Quercetin protects cardiomyoblasts against hypertonic cytotoxicity by abolishing intracellular Ca2+ elevations and mitochondrial depolarisation.

BACKGROUND AND AIM: Osmotic changes represent a burden for the body and their limitation would be beneficial. We hypothesized that ubiquitous natural compounds could guard against cytotoxic effects of osmotic stress. We evaluated the anti-hypertonic mechanism of quercetin and 2,3-dehydrosilybin in H9c2 cells in vitro. EXPERIMENTAL PROCEDURE: Protective effect of both compounds was determined by neutral red assay, cell apoptosis was estimated by measuring caspase-3 activity and verified by western blot and annexin V assay. Phosphorylation level of selected proteins was also detected. Mitochondrial membrane potential was evaluated using dye JC-1. Ca2+ signals were evaluated using genetically encoded fluorescent Ca2+ biosensor GCaMP7f. Formation of reactive oxygen species was measured using an oxidant-sensing probe dihydrofluorescein diacetate. KEY RESULTS: Quercetin protected H9c2 cells against hypertonic stress-induced cell death. We observed a significant increase in intracellular Ca2+ levels ([Ca2+]cyto) when cells originally placed in a hypertonic solution were returned to a normotonic environment. Quercetin was found to prevent this increase in [Ca2+]cyto and also the depolarization of mitochondrial membrane potential. CONCLUSIONS AND IMPLICATIONS: Quercetin, but not 2,3-dehydrosilybin, reduced adverse effects of osmotic stress mainly by dampening the elevation of [Ca2+]cyto and mitochondrial Ca2+ overload. This may consequently prevent MPTP pore opening and activation of apoptosis.

Water equivalent path length measurement in proton radiotherapy using time resolved diode dosimetry.

PURPOSE: To verify water equivalent path length (WEPL) before treatment in proton radiotherapy using time resolved in vivo diode dosimetry. METHODS: Using a passively scattered range modulated proton beam, the output of a diode driving a fast current-to-voltage amplifier is recorded at a number of depths in a water tank. At each depth, a burst of overlapping single proton pulses is observed. The rms duration of the burst is computed and the resulting data set is fitted with a cubic polynomial. RESULTS: When the diode is subsequently set to an arbitrary depth and the polynomial is used as a calibration curve, the "unknown" depth is determined within 0.3 mm rms. CONCLUSIONS: A diode or a diode array, placed (for instance) in the rectum in conjunction with a rectal balloon, can potentially determine the WEPL at that point, just prior to treatment, with submillimeter accuracy, allowing the beam energy to be adjusted. The associated unwanted dose is about 0.2% of a typical single fraction treatment dose.

Deterministic proton dose calculation from first principles.

The purpose of this paper is to find a deterministic pencil beam algorithm that computes, from first principles, the dose in some region of interest when a known heterogeneous terrain is irradiated by known proton beams. The terrain is discretized into slabs perpendicular to the nominal beam direction. Pencil beams (PBs) are transported through each slab using generalized Fermi-Eyges theory with the correct stopping and scattering powers for each material (no water-like assumption). At transverse heterogeneities PBs are divided into smaller ones using either redefinition (all PBs divided) or dynamic splitting (PBs divided one at a time as needed). Dynamic splitting recurs until the transverse heterogeneity is sufficiently well resolved. After a PB is transported, its dose contribution at the slab exit (if designated as a measuring plane) is added to each point of interest. The calculation depends solely on accurate descriptions of the terrain and of the incident beams. It does not require measurements such as effective source size and position. These follow from the beam line specifications. The calculation ignores nuclear reactions (hard scatters), as do other PB algorithms. Our first comparison with experiment confronts the widely used 'Hong' algorithm. The second is a simple study of collimator scatter and the third studies collimator scatter under more extreme conditions. All agree well with the high dose region. The latter two agree substantially with collimator scatter and thickness effects, ignored by conventional algorithms. The algorithm gives a good account of the high dose region, including realistic collimator effects. It is equally amenable to passive beam spreading or pencil beam scanning (PBS). It dispenses with measurements (commissioning) of beam line properties. In PBS it promises to be faster than conventional algorithms since virtual PBs are generated only as needed. These results justify further work towards a full-fledged therapy dose engine.

Cystic fibrosis: comparison of two mucolytic drugs for inhalation treatment (acetylcysteine and arginine hydrochloride).

Clinical, bronchoscopic, spirographic, scintigraphic, and chemical analyses were done in 24 children with cystic fibrosis to assess the mucolytic effects of acetylcysteine inhalations versus L-arginine hydrochloride aerosols. The latter drug is less active than acetylcysteine and should not be used to treat children with cystic fibrosis.

Test of GEANT3 and GEANT4 nuclear models for 160 MeV protons stopping in CH2.

Monte Carlo simulations are used for many problems in proton radiation therapy, some of which are sensitive to the nuclear interaction model. The available models have been little tested in the regime of interest, namely in their ability to predict the secondary particle yield, including their angle and energy, when 70-250 MeV protons stop in various materials. The present study provides one such test in carbon, complementing a previous one in copper. Using a multilayer Faraday cup we have measured the projected range distribution of charged nuclear secondaries from 160 MeV protons stopping in polyethylene (CH2). To test the popular GEANT Monte Carlo we have simulated the experiment with GEANT3 using the "Gheisha" (default) and "Fluka" models and with GEANT4.5 using the "low-energy" and "precompound" models. The GEANT3/Fluka and GEANT4/precompound simulations agree moderately well with the observed range distribution. The data are given in a convenient form for testing other Monte Carlo programs.

Nuclear interactions of 160 MeV protons stopping in copper: a test of Monte Carlo nuclear models.

To estimate the influence of nuclear interactions on dose or biological effect one uses Monte Carlo programs which include nuclear models. We introduce an experimental method to check these models at proton therapy energies. We have measured the distribution of charge deposited by 160 MeV protons stopping in a stack of insulated copper plates. A buildup region ahead of the main peak contains approximately 20% of the total charge and is entirely due to charged secondaries from inelastic nuclear interactions. The acceptance for charged secondaries is 100%. Therefore the data are a good benchmark for nuclear models. We have simulated the stack using GEANT with two nuclear models. FLUKA agrees fairly well with the measurement but GHEISHA, designed for much higher energies, does not. The experimental method will work for many other materials, including insulators. Therefore it can also be used for light nuclei.

Physical specifications of clinical proton beams from a synchrotron.

Tumor treatment with charged particle beams is a quickly developing field aimed to translate the potential advantages offered by the superior physical dose distribution and relative biological effectiveness of heavy charged particles into a real improvement of tumor therapy. To this purpose the new proton and light-ion radiation therapy facilities must be designed according to strict clinical specifications to provide a reliable and effective tool against cancer. This paper provides the performance specifications of the accelerator and of the beam transport and delivery systems of the Italian Hadrontherapy Centre, which should be satisfied to meet the clinical specifications. A discussion is given on the requirements on energy range, energy variability, beam intensity, lateral penumbra, distal dose falloff, source-to-surface distance, time structure of the extracted beam, raster scanning system specifications, and beam abort time. Though the physical specifications are given for a particular accelerator, they can be used as a general guideline for the design of future biomedical particle accelerator facilities.

A pencil beam algorithm for proton dose calculations.

The sharp lateral penumbra and the rapid fall-off of dose at the end of range of a proton beam are among the major advantages of proton radiation therapy. These beam characteristics depend on the position and characteristics of upstream beam-modifying devices such as apertures and compensating boluses. The extent of separation, if any, between these beam-modifying devices and the patient is particularly critical in this respect. We have developed a pencil beam algorithm for proton dose calculations which takes accurate account of the effects of materials upstream of the patient and of the air gap between them and the patient. The model includes a new approach to picking the locations of the pencil beams so as to more accurately model the penumbra and to more effectively account for the multiple-scattering effects of the media around the point of interest. We also present a faster broad-beam version of the algorithm which gives a reasonably accurate penumbra. Predictions of the algorithm and results from experiments performed in a large-field proton beam are presented. In general the algorithm agrees well with the measurements.

[Sonographic findings in the gallbladder in mucoviscidosis patients]. / Sonographische Befunde der Gallenblase bei Patienten mit Mukoviszidose.

The improved survival time of patients with mucoviscidosis has revealed some new complications. 137 patients were studied by sonography. The findings in the gall bladder have been compared with liver echogenicity. A micro-gall bladder was found in 37 patients (27%). 74 patients had a normal gall bladder (54%). Concretions were found in 22 (16%) of patients. 10 out of the 22 patients with concretions showed sonographic changes in the liver. In view of the frequent abdominal symptoms in patients with mucoviscidosis, sonography should be used routinely as a non-invasive method of investigation.

Logarithmic analog-to-digital converter using switched attenuators.

One can construct a successive-approximation analog-to-digital converter (ADC) whose output is proportional to the logarithm of the input voltage, by using independent electronically switched attenuators. The output step size of such an ADC corresponds to a constant relative change in the voltage being measured, rather than a constant absolute change as in a linear ADC. The principle described here is fully ''digital'' in that it depends only on the accuracy of resistors and not on the logarithmic I-V characteristic of any solid-state device. A practical ten-bit prototype conforms to the ideal logarithmic characteristic to about 1% over a four-decade input voltage range, 1 mV to 10 V; effectively, any input in that range is measured to about 1%. Complexity, cost, and speed are comparable to simple linear ADCs.

[Proposals for inhalation therapy with ultrasonic nebulizers (author's transl)]. / Behandlungsvorschläge für die Aerosoltherapie mit Ultraschallgeräten

With aerosols active substances (drugs) can be transported for treatment. Their effect depends on the choice of apparata, the drugs used, and the procedure of inhalation. The use of electronic nebulizers is effective because a sufficient volume of liquid substances can be nebulized by this way. Bronchospasmolytics, secretolytics, antiphlogistics, and antibiotics may be used. The right connexion of the patient, who should inhale in a closed system is important for an effective treatment. The patient is exposed to some hazards by contamination with inhaled bacteria, by hyperventilation, bronchospasm and by allergic reactions.

[Ultrasound changes of the pancreas in patients with mucoviscidosis]. / Sonographische Befunde am Pankreas bei Patienten mit Mukoviszidose.

Pancreas sonography was performed on 171 patients with cystic fibrosis. The pancreas was visualized in 138 patients (81%) and could not be visualized in 33. 125 patients (90%) had abnormal echogenicity of the pancreas. Cysts were found in 5 patients. Two patients showed a dilatation of the pancreatic duct. The pancreas was abnormal in 98% of all patients aged more than 6 years.

[Deposition of aerosols into the airways (author's transl)]. / Deponierung von Aerosolen in den Atemwegen.

The rate of powder absorbed in the lung greatly depends on the particle diameter, and amounts to 40--50% for 1 micrometer particles and 15--20% for 5 micrometer particles. Of importance for therapy was the information that single breath will deposit in the lung 15% of a powder aerosol of 2 micrometer diameter. The liquid aerosols as prevalently used in the therapy, were retained in the lung at a rate of 15% of the original amount when using ultrasonic apparatus. If calculated per minute of inhalation time, the amount absorbed by the lung amounted to 0.2 ml and that by the upper respiratory tract to 0.06 ml. Best deposition in the lung was obtained when inhaling in a closed system with valve-controlled aerosol stream, when using a mouthpiece, and when the test person inhaled with low respiratory rate, deep inspirations, short respiratory pause and complete exspiration. Mark inhalation with closed mouth gave only one tenth of the lung deposition reached with the breathing method described. The use of a mask showed good results, however, when the test person was breathing with open mouth. Only 0.07 ml/min were retained with jet nebulizer and mouth respiration. Combination with intermittent pressure respiration showed no convincing results.

The jamming avoidance response in Rhamphichthys rostratus: an alternative principle of time domain analysis in electric fish.

A Jamming Avoidance Response was found in the weakly electric fish Rhamphichthys rostratus, a South American pulse-Gymnotid. The analysis of the response suggests that it requires a key stimulus which is fundamentally different from that in previously described harmonic Gymnotids. It relies on a sensitivity for the direction of phase shifts of stimulus pulses relative to the fish's own electric organ discharge rather than on a sensitivity for beating frequencies.

[Fundamental investigations for the deposition of aerosols from radioactive solutions in the upper and lower airways (author's transl)]. / Grundsätzliche Untersuchungen zur Deponierung von Aerosolen aus radioaktiven Lösungen in den Atemwegen.

By means of 99mtechnetium diphosphonate and a scintillation camera we measured the deposition of aerosols. During normal breathing rhythm and without leading the aerosol by valves the retention in the lower airways was on an average of 5.6%, that is 0.07 ml/min. By installation of suitable valves for in- and expiration and mouth tubes, deep and complete expiration with breath holding the retention of the aerosol increases to 17.3-13.8% (0.22-0.17 ml/min); with normal breathing the deposition was only 9%. In the upper airways we found the following deposition rates: Nose/hypopharynx (inhalation via mask) 2.6%; Mouth and pharynx (after rinsing) 1.6%; Larynx 0.1%. A considerable part remains in the inhalation system; by special variations we were able to reduce this portion of the aerosol. After inhaling electro-aerosols (4 kv) the deposition in the lungs was 5.6%; the more the charge was reduced the more the deposition of the aerosol in the lung increased.

[Comparison of 2 pancreatic enzyme preparations in the treatment of digestive insufficiency in mucoviscidosis (cystic fibrosis)]. / Vergleich von zwei Pankreasenzym-Präparaten zur Behandlung der Verdauungsinsuffizienz bei Mukoviszidose (zystische Fibrose).

In an open trial 10 patients with cystic fibrosis were treated with two acid-protected pancreatic enzyme preparations formed as microtablets or pellets. The difference between Panzytrat 20,000 and Kreon is that with only 225 mg pancreatin, the former has twice the lipase activity of the latter. Therefore, the patients who had been taken Kreon were given only half the number of Panzytrat 20,000 capsules. There were no significant differences seen between the amounts of fecal fat nor in the fecal weight. In our study the fat absorption coefficient was somewhat too low with 67.4% for Kreon and 71.3% for Panzytrat 20,000 because of too low enzyme dosage, which was based only on an improvement of the clinical symptoms. Therefore, we would recommend a higher dose of 1000-1500 units of lipase/l g of dietary fat ingested. This requires the use of a preparation with high enzyme activity.

Subtle speech and motor deficits of children with congenital hypothyroid treated early.

This study surveyed the development and functioning of a group of 16 children with congenital hypothyroidism who had been followed closely since treatment was instituted at an average age of 15.6 days. This group of early-treated young children had no deficits in cognitive or adaptive functioning. Some isolated motor deficits were found, although results of the Finger-tapping and Marching subtests of the Reitan-Indiana battery did not replicate the New England Congenital Hypothyroid Collaborative (1985) finding of impaired performance. Speech deficits were documented in some. Congenitally hypothyroid children with delayed neonatal bone-age performed more poorly on most measures than those whose bone-age had been normal at birth.

Bronchial secretions and bronchial mucosa in children with cystic fibrosis: comparison of bronchoscopic, biochemical, bacteriological, microscopic and ultrastructural findings.

In children (mean age 12.1 +/- 2.9 years) with cystic fibrosis, 44 bronchoscopic examinations were done under general anaesthesia with muscle relaxation using a Friedel type ventilation bronchoscope. The endoscopic picture of the mucous membranes was compared with the state of the bronchial secretions, its bacteriologic findings and content of acid mucopolysaccharides and DNA fibres (semiquantitative estimations). In all patients biopsy of the mucous membrane (central part of the bronchial tree) was performed for light and electron microscopy. The degree of reddening, swelling of the mucous membrane and hypersecretion was in some agreement with the intensity of the cellular infiltration and the production of pus (microscopic investigation). Secondary ultrastructural changes were detected in nearly all children, consisting of cellular oedema, swelling of mitochondria, dilatation of the endoplasmatic reticulum, protrusion of cells and fusion of cilia, enlarged intercellular spaces, thickening of the epithelial basal membrane, increased number of goblet cells, microtubular abnormalities of the cilia, lesions of the apical cell membrane with loss of cilia and microvilli. These ultrastructural changes were not correlated with the above-mentioned signs of inflammation.