A 3D pencil-beam-based superposition algorithm for photon dose calculation in heterogeneous media.

In this work, a novel three-dimensional superposition algorithm for photon dose calculation is presented. The dose calculation is performed as a superposition of pencil beams, which are modified based on tissue electron densities. The pencil beams have been derived from Monte Carlo simulations, and are separated into lateral and depth-directed components. The lateral component is modeled using exponential functions, which allows accurate modeling of lateral scatter in heterogeneous tissues. The depth-directed component represents the total energy deposited on each plane, which is spread out using the lateral scatter functions. Finally, convolution in the depth direction is applied to account for tissue interface effects. The method can be used with the previously introduced multiple-source model for clinical settings. The method was compared against Monte Carlo simulations in several phantoms including lung- and bone-type heterogeneities. Comparisons were made for several field sizes for 6 and 18 MV energies. The deviations were generally within (2%, 2 mm) of the field central axis d(max). Significantly larger deviations (up to 8%) were found only for the smallest field in the lung slab phantom for 18 MV. The presented method was found to be accurate in a wide range of conditions making it suitable for clinical planning purposes.

Genetic analysis of susceptibility to Chlamydia trachomatis in mouse.

Chlamydia trachomatis is a bacterial pathogen that is a major cause of blindness and infertility in diverse populations across the world. In an effort to model genetic complexities that are observed in human populations and to identify novel genes involved in susceptibility to C. trachomatis, we have adapted a murine model of systemic infection for use in genetic analysis. In this model, chlamydial colonization and replication is measured in the spleens of mice shortly after intravenous delivery of C. trachomatis L2. Here, we show that C57BL/6J and C3H/HeJ inbred mice are differentially susceptible to this systemic infection. Additionally, fibroblasts cultured from C57BL/6J and C3H/HeJ embryos are differentially permissive for chlamydial replication. We have taken advantage of this natural variation to map quantitative trait loci on Chromosomes 2, 3, and 11 that segregate with the bacterial load in F2 cross progeny during the acute phase of C. trachomatis infection in vivo. To validate our mapping results, we also generated mice that are congenic for a portion of Chromosome 11 from the susceptible parent. This congenic interval confers increased susceptibility to C. trachomatis, both in vivo and in vitro, suggesting that our screen identified at least one gene that is involved in cellular resistance to C. trachomatis replication.

A 3D photon superposition/convolution algorithm and its foundation on results of Monte Carlo calculations.

Based on previous publications on a triple Gaussian analytical pencil beam model and on Monte Carlo calculations using Monte Carlo codes GEANT-Fluka, versions 95, 98, 2002, and BEAMnrc/EGSnrc, a three-dimensional (3D) superposition/convolution algorithm for photon beams (6 MV, 18 MV) is presented. Tissue heterogeneity is taken into account by electron density information of CT images. A clinical beam consists of a superposition of divergent pencil beams. A slab-geometry was used as a phantom model to test computed results by measurements. An essential result is the existence of further dose build-up and build-down effects in the domain of density discontinuities. These effects have increasing magnitude for field sizes < or =5.5 cm(2) and densities < or = 0.25 g cm(-3), in particular with regard to field sizes considered in stereotaxy. They could be confirmed by measurements (mean standard deviation 2%). A practical impact is the dose distribution at transitions from bone to soft tissue, lung or cavities.

New insights into physiology and pathophysiology by resistance-volume recordings.

This work deals with the assessment of airway resistance in the course of a single breath. The study showed the presence of an early increase in the resistance at the beginning of expiration, which intensifies during expiration and ends up with a sharp decline during expiring the last remaining volume of ca 350 ml. The dynamic changes in airway resistance over a breath depend on the disharmonic interplay between diaphragm function and bronchial wall tonus. Thus, airway resistance is not constant during breathing, as could be misleadingly judged from the total resistance averaged over a breath. The study underscores the importance of recording the resistance-volume curves alongside the standard flow-volume curves to be able to discern the peculiarities of airway resistance changes during a single breath. Knowing changes in the instantaneous airway resistance characteristic for a given lung pathology could appreciably improve the diagnostic and therapeutic powers.

The inverse problem of a Gaussian convolution and its application to the finite size of the measurement chambers/detectors in photon and proton dosimetry.

A Gaussian convolution kernel K is deduced as a Green's function of a Lie operator series. The deconvolution of a Gaussian kernel is developed by the inverse Green's function K(-1). A practical application is the deconvolution of measured profiles Dm(x) of photons and protons with finite detector size to determine the profiles Dp(x) of point-detectors or Monte Carlo Bragg curves of protons. The presented algorithms work if Dm(x) is either an analytical function or only given in a numerical form. Some approximation methods of the deconvolution are compared (differential operator expansion to analytical adaptations of 2 x 2 cm2 and 4 x 4 cm2 profiles, Hermite expansions to measured 6 x 6 cm2 and 20 x 20 cm2 profiles and Bragg curves of 80/180 MeV protons, FFT to an analytical 4 x 4 cm2 profile). The inverse problem may imply ill-posed problems, and, in particular, the use of FFT may be susceptible to them.

Lung function--clinical importance, problems, and new results.

This review tackles the usefulness of spirometry, a more than century old method of assessing pulmonary lung function. Variables measured with a spirometer, such as forced expiratory volume in 1 s, have long been the mainstays of the diagnosis and treatment of lung disorders. But there are problems with the reliability of spirometric measurements. The method depends on the cooperation of the investigated subject, which introduces a confounding subjective element and all too often results in test failure, and the results are evaluated against the predicted values that are based on a set of fixed factors, some of which, such as body height, are not in a straight proportion to the intrathoracic gas volume. Substantial spread of results arises, which makes a reliable assessment of lung function difficult. New methods, such as the resistance-volume curve, provide better information on airway behavior in different conditions. These new methods, which basically evolved from spirometry, show that the old idea of lung function analysis is still viable and may remain helpful for diagnosis and treatment of respiratory pathological states.

[Stability of lung function parameters: spirometry, body plethysmography and mouth occlusion pressure (p0.1)]. / Zur Stabilität lungenfunktionsanalytischer Parameter: Spirometrie, Bodyplethysmographie und Mundverschlussdruck (P0.1).

Spirometric, bodyplethysmographic and mouth occlusion results of 9 healthy probands were measured 9 - 11 times over a total of 28 - 39 days. Interindividual predicted values based on large studies show SDs of +/- 20 %, which is not acceptable for the judgement of individual values. Individual values are much less scattered (SD +/- 10 %). Each test person showed a differing individual range of 75 - 140 %. Functional basic facts can be derived from the different levels of individual values. Early changes in the individual range are of special interest. For the evaluation of individual results the earliest possible basic values are of importance.

On the role of the interactions of ions with external magnetic fields in physiologic processes and their importance in chronobiology.

Homage to the scientific work of Franz Halberg is inevitably connected with the development and importance of chronobiology and its applications in chronomedicine. We show that nonlinear reaction-diffusion systems with feedsideward coupling give rise to oscillations between different limit cycles favoring either inhibition or stimulation of the growth or decay of a component. The inclusion of the diffusion part of each concentration distribution offers the possibility of also taking into account the interaction of charged constituents with external magnetic fields. Concentration oscillations between different limit cycles of the constituents can thus be stabilized. It is assumed that the z-component of the external magnetic field is related to the rather weak solar magnetic field (ca. 10(-9) Tesla). Periods of about one week result for some positive (Mg2+, Ca2+, K+) and negative (e.g. Cl-) ions and some organic acids containing phosphates. The resonance time of a free proton H+ determining the oscillations of the pH-value is about 1 day and that of OH1 is about 3.5 days (half a week). The influence of the geomagnetic field (x- or y-component) in the same range is of a few to ca. 20-30 minutes in the case of charged proteins. An essential condition for this separation is that in general the geomagnetic field does not coincide with the z-component of the solar magnetic field. As an example, the role of the timedependence of the growth and ATP-concentration of the irradiation of the tumor spheroid C3H-MA (mammary adenocarcinoma of mice) is presented.

[Stress test blood gas analysis in chronic obstructive lung diseases]. / Die Belastungs-Blutgasanalyse bei chronisch obstruktiven Lungenerkrankungen.

This study was conducted to investigate the clinical value of blood gas analysis during exercise in patients with COPD and healthy controls using the new criteria of the Deutsche Gesellschaft für Pneumologie (DGP) for performance and interpretation of blood gas analysis during exercise. A total of 64 patients with COPD (age: 63.7 +/- 10.1 years) and 35 healthy controls (age: 35.0 +/- 14.3 years) exercised on a bicycle ergometer to their submaximal capacity under steady state conditions (patients: 44.4 +/- 24.6 watt vs. 102.4 +/- 32.1 watt; p < 0.01). A pathological response for PaO2 occurred in 3 of 35 controls (8.6%) and 14 of 64 patients (21.9%; p < 0.01). A decrease in PaO2 yielded a sensitivity of 28% and a specificity of 92% in respect of patients with emphysema. Significant associations of lung function parameters at rest and blood gases under exercise were found by linear regression analysis (airway resistance (Rt): beta = -0.48; p < 0.001) and PaCO2 (FEV1: beta = -0.27; p < 0.05). This study demonstrates that in patients with COPD parameters of lung function and blood gas analysis at rest are already good predictors of gas exchange under exercise conditions. In individual cases, however, prediction may not be possible. This underlines the importance of the exercise test to investigate gas exchange under diagnostic (i.e. dyspnoea, medical opinion) and therapeutic aspects (i.e. therapy control). For COPD patients, the rule of the DGP yielded a poor sensitivity, but an excellent specificity in the diagnosis of emphysema, which yields confirmation of the diagnosis only in conjunction with, and complementary to, other methods.

The flow-volume curve in patients with obstructive airway diseases partial analysis and functional importance.

Flow-volume curves in patients with obstructive airway disease differs from that observed in healthy subjects. Two types of pathological curves can be differentiated: these with clear sharp bend and intermediate forms characterised by the different grade of concavity of the descending segments plotted against X-axis. The aim of our present investigation is to elucidate the mechanisms which determines the forced expiratory airflow course in patients with obstructive airway diseases. Patients with sharp bend curves show changes of the several lung function data which are more advanced than in subjects with the intermediate forms of the flow-volume curves. In cases of bend curves the volume of the forced expiration can be differentiated on the two parts: circumferential and serial. Circumferential volume exhaled on the very beginning of the expiration (above the bend) amounts 0.118L in average. This volume depends on the expiratory narrowing of the bronchi from the 1-st to 9-th generation. The serial volume contained between the bend and the end of expiration amounts about 95% of the expired volume. Flow limitation occurs in 5-th to 9-th generations which is manifested by the strong increase of the flow resistance. The intermediate types of the flow-volume curves is caused by the inhomogenous emptying of the lung together with corresponding volume dependent narrowing of the bronchi. The same mechanisms can be detected even on the bodypletysmographic tidal breathing resistance curves. The concave and particularly bend flow-volume curves has been attributed to the pulmonary emphysema. This is not entirely truth. Other conditions leading to inhomogenic emptying of the lung due to airway and parenchymal changes (such as lung cicatrisation) can influence expiratory flow course resulting in concave or even bend flow-volume relationships.

[Clinical investigation of the action of tramazoline inpatients with chronic obstructive bronchitis. The importance of mucosal swelling]. / Klinische Untersuchungen zur Wirkung von Tramazolin bei Patienten mit chronisch obstruktiver Bronchitis. Ein Beitrag zur Bedeutung der Schleimhaustschwellung.

Swelling of the bronchial mucosa is discussed as part of the increased airways on patients with obstructive bronchitis (OB). The excellent effect of alpha-receptor-stimulants like tramazoline for the deblockage of the nasal mucosa has been previously established experimentally as well as clinically. On 19 patients with OB tramazoline (CAS 74195-73-6) aerosol (Rhinospray) (0.14 (n = 9) resp. 0.19 (n = 10 mg) was administered into the bronchial system. There were no effects seen on airways resistance nor on the intrathoracic gas volume. The important improvement on patients with OB and nasal blockage at the same time seen after tramazoline aerosol given into the nose is caused only by the effect on the nasal mucosa.

ACE inhibition decreases postoperative mortality in rats with left ventricular hypertrophy and myocardial infarction.

UNLABELLED: In male Sprague Dawley rats with left ventricular hypertrophy (LVH) and hypertension induced by aortic constriction (AC) and subsequent myocardial infarction (MI) by occlusion of the left coronary artery the effects of ACE inhibition with ramipril (RA 1 mg/kg/day via the drinking water during 6 weeks) on survival as well as cardiac function and metabolism were investigated. Respective groups (sham AC; AC; AC + sham MI; normotensive animals with sham MI; MI; MI + RA) served as comparisons. Following MI hypertensive rats with AC and LVH revealed an increased postoperative mortality (68%) when compared to normotensives without AC (28%). ACE inhibition with ramipril significantly reduced mortality in hypertensive rats by 26%. Untreated hypertensive animals with LVH clearly showed reduced MI size (6.2 +/- 2.3%) in comparison with untreated normotensive animals and MI (31.0 +/- 3.3%). In hypertensive rats with MI which died during the study a significant increase in infarct size was found compared to those which survived MI. In normotensive animals ramipril reduced infarct size by 50%. Due to the quite small infarct size observed in hypertensive rats, ACE inhibition did not further reduce MI in these animals. LVH as well as hydroxyproline/proline ratio was diminished by ACE inhibitor treatment. In the isolated hearts of ramipril treated rats contractility was improved when compared to the respective untreated groups with MI. In the coronary effluent of isolated hearts from rats with AC and MI lactate dehydrogenase and creatine kinase activities as well as lactate levels were increased. Ramipril treatment starting one week before MI normalized these parameters and in addition increased prostacyclin output. Hearts with MI from treated normotensive animals contained increased energy rich phosphates when compared to hearts from untreated rats with MI. CONCLUSIONS: Hypertensive rats with LVH undergoing MI experience increased postoperative mortality probably due to a reduced tolerance to myocardial ischemia and occurrence of arrhythmias. In these animals ACE inhibition with ramipril increased survival. Both, increased survival in hypertensive and reduction in infarct size in normotensive rats by ACE inhibition with ramipril was accompanied by an improved myocardial metabolism.

Effects on the lung function of exposure to carbon black dusts. Results of a study carried out on 677 members of staff of the DEGUSSA factory in Kalscheuren/Germany.

Spirometry, full-bodyplethysmography, and inhalation challenge tests are the most frequently used methods for lung function testing. In all, 677 examinations were performed among exposed employees at the Degussa carbon black plant in Kalscheuren/Germany using the above mentioned methods, in order to detect whether there is a measurable impact of carbon black fine dust on pulmonary function, or a higher prevalence of obstructive air-way diseases among the study candidates, and whether fine dust exposure is related to the prevalence of bronchial hyperresposiveness. Within the smokers' group carbon black dust exposure reveals a (minimal) impact upon the lung function of the study subjects. However, the impact of fine dust exposure within that group is less significant than the influence of smoking on pulmonary function. Nevertheless, smokers are displaying significant more frequently signs of obstructive airway diseases compared with nonsmokers. In the smokers' group we found 7.3% of study subjects with signs of obstructive airway diseases compared with 3.9% in the group of nonsmokers. No significant impact of fine dust exposure on lung function could be detected within former- and nonsmokers. The overall percentage of 5.1% is not higher than that of subjects with bronchial hyperresponsiveness in other comparable studies.

Lung function testing: the dilemma of predicted values in relation to the individual variability.

Quantitated lung function parameters are usually interpreted in relation to so-called "normal ranges' obtained from healthy study groups. The aim of this paper is the critical review of formulas and the evaluation of intraindividual variation in modern lung function testing. To which extent is the total variation of lung function parameters in cross-sectional studies (usually serving as basis for the normal range) attributed to the intraindividual variation between repeated measurements? This question raises a further question: are lung function values in the normal range really normal? To assess spirometric and body plethysmographic parameters 26 healthy subjects from three medical centers underwent 30-72 measurements over a period of 2 months for the determination of variations due to (1) intraindividual variation over time and (2) interindividual variation. For each subject, predicted values of different lung function parameters published by Quanjer et al. [Eur Respir J 1993; 6:5-40.1], of intrathoracic gas volume by Ulmer et al. [Die Lungenfunktion; Stuttgart, Thieme, 1991] and of total airway resistance by Ruehle and Matthys [Pneumologie 1976;153:223] were applied. When converted into percent predicted and adjusted for differences in medical centers, the intraindividual standard deviation was estimated to be about half of the interindividual standard deviation. We conclude that the normal range of lung function parameters derived from the standard deviation within populations is too wide for the assessment of individual values. Interpretation of individual lung function measurements should primarily be based on the "individual normal range' derived from former lung function measurements of the individual and only secondly on the "predicted value'.

[Responder and non-responder in the bronchodilator test?]. / Responder und Non-Responder im Bronchodilatationstest?

In 15 patients with chronic airflow obstruction 0.2 mg salbutamol was administered to determine reversibility within 15 minutes ("test effect"). Subsequently, maximum 24-hour effects of three beta 2-agonists (fenoterol 0.2 mg, salbutamol 0.2 mg, salmeterol 0.05 mg, each by MDI) were determined in random order ("best effect"). Airways obstruction was measured by FEV1, MEF50, MEF25, airway resistance Raw and thoracic gas volume TGV. "Best effects" were compared with "test effects". As a whole test effects were significantly smaller than best effects, often not reaching a 15% change, normally achieved during the 24-hour observation. Significant correlations existed between FEV1 and the corresponding values of Raw, MEF50 and MEF25, although there were considerable individual differences between test results. The reduction of TGV after a beta 2-agonist was significantly related to TGV-baseline values. We conclude in line with other authors that tests of acute reversibility of airways obstruction cannot reliably differentiate between "responders" and "non-responders" and that such tests may mislead if used for the differentiation of asthma and COPD.

[Effect duration and treatment effectiveness of salmeterol, fenoterol and salbutamol in severe forms of respiratory tract obstruction]. / Wirkdauer und Wirkstärke von Salmeterol, Fenoterol und Salbutamol bei schweren Formen obstruktiver Atemwegserkrankungen.

Duration and intensity of bronchodilator action of 0.2 mg Fenoterol, 0.2 mg Salbutamol, and 0.05 mg Salmeterol were investigated in 15 subjects with COPD over a period of 12 hours. Airway resistance and FEV1 were measured and subjective side effects noted. Salbutamol MDI was used as rescue medication. Airway resistance and FEV1 demonstrated significant bronchodilation with all bronchodilator drugs after 15 min and maximum bronchodilation between 1 and 2 hrs. After 3 to 5 hrs. bronchodilator effects of fenoterol and salbutamol are lost by at least 50%, whereas this effect is only seen after 8 to 9.5 hrs. with salmeterol. There were considerable individual differences of the efficacy of all three drugs. However, salmeterol was equally efficaceous, compared to fenoterol and salbutamol, but its duration was at least twice as long. Consequently, rescue medication was used in only about 50% of the cases. Side effects of all substances were comparable. From these data it may be concluded that the efficacy of beta2-adrenergic agonists is comparable, irrespective of the duration of action of a single administration, if repeated administrations are used with short acting substances. In addition, this study confirmed that in individual patients a) the response to beta2-adrenergic agonists is variable and b) that different lung function parameters such as airway resistance and FEV1 may give different results.

Radiogenic responses of normal cells induced by fractionated irradiation--a simulation study. Part II. Late responses.

AIM: Based on controlled theory, a computed simulation model has been constructed which describes the time course of slowly responding normal cells after irradiation exposure. Subsequently, different clinical irradiation schemes are compared in regard to their delayed radiogenic responses referred to as late effects in radiological terminology. METHOD: A cybernetic model of a parenchymal tissue consisting of dominantly resting functional cells has been developed and transferred into a computer model. The radiation effects are considered by characteristic cell parameters as well as by the linear-quadratic model. RESULTS: Three kinds of tissue (brain and lung parenchyma of the mouse, liver parenchyma of rat) have been irradiated in the model according to standard-, super-, hyperfractionation and a single high dose per week. The simulation studies indicate that the late reaction of brain parenchyma to hyperfractionation (3 x 1.5 Gy per day) and of lung parenchyma tissue with regard to all fractionation schemes applied is particularly severe. In contrast to these observations the behavior of liver parenchyma is not unique: If Dtotal amounts to 60 Gy there is no evidence for compensation of radiation damages, but if Dtotal is restricted to 30 Gy the corresponding evidence can be expected for all schemes. In the case of a high single dose of 6 Gy a reduction of the recovery time from 1 week to 2...2 days yields also an indication of a severe damage, even if Dtotal amounts only to 30 Gy. CONCLUSIONS: A comparison of the simulation results basing to the survival of cell numbers with clinical experience and practice shows that the clinical reality can qualitatively be represented by the model. This opens the door for connecting side effects to normal tissue with the corresponding tumor efficacy (discussed in previous papers). The model is open to further refinement and to discussions referring to the phenomenon of late effects.