half of current lung cancer estimates based on the linear hypothesis. The model also predicts a slight dose rate effect; e.g., at a cumulative exposure of 20 WLM, calculated lung cancer incidence for an exposure rate 0.27 WLM/year (assuming an exposure time of 73 years) is smaller by a factor of 1.2 than that for an exposure rate of 10 WLM/year.

Air Pollutants, Occupational↗

PubMed2001

Phospholipase Cgamma binds alpha1beta1 integrin and modulates alpha1beta1 integrin-specific adhesion.

Integrin adhesion receptors have been implicated in bidirectional signal transduction. The dynamic regulation of integrin affinity and avidity as well as post-ligand effects involved in outside-in signaling depends on the interaction of integrins with cytoskeletal and signaling proteins. In this study, we attempted to identify cytoplasmic binding partners of alpha(1)beta(1) integrin. We were able to show that cell adhesion to alpha(1)beta(1)-specific substrates results in the association of phospholipase Cgamma (PLCgamma) with the alpha(1)beta(1) integrin independent of PLCgamma tyrosine phosphorylation. Using peptide-binding assays, the membrane proximal sequences within the alpha(1)beta(1) integrin subunits were identified as binding sites for PLCgamma. In particular, the conserved sequence of beta(1) subunit binds the enzyme very efficiently. Because purified PLCgamma also binds the integrin peptides, binding seems to be direct. Inhibition of PLC by leads to reduced cell adhesion on alpha(1)beta(1)-specific substrates. Cells lacking the conserved domain of the alpha(1) subunit fail to respond to the PLC inhibition, indicating that this domain is necessary for PLC-dependent adhesion modulation of alpha(1)beta(1) integrin.

Amino Acid Motifs↗