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PubMed1989

The irradiation of V79 mammalian cells by protons with energies below 2 MeV. Part I: Experimental arrangement and measurements of cell survival.

The relative biological effectiveness (RBE) has been determined for protons with mean energies of 1.9, 1.15 and 0.76 MeV, from measurements of the survival of V79 Chinese hamster cells. The cells are supported as a monolayer and are swept through a beam of scattered protons produced using a 4 MeV Van de Graaff accelerator. An estimation of the dose and unrestricted linear energy transfer (LET) variation within the sensitive volume of the cells is given for the three proton energies. The RBEs for cell survival (relative to 250 kVp X-rays) at the 10 per cent survival level are 1.6, 1.9 and 3.36 for protons with track-average LETs of 17, 24 and 32 keV microns-1 respectively, and the data suggest that protons are most effective at about 40-50 keV microns-1. It is shown that the proton RBEs can be reconciled with those of other light ions if plotted against z*2/beta 2 (where z* is the effective charge and beta is the relative velocity) rather than against LET.

Animals↗
PubMed1998

Inactivation of C3H10T1/2 cells by low energy protons and deuterons.

PURPOSE: To determine the RBE-LET relationship for C3H10T1/2 cell inactivation by protons in the LET range 11-33 keV/microm and to compare inactivation frequencies induced in C3H10T1/2 cells by protons and deuterons at two matching LET values in the range 11-20 keV/microm. MATERIALS AND METHODS: C3H10T1/2 cells were irradiated with protons and deuterons at the radiobiological facility set up at the 7MV Van de Graaff accelerator at the LNL, Legnaro, Padova. Gamma rays from 60Co were used as reference radiation. RESULTS: Proton RBE values (alpha/alphagamma) for inactivation of C3H10T1/2 cells are constant around a value of 2 between 11 and 20 keV/microm and then rise sharply to reach a value of 4.2+/-1.0 at 33 keV/microm. Deuteron RBE values are 1.7+/-0.4 and 2.2+/-0.6 at LET values of 13 and 18 keV/microm respectively. CONCLUSIONS: Proton RBE values with C3H10T1/2 cells are significantly larger than unity at LET values as low as 11 keV/microm. No difference in effectiveness for inactivation of C3H10T1/2 has been found between protons and deuterons at two LET values in the range 10-20 keV/microm.

Animals↗
PubMed1984

Volume-responsive sodium and proton movements in dog red blood cells.

Shrinkage of dog red blood cells (RBC) activates a Na transport pathway that is Cl dependent, amiloride sensitive, and capable of conducting Na-proton counterflow. It is possible to establish transmembrane gradients for either Na or protons and to demonstrate that each cation species can drive reciprocal movements of the other. The nature of the coupling between Na and proton movements was investigated using the fluorescent probe diS-C3(5) and also by an indirect method in which K movements through valinomycin channels were used to draw inferences about the membrane potential. No evidence was found to suggest that the Na-proton pathway activated by shrinkage of dog RBC is a conductive one. By exclusion, it is presumed that the coupling between the counterflow of Na and protons is electroneutral. The volume-activated Na-proton fluxes in dog RBC have certain properties that distinguish them from similar transport pathways in other cell types.

Amiloride↗
PubMed1995

Dose calculations in proton beams: range straggling corrections and energy scaling.

Three-dimensional dose planning systems employing accurate proton transport algorithms are essential for calculating absorbed dose distributions in proton therapy. In this paper, a pencil beam algorithm for the transport of protons in materials of interest for radiation therapy is developed. The Fermi-Eyges multiple-scattering theory is used to derive transport equations for calculating proton fluence and absorbed dose distributions. The multiple-scattering theory of Molière is used to predict mean square scattering angles and to develop an expression for calculating the root mean square (RMS) radial spread of a proton pencil beam, as a function of depth, in an arbitrary scattering material. A correction factor is suggested to account for the decrease in the radial spread at the end of the range due to range straggling. The effects of neglecting large-angle scattering events and the possibility of incorporating such events into the pencil beam algorithm are discussed. An energy scaling technique for determining the water-equivalent surface energy at a given depth in a heterogeneous scattering medium is developed. The water-equivalent energy, giving the same Molière scattering parameter B in water, is determined and the 1/e angle in water is scaled to the appropriate width in the scattering material. By using stored analytically or Monte Carlo calculated pencil beam distributions in water, the large-angle single-scattering events may be incorporated by approximating the scattering in an arbitrary material by the scattering in water for protons of the appropriate water-equivalent surface energy.

Algorithms↗
PubMed1995

Ionization chamber dosimetry of proton beams using cylindrical and plane parallel chambers. Nw versus Nk ion chamber calibrations.

Determinations of the absorbed dose in a 170 MeV proton beam have been performed using seven ionization chambers of different types: five cylindrical (two FWT IC-18 and three NE-2571, of which one was modified to have the central electrode made of graphite) and two plane parallel (NACP-02 and Roos FK-6). The ionization was converted into absorbed dose in the proton beam according to the generalization of the formalism provided by the IAEA Code of Practice (TRS 277), which enables the use of the same equations for all kinds of beam used in radiotherapy. The absorbed dose obtained with the two IC-18 chambers, a chamber type commonly used as a reference in proton beams, was up to 1.5% lower than that obtained with the Farmer NE-2571 chamber, which was used as the reference in this work when calibration factors in terms of NK were used. To investigate this difference, experimental ND factors for six chambers (the two IC-18 chambers, the NACP-02, the FK-6 and two of the NE-2571 chambers) were determined in a high-energy electron beam. The procedure commonly recommended for plane parallel ion chambers was used for all the chambers, using the same reference chamber, a Farmer NE-2571. In the 170 MeV proton beam all the ND factors yielded consistent absorbed dose determinations within the estimated experimental uncertainties. This finding calls into question the value of the product kattkm for the IC-18 chamber given by the IAEA Code of Practice used in this comparison, and points at possible chamber to chamber variations that theoretical kattkm factors cannot predict. The investigations enabled the determination of the Pwall(60Co) factor of the Roos FK-6 plane parallel chamber, yielding 1.003 +/- 0.5%, and a correction for the effect of the aluminium central electrode of NE-2571 chambers in proton beams, equal to 1.003 +/- 0.4%. Two of the chambers (the plane parallel FK-6 and the modified cylindrical NE-2571) were provided with calibration factors in terms of absorbed dose to water, Nw, at the quality of 60Co by the Primary Standard Dosimetry Laboratory in Germany (PTB). Using the Nw formalism excellent agreement was found with the determination based on the experimental ND, giving support to the implementation of the NW procedure in therapeutic proton beams.

Humans↗
PubMed1995

Deduction of the air w value in a therapeutic proton beam.

Utilization of air-filled ionization chambers with 60Co-based reference calibrations in proton dosimetry requires application of water to air stopping power ratios and the mean energy required to produce an ion pair (W or w). Accepted uncertainties in current w values for protons leads to a dosimetric uncertainty of 4 per cent when ionization chambers are employed to measure absorbed dose. For this reason, proton dosimetry protocols recommend the use of calorimetry as the absorbed dose standard. We used calorimetry in conjunction with an ionization chamber with 60Co reference calibrations to deduce the proton w value in the entrance region of a 250 MeV proton beam: 34.2 +/- 0.5 eV. Application of this w value, with its 1.5 per cent uncertainty, allows determination of dose in therapeutic proton beams, with uncertainties comparable to photon and electron values.

Air↗
PubMed1998

Experimental W values of low-energy protons in the alkane series from methane to pentane.

Accurate measurements of the mean energy expended in a gas per ion pair formed (W value) for protons slowed down in alkanes are needed (i) in the fields of neutron metrology and microdosimetry, and (ii) in the field of basic radiation research to check the validity of theoretical models describing the degradation of protons in matter. Here, data for protons at energies of less than 100 keV are of particular interest because W increases strongly with decreasing proton energy in the very low-energy region and shows some structure between 10 keV and 100 keV. For these reasons, the energy dependence of W was studied for completely slowed down monoenergetic protons in the alkane series from methane to pentane at energies 1 keV < or = T < or = 100 keV, by measuring the positive ionization yield produced in a plane-parallel ionization chamber. The final results, which have uncertainties of less than 1.5%, are given in tabular form and also in an analytical representation. They were used to determine the differential value omega of the mean energy expended in a gas per ion pair formed and to analyse differences in proton degradation in the alkanes as a function of the number of carbon atoms.

Alkanes↗
PubMed2000

Comparison of dosimetry recommendations for clinical proton beams.

The formalism and data in the two most recent dosimetry recommendations for clinical proton beams, ICRU Report 59 and the forthcoming IAEA Code of Practice, are compared. Chamber calibrations in terms of air kerma and absorbed dose to water are considered, including five different cylindrical ionization chamber types commonly used in proton beam dosimetry. The methodology for both types of calibration for ionization chambers is described in ICRU Report 59. The procedure based on air kerma calibrations is compared with an alternative formalism based on IAEA Codes of Practice (TRS-277, TRS-381), modified for proton beams. The new IAEA Code of Practice is exclusively based on calibrations in terms of absorbed dose to water and a direct comparison with ICRU Report 59 recommendations is made. Common to the two formalisms are the fundamental quantities Wair and w(air) and their atmospheric conditions of applicability. The difference in the recommended values of the ratio w(air)/Wair (protons to 60Co) is as large as 2.3%. The use of Wair and w(air) values for dry air (IAEA) and for ambient air (ICRU) is a contribution to the discrepancy, and the ICRU usage is questioned. For air kerma based chamber calibrations, ICRU Report 59 does not take into account the effect of different compositions of the build-up cap and chamber wall on the calibration beam quality. For the chamber types included in the study, this introduces discrepancies of up to 1.1%. Combined with differences in the recommended basic data, discrepancies in absorbed dose determination in proton beams of up to 2.1% are found. For the absorbed dose to water based formalism, differences in the formalism, notably the omission of perturbation factors for 60Co in ICRU 59, and data yield discrepancies in calculated kQ factors, and in absorbed dose determinations, between -1.5% and +2.6%, depending on the chamber type and the proton beam quality.

Air↗
PubMed2002

In-beam PET measurements of beta+ radioactivity induced by proton beams.

Our first in-beam PET measurements of the beta+ activation induced by proton irradiation are presented. Monoenergetic proton beams in the energy and intensity range suited for the treatment of deep-seated tumours were delivered by the synchrotron of the Gesellschaft für Schwerionenforschung Darmstadt (GSI). They were stopped in PMMA blocks placed in the centre of the field of view of the positron camera that is installed in the heavy ion tumour treatment facility at GSI. The beta+ activity signal was found to be three times larger than that produced by carbon ions at the same range and applied physical dose. The reconstructed spatial beta+ activity distributions were analysed and compared with the production of positron emitters predicted by a calculation based on experimental cross-sections and on the proton flux given by the FLUKA Monte Carlo code. The shape of the depth-activity profiles was well reproduced by the model and the correlation with the proton range and the depth-dose distributions was carefully investigated. Despite the non-trivial range determination from the beta+ activity distribution in the proton case, our experimental investigation supports the feasibility of an in situ proton therapy monitoring by means of in-beam PET, as already clinically implemented for the monitoring of carbon ion therapy at GSI Darmstadt.

Carbon↗
PubMed2002

Dosimetry using plane-parallel ionization chambers in a 75 MeV clinical proton beam.

Reference ionization chamber dosimetry in clinical proton beams is generally performed with cylindrical ionization chambers. However, when the measurement is performed in the presence of a large depth dose gradient or in a narrow spread out Bragg peak (SOBP), it could be advisable to use a plane-parallel chamber. Few recommendations and studies have been devoted to this subject. In this paper, experimental information on perturbation correction factors for four plane-parallel ionization chamber types in proton beams is presented. The experiments were performed in 75 MeV modulated and non-modulated proton beams. Monte Carlo calculations have been performed to support the conclusions of the experimental work. Overall, we were not able to find experimental evidence for significant differences between the secondary electron perturbation correction factors for plane-parallel chambers and those for a cylindrical NE2571. We found experimental ratios of perturbation correction factors that did not differ by more than 0.6% from unity for a Roos and two NACP02 chambers, and by not more than 1.2% for a Calcam-2 and two Markus chambers. Monte Carlo simulations result in corrections that are limited to 0.6% in absolute value, but given the overall uncertainties of the measurements, the deviations of the correction factors from unity could not be resolved from the experimental results. The results of the simulations thus support the experimental conclusion that perturbation correction factors for the set of plane-parallel chambers in both proton beams (relative to NE2571) do not deviate from unity by more than 1.2%. This confirms, within the experimental uncertainties, the assumption that the overall perturbation correction factor for a plane-parallel chamber in a low-energy proton beam is unity, made in IAEA TRS-398 and other dosimetry protocols. Given the large uncertainties of the gradient correction factors to be applied when using a cylindrical ionization chamber in a narrow SOBP or in the presence of a strong depth dose gradient, the level of agreement between plane-parallel and cylindrical ionization chambers observed in this study shows that plane-parallel chambers are a reliable alternative for reference dosimetry in low-energy proton beams.

Calibration↗
PubMed1999

Use of proton-pump inhibitors in complicated ulcer disease and upper gastrointestinal tract bleeding.

The use of proton-pump inhibitors in the management of complicated peptic ulcer disease and upper gastrointestinal bleeding is described. Treatment of peptic ulcers in patients who are Helicobacter pylori positive should include antimicrobial therapy to eradicate the infection; based on considerations of primary antimicrobial resistance and safety, one recommended regimen is the combination of a proton-pump inhibitor (lansoprazole 30 mg or omeprazole 20 mg), clarithromycin 500 mg, and amoxicillin 1 g, each twice daily for 14 days. The proportion of H. pylori-negative ulcers has increased in the United States, now accounting for 39% of patients with ulcers who report no intake of nonsteroidal anti-inflammatory drugs (NSAIDs). Compared with H. pylori-positive ulcers, H. pylori-negative ulcers are more aggressive, characterized by high recurrence rates and increased risk of bleeding and perforation. Long-term therapy with a proton-pump inhibitor may be useful in these patients. Acid suppressants may also have a role in the initial treatment of patients who have a bleeding ulcer, including those associated with NSAID use. For patients who require continuous NSAID therapy, proton-pump inhibitors have been shown to heal a significantly higher percentage of peptic ulcers in eight weeks than histamine H2-receptor antagonists, and maintenance therapy with either lansoprazole or omeprazole reduces ulcer recurrence. Preliminary data suggest a role for proton-pump inhibitors in the prevention of stress ulcers among critically ill patients. Proton-pump inhibitors play an important role in the treatment of both H. pylori-negative and H. pylori-positive peptic ulcers, as well as in upper gastrointestinal tract bleeding. Further study is needed regarding their role in preventing stress ulcers in critically ill patients.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1986

Comparative structural analysis of 1-methyladenosine, 7-methylguanosine, ethenoadenosine and their protonated salts IV: 1H, 13C, and 15N NMR studies at natural isotope abundance.

The 1H, 13C, and 15N NMR spectra of neutral and protonated forms of the nucleosides 1-methyladenosine (m1A), 7-methylguanosine (m7G) and ethenoadenosine (EA), as a model compound, have been analyzed in order to assign the site of protonation in m1A and m7G. Protonation of these nucleosides occurs in the pyrimidine ring of m1A and EA and in the imidazole ring of m7G, with the charge being distributed rather than localized. Structural differences for both m1A and m7G were observed in solution and compared with those existing in the crystal state of monomers as well as in tRNA where these nucleosides occur quite often. The protonated nucleoside structures in solution compared favorably in sugar pucker and glycosidic bond conformations with x-ray crystallographic data. Methyl group carbon chemical shifts of the protonated mononucleosides corresponded to those of the methyls of the respective nucleosides in native tRNA structures. Therefore, the tRNA methyl group carbon chemical shifts are indicative of fully protonated nucleosides in the native, three dimensional structure of the nucleic acid.

Adenosine↗
PubMed2002

Stable expression of gastric proton pump activity at the cell surface.

Stable cell lines expressing the gastric proton pump alpha- and/or beta-subunits were constructed. The cell line co-expressing the alpha- and beta-subunits showed inward Rb(+) transport, which was activated by Rb(+) in a concentration-dependent manner. In the alpha+beta-expressing cell line, rapid recovery of intracellular pH was also observed after acid load, indicating that this cell line transported protons outward. These ion transport activities were inhibited by a proton pump inhibitor, 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile (SCH 28080). In a membrane fraction of the alpha+beta-expressing cell line, K(+)-stimulated ATPase (K(+)-ATPase) activity and the acylphosphorylation of the alpha-subunit were observed, both of which were also inhibited by SCH 28080. The specific activity and properties of the K(+)-ATPase were comparable to those found in the native gastric proton pump. In the stable cell lines, the alpha-subunit was retained in the intracellular compartment and was unstable in the absence of the beta-subunit, but it was stabilized and reached the cell surface in the presence of the beta-subunit. On the other hand, the beta-subunit was stable and able to travel to the cell surface in the absence of the alpha-subunit. These cell lines are ideal for the structure-function study of ion transport by the gastric proton pump as well as for characterization of the cellular regulation of surface expression of the functional proton pump.

Biological Transport↗
PubMed1987

Flash-induced proton release in Rhodopseudomonas sphaeroides spheroplasts.

Proton release by flash excitations was measured with right-side-out vesicles prepared from Rhodopseudomonas sphaeroides by lysozyme-EDTA treatment followed by hypotonic treatment. Absorbance change at 586 nm in the presence of bromcresol purple was measured to monitor the pH change. In the presence of horse heart cytochrome c, which catalyzes the electron transfer from the cytochrome b-c1 complex to the primary electron donor, the single-turnover flash elicited release of about two protons per primary electron donor, which was rereduced rapidly by the added cytochrome c. The halftime of the proton release was about 70 ms at pH 6.3 and at a redox potential of about 150 mV. The rate was considerably lower than that of the electron transfer from the cytochrome b-c1 complex to cytochrome c. However, multiple flashes with intervals of 60 ms caused release of the same amount of protons as that by flashes with longer intervals. This indicated that the proton release itself was rapid, but delocalization was slower. Antimycin A inhibited the proton release, and myxothiazol almost completely abolished it.

Biological Transport↗
PubMed2002

Glow curve analysis applied to the discrimination of X ray versus proton irradiation.

Three types of thermoluminescence dosemeters (TLDs): LiF:Mg,Ti (TLD-100), CaF2:Tm (TLD-300), and alpha-Al2O3:C (TLD-500), were investigated for their glow curve response to separate X ray and proton irradiations. The glow curve structure for each individual TLD's exposure to the X ray and proton irradiations was analysed and compared. Distinguishable differences between the glow curve structure characteristic of each type of radiation were observed. The proton TLD-100 glow curve has revealed a complex high-temperature peak structure that was used for the proton/X ray discrimination algorithm. Proton irradiation of TLD-300 resulted in an apparent switch in the relative heights of peaks 3 and 5 as compared to X ray. In TLD-500, proton irradiation produced a more subtle difference in the glow curve with an increase in the ratio between high- and low-temperature peaks. Results demonstrate promising differences in glow curve structure present allowing for discrimination between X ray and proton radiation field exposures.

Calcium Fluoride↗
PubMed1996

Nicotinamide nucleotide transhydrogenase: a model for utilization of substrate binding energy for proton translocation.

The energy-transducing nicotinamide nucleotide transhydrogenases of mammalian mitochondria and bacteria are structurally related membrane-bound enzymes that catalyze the direct transfer of a hydride ion between NAD(H) and NADP(H) in a reaction that is coupled to transmembrane proton translocation. The protonmotive force alters the affinity of the transhydrogenase for substrates, accelerates the rate of hydride ion transfer from NADH to NADP, and shifts the equilibrium of this reaction toward NADPH formation. Transhydrogenation in the reverse direction from NADPH to NAD is accompanied by outward proton translocation and formation of a protonmotive force. In reverse transhydrogenation, the enzyme utilizes substrate binding energy for proton pumping. Therefore, with regard to the mechanism of energy transduction, the transhydrogenase works according to the same principles as the ATP synthase complex of mitochondria and bacteria, the proton and cation ATPases, and possibly certain redox-linked proton pumps. However, the relatively simple structure of the transhydrogenase recommends it as a model for study of the utilization of binding energy for vectorial translocation of protons and other cations.

Amino Acid Sequence↗
PubMed1984

Effects of volatile anesthetics on light-induced proton uptake of rhodopsin in bovine rod outer segment disk membrane.

The effects of volatile anesthetics upon the function of bovine rhodopsin were estimated from the measurements of light-induced proton uptake. The light-induced pH changes were measured at both 20 degrees C and 37 degrees C with suspensions to which volatile anesthetics were added in the liquid form. Each anesthetic depressed the light-induced proton uptake concentration-dependently. The anesthetic-induced depression was greater at 37 degrees C than at 20 degrees C. For each anesthetic the concentration needed to depress the proton uptake by 10% was roughly identical to that used clinically. Anesthetics also were added to the suspensions in the gaseous form with air. The light-induced proton uptake was decreased in proportion to the partial pressure of the anesthetic. The partial pressures of halothane and methoxyflurane that depressed the proton uptake by 10% at 37 degrees C were 2.0 x 10(-7) and 1.1 x 10(-2) atm., respectively. From these facts it is suggested that volatile anesthetics affect the light-induced conformational changes of rhodopsin molecule during the metarhodopsin I to metarhodopsin II transition and cause inhibition of the light-induced proton uptake of rhodopsin in the rod outer segment disk membrane.

Anesthetics↗
PubMed1996

Proton-pump inhibitors are the treatment of choice in acid-related disease.

INCREASING INTRAGASTRIC PH: Effective treatment of acid-related disease requires an increase in intragastric pH. The two principal pharmacological methods of attaining this goal are (1) using histamine (H2)-receptor antagonists to block H2-receptors on the parietal cell and (2) using proton-pump inhibitors to stop acid production acid at its source. H2-RECEPTOR ANTAGONISTS: H2-receptor antagonists bind loosely and non-covalently to receptors on the parietal cell. They represented a great advance when they first appeared, bringing relief to many patients and improving the standard of care, with fewer operations and hospitalizations and a generally improved quality of life. However, many patients do not respond to these drugs, either because of the nature of the disease or because of resistance to the agent. PROTON-PUMP INHIBITORS: Proton-pump inhibitors represent an advance in the therapy of acid-related disease because they inhibit all acid production, no matter what the source of the stimulus, by binding covalently to the proton pump. Compared with H2-receptor antagonists, the effect of proton-pump inhibition is longer-lasting, faster-acting, and more effective, curing 99% of patients resistant to H2-receptor antagonist therapy. These properties make proton-pump inhibitors the treatment of choice for acid-related diseases.

Anti-Ulcer Agents↗