Validation of histogram-based virtual source models for different IGRT kV-imaging systems.

PURPOSE: Image-guided radiotherapy (IGRT) improves tumor control but its intensive use may entrain late side effects caused by the additional imaging doses. There is a need to better quantify the additional imaging doses, so they can be integrated in the therapeutic workflow. Currently, no dedicated software enables to compute patient-specific imaging doses on a wide range of systems and protocols. As a first step toward this objective, we propose a common methodology to model four different kV-imaging systems used in radiotherapy (Varian's OBI, Elekta's XVI, Brainlab's ExacTrac, and Accuray's Cyberknife) using a new type of virtual source model based on Monte Carlo calculations. METHODS: We first describe our method to build a simplified description of the photon output, or virtual source models (VSMs), of each imaging system. Instead of being constructed using measurement data, as it is most commonly the case, our VSM is used as the summary of the phase-space files (PSFs) resulting from a first Monte Carlo simulation of the considered x-ray tube. Second, the VSM is used as a photon generator for a second MC simulation in which we compute the dose. Then, the proposed VSM is thoroughly validated against standard MC simulation using PSFs on the XVI system. Last, each modeled system is compared to profiles and depth-dose-curve measurements performed in homogeneous phantom. RESULTS: Comparisons between PSF-based and VSM-based calculations highlight that VSMs could provide equivalent dose results (within 1% of difference) than PSFs inside the imaging field-of-view (FOV). In contrast, VSMs tend to underestimate (for up to 20%) calculated doses outside of the imaging FOV due to the assumptions underlying the VSM construction. In addition, we showed that the use of VSMs allows reducing calculation time by at least a factor of 2.8. Indeed, for identical simulation times, statistical uncertainties on dose distributions computed using VSMs were much lower than those obtained from PSF-based calculations. CONCLUSIONS: For each of the four imaging systems, VSMs were successfully validated against measurements in homogeneous phantoms, and are therefore ready to be used for future preclinical studies in heterogeneous or anthropomorphic phantoms. The cross system modeling methodology developed here should enable, later on, to estimate precisely and accurately patient-specific 3D dose maps delivered during a large range of kV-imaging procedures.

Development and implementation in the Monte Carlo code PENELOPE of a new virtual source model for radiotherapy photon beams and portal image calculation.

This work aims at developing a generic virtual source model (VSM) preserving all existing correlations between variables stored in a Monte Carlo pre-computed phase space (PS) file, for dose calculation and high-resolution portal image prediction. The reference PS file was calculated using the PENELOPE code, after the flattening filter (FF) of an Elekta Synergy 6 MV photon beam. Each particle was represented in a mobile coordinate system by its radial position (r s ) in the PS plane, its energy (E), and its polar and azimuthal angles (φ d and θ d ), describing the particle deviation compared to its initial direction after bremsstrahlung, and the deviation orientation. Three sub-sources were created by sorting out particles according to their last interaction location (target, primary collimator or FF). For each sub-source, 4D correlated-histograms were built by storing E, r s , φ d and θ d values. Five different adaptive binning schemes were studied to construct 4D histograms of the VSMs, to ensure histogram efficient handling as well as an accurate reproduction of E, r s , φ d and θ d distribution details. The five resulting VSMs were then implemented in PENELOPE. Their accuracy was first assessed in the PS plane, by comparing E, r s , φ d and θ d distributions with those obtained from the reference PS file. Second, dose distributions computed in water, using the VSMs and the reference PS file located below the FF, and also after collimation in both water and heterogeneous phantom, were compared using a 1.5%-0 mm and a 2%-0 mm global gamma index, respectively. Finally, portal images were calculated without and with phantoms in the beam. The model was then evaluated using a 1%-0 mm global gamma index. Performance of a mono-source VSM was also investigated and led, as with the multi-source model, to excellent results when combined with an adaptive binning scheme.

Denoising techniques combined to Monte Carlo simulations for the prediction of high-resolution portal images in radiotherapy treatment verification.

This work investigates the possibility of combining Monte Carlo (MC) simulations to a denoising algorithm for the accurate prediction of images acquired using amorphous silicon (a-Si) electronic portal imaging devices (EPIDs). An accurate MC model of the Siemens OptiVue1000 EPID was first developed using the penelope code, integrating a non-uniform backscatter modelling. Two already existing denoising algorithms were then applied on simulated portal images, namely the iterative reduction of noise (IRON) method and the locally adaptive Savitzky-Golay (LASG) method. A third denoising method, based on a nonparametric Bayesian framework and called DPGLM (for Dirichlet process generalized linear model) was also developed. Performances of the IRON, LASG and DPGLM methods, in terms of smoothing capabilities and computation time, were compared for portal images computed for different values of the RMS pixel noise (up to 10%) in three different configurations, a heterogeneous phantom irradiated by a non-conformal 15 × 15 cm(2) field, a conformal beam from a pelvis treatment plan, and an IMRT beam from a prostate treatment plan. For all configurations, DPGLM outperforms both IRON and LASG by providing better smoothing performances and demonstrating a better robustness with respect to noise. Additionally, no parameter tuning is required by DPGLM, which makes the denoising step very generic and easy to handle for any portal image. Concerning the computation time, the denoising of 1024 × 1024 images takes about 1 h 30 min, 2 h and 5 min using DPGLM, IRON, and LASG, respectively. This paper shows the feasibility to predict within a few hours and with the same resolution as real images accurate portal images, combining MC simulations with the DPGLM denoising algorithm.

Effect of exercise on levels of cyclo-oxygenase mediators in exhaled breath condensate in elite athletes.

AIM: Physical exercise requires adaptation from the airways, which includes bronchodilation. Prostaglandins are involved in airway regulation and their plasma level changes during exercise. The purpose of this study was to investigate the effect of symptom-limited exercise on the levels of prostaglandin E(2) (PGE2) and thromboxane B2 (TXB2) in the airways of elite sportsmen. METHODS: Thirty healthy judo competitors, 15 women and 13 men, aged between 16 and 30 years, participated in this study. Subjects completed a standardized maximal treadmill exercise test. Exhaled breath condensate was collected for non-invasive sampling of the airway lining fluid before and immediately after the exercise. PGE2 and TXB2 levels were determined by commercially available radioimmunoassay. Data are given as median (range). RESULTS: Baseline levels of PGE2 and TXB2 were not different between male and female subjects. Exercise caused a significant increase both in PGE2 and TXB2 concentrations in male subjects (from 180 [100-350] to 240 [115-720] pg/mL, P<0.01 and from 24 [0-80] to 37 [0-110] pg/mL, P<0.05, respectively), but not in female subjects. CONCLUSION: Our data indicate that physical exercise modulates the airway level of PGE2 and TXB2 in healthy subjects. These changes may play an important role in the airway adaptation to exercise.

Exhaled breath condensate pH standardised for CO2 partial pressure.

Exhaled breath condensate (EBC) pH is considered to reflect the acid-base balance of the airways. Current pH measurements do not take into account the effect of CO2. The aim of the present study was to determine the effect of condensate CO2 partial pressure on pH and to provide a more precise mode of EBC pH determination. Condensate pH and CO2 partial pressure were measured in parallel from 12 healthy volunteers and 12 asthmatics using a blood gas analyser in neat, argon de-aerated and CO2-loaded samples. The regression analysis was used to test the relationship between pH and CO2, and to calculate the pH at a CO2 level of 5.33 kPa (physiological alveolar CO2 partial pressure). Reproducibility of different pH readings was compared using the Bland-Altman test. Condensate CO2 concentration was variable both in neat and argon de-aerated samples. There was a close negative logarithmic relationship between CO2 and pH. Calculation of pH at a CO2 level of 5.33 kPa provided reproducibility approximately six times as good as that of the currently used measurements. Condensate CO2 partial pressure influences pH measurements. Determination of pH at a standard CO2 level provides the most reproducible condensate pH values to date.

The effect of allergic rhinitis on adenosine concentration in exhaled breath condensate.

BACKGROUND: Patients with allergic rhinitis (AR) frequently develop asthma. This initiating inflammation in the lower airways may result in increased levels of inflammatory mediators such as adenosine in the exhaled breath. OBJECTIVE: We compared adenosine levels in exhaled breath condensate (EBC) and both exhaled and nasal nitric oxide (NO) levels of AR patients and healthy control subjects. We also tested whether inhalation through inflamed nasal cavity during EBC sampling influences adenosine concentrations in exhaled air. METHODS: Exhaled and nasal NO levels were measured and EBC samples (at oral inhalation) were collected from 27 patients and 15 healthy controls. EBC collection was repeated after 15 min with subjects inhaling through their nose. Adenosine was measured by HPLC and NO was determined by chemiluminescence. RESULTS: The concentration of EBC adenosine was higher in patients with AR than in healthy controls (12.4+/-1.3 nM vs. 6.5+/-0.7 nM, P=0.0019) and this was accompanied by an increase in the concentration of exhaled NO (10.2+/-1.3 ppb vs. 5.3+/-0.5 ppb; P=0.0099, respectively). No difference in nasal NO was detected. EBC adenosine concentration showed a significant positive correlation with the level of exhaled NO. In contrast to healthy control subjects, patients with rhinitis had higher levels of exhaled adenosine when inhaling via the nose instead of the mouth (17.7+/-2.8 nM, P=0.007). CONCLUSION: When compared with healthy subjects, patients with AR exhibit an increased concentration of exhaled adenosine and a related increase in exhaled NO concentration. EBC adenosine is further increased when rhinitis patients inhale through their nose than via their mouth. Our data suggest that non-asthmatic patients with rhinitis may have subclinical inflammation in their lower airways.

Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma.

Persistent airway inflammation may require the use of different markers for monitoring airway inflammation. In this study, the authors investigated whether adenosine, which may be produced in allergic inflammatory conditions, could be measured with good reproducibility in exhaled breath condensate (EBC), and whether its concentration was elevated in patients with asthma. EBC adenosine and exhaled nitric oxide (eNO), a noninvasive marker of asthmatic airway inflammation, were measured in 40 healthy volunteers and 43 patients with allergic bronchial asthma. Repeatability of adenosine measurement was checked in 20 pairs of samples collected from healthy control subjects. Adenosine was detectable in all EBC samples by the applied high-performance liquid chromatographic method. The mean difference between repeated measurements of adenosine was -0.1 nM and all differences were within the coefficient of repeatability. Adenosine concentration was higher in steroid-naive patients (n=23) compared with healthy control subjects and steroid-treated patients (n=20). In patients with worsening symptoms of asthma (n=23), adenosine concentration was elevated compared with those in a stable condition (n=20). Furthermore, adenosine concentrations were related to eNO levels in asthmatic patients. These results, showing good reproducibility of adenosine measurements and increased adenosine concentrations in steroid-naive patients and in patients with worsening of asthmatic symptoms, indicate that adenosine measurement in exhaled breath condensate might be an acceptable novel method to investigate the role of local production of adenosine in the airways.

Anti-inflammatory and antipyretic effects of Trigonella foenum-graecum leaves extract in the rat.

Anti-inflammatory and antipyretic effects of the Trigonella foenum-graecum (TFG) leaves extract, an Iranian medicinal plant, were examined. For anti-inflammatory activity, the formalin-induced edema model was used. Hyperthermia was induced by intraperitoneal injection of 20% (w/v) aqueous suspension of brewer's yeast. Sodium salicylate (SS) was used as a positive control. Both TFG and SS significantly reduced formalin-induced edema in single dose (TFG 1000 and 2000 mg/kg, SS 300 mg/kg) and chronic administration (TFG 1000 mg/kg and SS 300 mg/kg). TFG and SS also significantly reduced hyperthermia induced by brewer's yeast in 1 and 2 h after their administration. The results indicate that the TFG leaves extract possess anti-inflammatory as well as antipyretic properties in both i.p. and p.o. administration. Phytochemical studies indicate that alkaloids, cardiac glycosides, and phenols are the major component in the extract. Although existence of three anti-inflammatory, analgesic and antipyretic effects in this extract suggest a NSAID-like mechanism for it, but the presence of alkaloids, the absence of other effective compounds such as flavonoids, saponins, steroids, etc., and also its analgesic effect on tail-flick test that usually is not produced by NSAIDs, suggest another mechanism for the extract. So the possibility of alkaloids as effective compounds, in this extract, increases.

Coronary metabolic adaptation restricted by endothelin in the dog heart.

Endothelin elicits long-lasting vasoconstriction in the coronary bed. This remarkable spastic response raises the question whether or not the metabolic adaptive mechanisms of the coronaries are activated under endothelin effect. The role of the compensatory mediators adenosine and inosine was investigated before and after intracoronary (i.c.) administration of endothelin-1 (ET-1, 1.0 nmol) using 1-min reactive hyperemia (RH) tests on in situ dog hearts (n=15) with or without blocking the ATP-sensitive potassium (K+(ATP)) channels by glibenclamide (GLIB, 1.0 micromol min(-1), i.c.). The release of adenosine and inosine via the coronary sinus was measured by HPLC during the first minute of RH. Endothelin-1 reduced baseline coronary blood flow (CBF) and RH response (hyperemic excess flow (EF) control vs. ET-1: 81.7+/-13.6 vs. 43.4+/-10.9 ml, P<0.01), while it increased the net nucleoside release (adenosine, control vs. ET-1: 58.9+/-20.4 vs. 113.7+/-39.4 nmol, P<0.05; inosine: 242.1+/-81.8 vs. 786.9+/-190.8 nmol, P<0.05). GLIB treatment alone did not change baseline CBF but also reduced RH significantly and increased nucleoside release (EF control vs. GLIB: 72.1+/-11.7 vs. 31.9+/-5.5 ml, P<0.01; adenosine: 18.8+/-4.6 vs. 63.0+/-24.8 nmol, P<0.05; inosine: 113.0+/-37.2 vs. 328.2+/-127.5 nmol, P<0.05). Endothelin-1 on GLIB-treated coronaries further diminished RH and increased nucleoside release (EF: 21.5+/-8.0 ml, P<0.05 vs. GLIB; adenosine: 75.3+/-28.1 nmol, NS; inosine: 801.9+/-196.6 nmol, P<0.05 vs. GLIB). The data show that ET-1 reduces metabolic adaptive capacity of the coronaries, and this phenomenon is due to decreased vascular responsiveness and not to the blockade of ischemic mediator release from the myocardium. The coronary effect of ET-1 may partially be dependent on K+(ATP) channels.

Enhanced accumulation of pericardial fluid adenosine and inosine in patients with coronary artery disease.

Adenosine and inosine are believed to have cardioprotective effects. However, little is known about their possible role in the metabolic autoregulation of human coronaries and in pathologic conditions with supply/demand imbalance of the heart such as coronary artery disease. Since these low molecular weight nucleosides freely diffuse through the monolayer of the visceral pericardium, adenosine and inosine concentrations in pericardial fluid may well reflect the conditions in cardiac interstitium. The pericardial fluid and systemic venous blood adenosine and inosine concentrations were measured in 98 human subjects undergoing heart surgery for coronary artery disease or valvular heart disease. Adenosine and inosine concentrations were measured by HPLC with UV detection. In subjects with coronary artery disease pericardial fluid nucleoside concentrations were significantly higher than in patients with valvular heart disease (adenosine: 1545 (996-3146) nmol/L [median (25th-75th quartiles)] vs. 738 (390-2527) nmol/L, P<0.01; inosine: 658 (321-1331) nmol/L vs. 347 (159-1037) nmol/L, P<0.05), while in both patient groups pericardial fluid nucleoside concentrations were higher by an order of magnitude than in venous plasma. Our results show the enhanced release of adenosine and inosine by the ischemic myocardium as a marker of supply/demand imbalance and support the hypothesis that these cardiac nucleosides may have an important role in the adaptation of coronary blood flow in human coronary artery disease.

Elevated circulating adenosine level potentiates antigen-induced immediate bronchospasm and bronchoconstrictor mediator release in sensitized guinea pigs.

BACKGROUND: Adenosine causes bronchoconstriction in asthmatic patients, and it is also accepted that adenosine influences histamine release from activated human mast cells and basophils in vitro. OBJECTIVE: In this study we tested the hypothesis that adenosine potentiates both the airway narrowing and the release of bronchoconstrictor mediators induced by ovalbumin challenge in sensitized guinea pigs. METHODS: After ovalbumin sensitization, 4 groups were studied: control group, adenosine group (ADO), ovalbumin group (OA), and adenosine plus ovalbumin group (ADO + OA). Changes in airway resistance were assessed from continuously recorded pulmonary insuffilation pressure (PIP). The concentration of histamine, PGD2, and thromboxane B2 were determined from bronchoalveolar lavage fluids. RESULTS: Adenosine alone (6 mg/kg intravenously) did not influence baseline values of PIP and the mediator concentrations; however, ovalbumin (10 mg/kg intravenously) increased both the PIP and the levels of the measured mediators compared with the control and ADO groups. When ovalbumin challenge was preceded by adenosine administration, both PIP and mediator levels were significantly enhanced compared with values obtained after simple ovalbumin provocation (ADO + OA vs OA: P <.05). CONCLUSION: These results suggest that adenosine potentiates the airway narrowing induced by ovalbumin challenge and that this effect may develop through facilitation of the release of bronchoconstrictor mediators during the immediate airway response.

Compensation of endothelin-1-induced coronary vasoconstriction.

The vasodilator capacity of the coronaries was determined by the reactive hyperemia (RH) test in open-chest anesthetized dogs. The myocardial release of adenine nucleosides (adenosine and inosine) was measured by the HPLC-UV method. In group I (n = 9) after the control RH test, a bolus injection of endothelin-1 (ET-1; 1.0 nmol i.c.) was administered and was followed by a second RH test. In group II (n = 9), glibenclamide (GLIB) was infused continuously (1.0 mumol/min i.c.) and RH tests were performed during the control period and then before and after bolus injection of ET-1. In contrast to the significant reduction of the RH response after ET-1 in group I and after GLIB in group II, the nucleoside release into the coronary sinus during the first minute of the RH test was significantly higher (adenosine release 0.05 +/- 0.02 vs. 0.10 +/- 0.04 mumol, and 0.02 +/- 0.00 vs. 0.08 +/- 0.02 mumol; p < 0.05). Injection of ET-1 did not result in further RH reduction in GLIB-pretreated dogs (group II) but significantly increased nucleoside release. High doses of ET-1 activated the metabolic compensatory mechanisms of the myocardium and thereby increased the release of adenine nucleosides into the venous blood of the heart. However, whether these metabolites can exert any significant compensatory vasodilator effects appears doubtful.

Gender, dietary copper and carbohydrate source influence cardiac collagen and lysyl oxidase in weanling rats.

The present investigation was conducted to determine the effects of consumption of diets containing fructose or cornstarch on cardiac collagen metabolism in weanling male and female rats fed copper-deficient or copper-adequate diets for 5 wk. Although both male and female rats that consumed the copper-deficient diet containing fructose were similarly copper deficient, only the males showed severe cardiac pathologies and two died prematurely due to heart-related abnormalities. These pathologies were accompanied by a significant reduction of cardiac lysyl oxidase activity and elevated soluble and total cardiac collagen concentrations compared with rats fed copper-adequate diets. These abnormalities were less severe in copper-deficient rats fed cornstarch. The data show that the activity of the copper-containing enzyme lysyl oxidase is affected by both dietary carbohydrate and gender. The pathologies of heart tissue could be the result of abnormal crosslinking of collagen induced by the combination of copper deficiency, fructose feeding and the sex of the rats.

Effects of arachidonic acid and prostaglandin F2 alpha in isolated rat lungs.

Isolated rat lungs were ventilated and perfused by saline-Ficoll perfusate at a constant flow. The baseline perfusion pressure (PAP) correlated with the concentration of 6-keto-PGF1 alpha the stable metabolite of PGI2 (r = 0.83) and with the 6-keto-PGF1 alpha/TXB2 ratio (r = 0.82). A bolus of 10 micrograms exogenous arachidonic acid (AA) injected into the arterial cannula of the isolated lungs caused significant decrease in pulmonary vascular resistance (PVR) which was followed by a progressive increase of PVR and edema formation. Changes in perfusion pressure induced by AA injection also correlated with concentrations of the stable metabolites (6-keto-PGF1 alpha: r = -0.77, TxB2: -0.76), and their ratio: (6-keto-PGF1 alpha/TXB2: r = -0.73). Injection of 10 and 100 micrograms of PGF2 alpha into the pulmonary artery stimulated the dose-dependent production of TXB2 and 6-keto-PGF1 alpha. No significant correlations were found between the perfusion pressure (PAP) which was increased by the PGF2 alpha and the concentrations of the former stable metabolites. The results show that AA has a biphasic effect on the isolated lung vasculature even in low dose. The most potent vasoactive metabolites of cyclooxygenase, prostacyclin and thromboxane A2 influence substantially not only the basal but also the increased tone of the pulmonary vessels.

Breathing pattern of spontaneously hypertensive rats.

The trachea of rats anaesthetized with sodium pentobarbitone was cannulated and the air flow velocity and the pressure of the oesophagus were measured. In the spontaneously hypertensive rats the breathing frequency was higher, the tidal volume and the effective lung resistance were smaller than that of the normotensive Wistar rats. It seems that the neurohumoral control of respiration in SHR animals differs from that of normotensive rats.

Effects of propranolol, nalorphine and haloperidol on the breathing and on the metabolism of PGI2 and TXA2 of normotensive and spontaneously hypertensive rats.

The influence of propranolol, nalorphine and haloperidol on the breathing pattern and on the blood levels of cyclooxygenase products of anaesthetized spontaneously-breathing normotensive Wistar rats (WR) and of spontaneously hypertensive rats (SHR) were investigated. The respiratory rate was higher and the effective lung resistance was smaller in the SHR than in the WR. Breathing frequency decreased after nalorphine in both groups, while only in SHR after haloperidol. Propranolol augmented the dynamic lung resistance in both groups. The blood 6-keto-PGF1 alpha level was higher and the TXB2 level was lower in the SHR than in the WR. The central inspiratory activity as well as the levels of peripherally acting substances involved in the regulation of respiration and in the control of bronchial smooth muscle tone are different in the SHR and WR.

Serum angiotensin converting enzyme values in chronic obstructive pulmonary disease.

Angiotensin converting enzyme (ACE) is stored in the endothelium. Its activity depends--among others--on the O2-concentration of the blood. Aim of the study was to examine the serum ACE values in chronic obstructive lung diseases (bronchial asthma, chronic bronchitis, lung fibrosis etc.). At the time of blood sampling, blood-gas tensions and respiratory function parameters of the patients were also determined. On the basis of the blood-gas parameters and SACE x + SD and x--SD values, obtained from the normoxic-normocapnic group, the patients could be divided into sub-groups. In contrast to data in the literature increased enzyme levels in response to hypoxia could be found only in patients suffering from a pulmonary disease associated with severe tissue damage.

The primary structure of human beta-lipotropin. Further peptide sequencing resolves the controversy and suggests the existence of only one human beta-lipotropin.

Human beta-lipotropin isolated in Hungary from frozen pituitary glands was purified by high-performance liquid chromatography in Canada. The amino acid sequence of the first 30 residues was determined. Trypsin, trypsin/papain, and trypsin/thermolysin fragments were obtained for the disputed region containing residues 9-25 of beta-lipotropin. Their amino acid composition and sequence established beyond doubt that only one human beta-lipotropin sequence is present. These results suggest the presence of only one gene coding for human pro-opiomelanocortin, the precursor of adrenocorticotropin and beta-endorphin and resolve the controversy over the sequence of human beta-lipotropin.

Action of cathepsin D on human beta-lipotropin: a possible source of human "beta-melanotropin".

Highly purified calf brain cathepsin D (EC 3.4.23.5) selectively splits the Leu77-Phe78 and Ala36-Ala37 peptide bonds of human beta-lipotropin. It is suggested that the formation of human "beta-melanotropin" from gamma-lipotropin, and that of gamma-endorphin from beta-endorphin, is due to the action of cathepsin D during isolation procedures.