Determination of dosimetrical quantities used in microbeam radiation therapy (MRT) with Monte Carlo simulations.

Microbeam radiation therapy (MRT) is being performed by using an array of narrow rectangular x-ray beams (typical beam sizes 25 microm X 1 cm), positioned close to each other (typically 200 microm separation), to irradiate a target tissue. The ratio of peak-to-valley doses (PVDR's) in the composite dose distribution has been found to be strongly correlated with the normal tissue tolerance and the therapeutic effect of MRT. In this work a Monte Carlo (MC) study of the depth- and lateral-dose profiles in water for single x-ray microbeams of different shapes and energies has been performed with the MC code PENELOPE. The contributions to the dose deposition from different interaction types have been determined at different distances from the center of the microbeam. The dependence of the peak dose, in a water phantom, on the microbeam field size used in the preclinical trials, has been demonstrated. Composite dose distributions for an array of microbeams were obtained using superposition algorithms and PVDR's were determined and compared with literature results obtained with other Monte Carlo codes. The dependence of the PVDR's on microbeam width, x-ray energy used, and on the separation between adjacent microbeams has been studied in detail.

Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas.

PURPOSE: Microbeam radiation therapy (MRT), a novel experimental radiosurgery that largely spares the developing CNS and other normal tissues, is tolerated well by developing animals and palliates advanced 9LGS tumors. This report, to our knowledge, is the first demonstration that gene-mediated immunotherapy (GMIMPR) enhances the efficacy of MRT for advanced 9LGS tumors. METHODS: Seventy-six male Fischer 344 rats were implanted ic with 10(4)9LGS cells on d0. By d14, the cells had generated approximately approximately 40 mm3 ic 9LGS tumours, experimental models for therapy of moderately aggressive human malignant astrocytomas. Each of the 14 untreated (control) rats died from a large (>100 mg) ic tumor before d29 (median, d21). On d14, the remaining 62 rats were given deliberately suboptimal microbeam radiation therapy (MRT) by a single lateral exposure of the tumor-bearing zone of the head to a 10.1 mm-wide, approximately approximately 11 mm-high array of 20-39 microm-wide, nearly parallel beams of synchrotron wiggler-generated radiation (mainly approximately 50-150 keV X-rays) that delivered 625 Gy peak skin doses at approximately approximately 211 microm ctc intervals in approximately approximately 300 ms either without additional treatments (MRT-only, 25 rats), with post-MRT GMIMPR (MRT+GMIMPR, 23 rats: multiple sc injections of irradiated (clonogenically-disabled) GM-CSF gene-transfected 9LGS cells), or with post-MRT IMPR (MRT+IMPR, 14 rats: multiple sc injections of irradiated (clonogenically-disabled) 9LGS cells. RESULTS: The median post-implantation survivals of rats in the MRT-only, MRT+GMIMPR and MRT+IMPR groups were over twice that of controls; further, approximately approximately 20% of rats in MRT-only and MRT+IMPR groups survived >1 yr with no obvious disabilities. Moreover, over 40% of MRT+GMIMPR rats survived >1 yr with no obvious disabilities, a significant (P<0.04) increase over the MRT-only and MRT+IMPR groups. SIGNIFICANCE: These data suggest that the combination of MRT+GMIMPR might be better than MRT only for unifocal CNS tumors, particularly in infants and young children.

Cellular uptake of phosphorothioate oligonucleotide facilitated by cationic porphyrin: a microfluorescence study.

Cationic 5,10,15,20-tetrakis (1-methyl-4-pyridyl) porphyrin was tested as a delivery agent for oligonucleotides. By using fluorescence microimaging, it has been shown that complexation of the porphyrin to the phosphorothioate analog of dT(15) labeled by rhodamine enabled its nonendocytic penetration into the cell and regular distribution in the cytoplasm and preferentially into the nucleus. Time-resolved microfluorescence spectroscopy revealed that the oligonucleotide integrity was kept. A small fraction of the porphyrin molecules seems to undergo change of the binding mode after internalization, probably due to duplex formation between the oligonucleotide and its cellular target sequences, or due to dissociation of the porphyrin from the oligonucleotide and subsequent interactions in the cellular environment.

[Severe vertigo after a scuba-dive to 29 meters]. / Der PRAXIS-Fall. Starker Schwindel nach einem Tauchgang in 29 Meter Tiefe.

A 27-year-old flight instructor experienced 5 to 10 minutes after a scuba-dive to 29 m, which lasted totally 50 minutes, dizziness, nausea and severe vertigo. The symptoms lasted about an hour. The patient vomited several times and noted sudden onset headache and vertigo lasting the following three days. Hyperbaric oxygen therapy was started 30 hours after the event because decompression sickness was suspected. Transthoracic echocardiographic evaluation showed a patent foramen ovale. Diving accidents may be caused by decompression sickness, the formation of a free intravascular gas phase (bubbles) may result in transatrial shunting in the presence of a patent foramen ovale and may lead to neurological signs and symptoms. In this context the diver was advised to undergo closure of the atrial septal defect. Five months after the incident the patient underwent successful transcatheter occlusion of the PFO.

Comparison of Monte Carlo simulations of photon/electron dosimetry in microscale applications.

It is important to establish reliable calculational tools to plan and analyse representative microdosimetry experiments in the context of microbeam radiation therapy development. In this paper, an attempt has been made to investigate the suitability of the MCNP4C Monte Carlo code to adequately model photon/electron transport over micron distances. The case of a single cylindrical microbeam of 25-micron diameter incident on a water phantom has been simulated in detail with both MCNP4C and the code PSI-GEANT, for different incident photon energies, to get absorbed dose distributions at various depths, with and without electron transport being considered. In addition, dose distributions calculated for a single microbeam with a photon spectrum representative of the European Synchrotron Radiation Facility (ESRF) have been compared. Finally, a large number of cylindrical microbeams (a total of 2601 beams, placed on a 200-micron square pitch, covering an area of 1 cm2) incident on a water phantom have been considered to study cumulative radial dose distributions at different depths. From these distributions, ratios of peak (within the microbeam) to valley (mid-point along the diagonal connecting two microbeams) dose values have been determined. The various comparisons with PSI-GEANT results have shown that MCNP4C, with its high flexibility in terms of its numerous source and geometry description options, variance reduction methods, detailed error analysis, statistical checks and different tally types, can be a valuable tool for the analysis of microbeam experiments.

MOSFET dosimetry for microbeam radiation therapy at the European Synchrotron Radiation Facility.

Preclinical experiments are carried out with approximately 20-30 microm wide, approximately 10 mm high parallel microbeams of hard, broad-"white"-spectrum x rays (approximately 50-600 keV) to investigate microbeam radiation therapy (MRT) of brain tumors in infants for whom other kinds of radiotherapy are inadequate and/or unsafe. Novel physical microdosimetry (implemented with MOSFET chips in the "edge-on" mode) and Monte Carlo computer-simulated dosimetry are described here for selected points in the peak and valley regions of a microbeam-irradiated tissue-equivalent phantom. Such microbeam irradiation causes minimal damage to normal tissues, possible because of rapid repair of their microscopic lesions. Radiation damage from an array of parallel microbeams tends to correlate with the range of peak-valley dose ratios (PVDR). This paper summarizes comparisons of our dosimetric MOSFET measurements with Monte Carlo calculations. Peak doses at depths <22 mm are 18% less than Monte Carlo values, whereas those depths >22 mm and valley doses at all depths investigated (2 mm-62 mm) are within 2-13% of the Monte Carlo values. These results lend credence to the use of MOSFET detector systems in edge-on mode for microplanar irradiation dosimetry.

Detection of genetically divergent clone mates in apomictic dandelions.

This study aims to identify genetically diverged clone mates in apomictic dandelions. Clone mates are defined as individuals that may have diverged as a result of mutation accumulation and that have undergone only clonal reproduction since their most recent common ancestor. Based on distinctive morphology and an aberrant and rare chloroplast haplotype, northwest European individuals of Taraxacum section Naevosa are well suited for the detection of clonal lineages in which mutation has occurred. In the case of strictly clonal reproduction, nuclear genetic variability was expected to be hierarchically organized. Nucleotide polymorphisms in internal transcribed spacer (ITS) sequences, however, were incompatible with a clonal structure of the Norwegian individuals, probably due to persistent ancestral polymorphisms that pre-date the origin of the Naevosa clone. This interpretation is supported by the presence of ITS variants in section Naevosa that were also found in distantly related dandelions. In contrast to the ITS sequence data, amplified fragment length polymorphisms (AFLPs), isozymes and microsatellites strongly supported the contention of prolonged clonal reproduction and mutation accumulation in Norwegian Naevosa. Because these markers are generally considered to be more variable and more rapidly evolving than ITS sequences, mutations in these markers probably evolved after the origin of the clone. Within the Norwegian clone, a surprising number of markers distinguished the clone mates. As a consequence, incorporation of mutation in the detection of clone mates is anticipated to have a big impact on estimates of size, geographical range and age of clones as well as on experimental designs of studies of clonal plants.

Comparison of different cell-cluster models for cell-level dosimetry.

An important factor in dose calculations for targeted radionuclide therapy is the cell-cluster model used. We developed a cell-cluster model based on optimization through mechanical hard-sphere collisions. The geometrical properties and the dosimetric effects of the new model were compared with those of two previous models, i.e. the traditional lattice model and our CellPacker model in which the cells are individually and systematically piled as a cluster. The choice of the cell-cluster model has an effect on the calculated mean absorbed doses in the cells. While CellPacker produces clusters with distinct tumour-healthy tissue interface, our new model is able to make the interface diffuse. Outside the interface the new model is capable to pack cells tighter than CellPacker enabling the description of tissues of higher cellular density. Our two cluster models make it possible to construct the cluster model according to the tissue in question.

-CH2- lengthening of the internucleotide linkage in the ApA dimer can improve its conformational compatibility with its natural polynucleotide counterpart.

The complete family of ApA phosphonate analogues with the internucleotide linkage elongated by insertion of a -CH2- group was prepared and the hybridisation and structural properties of its members in interaction with polyuridylic acid were investigated using an original 2D Raman approach. Except for the conformationally restricted A(CH)pA(2'3'endo-5') modification, all of the isopolar, non-isosteric analogues form triplex-like complexes with poly(rU) at room temperature, in which two polymer strands are bound by Watson-Crick and Hoogsteen bonds to a central pseudostrand consisting of a 'chain' of A-dimers. For all of these dimers, the overall conformation of the triplexes was found to be similar according to their extracted Raman spectra. A simple semi-empirical model was introduced to explain the observed dependency of the efficiency of triplex formation on the adenine concentration. Apparently, for most of the modifications studied, the creation of a stable complex at room temperature requires the formation of a central pseudostrand, consisting of several adenine dimers. Molecular dynamics calculations were finally performed to interpret the differences in 'cooperative' behaviour between the different dimers studied. The results indicate that the exceptional properties of the Ap(CH2)A(3'-5') dimer could be caused by the 3D conformational compatibility of this modified linkage with the second (Hoogsteen) poly(rU) strand.

Radiation spectra of 111In, 113mIn and 114mIn.

The radiation spectra of 111In, 113In, and 114mIn are calculated with the Monte Carlo computer program IMRDEC. The relaxation probabilities are taken from the EADL file of the Lawrence Livermore National Laboratory. Because this file does not include data for some N and O transitions, these were additionally determined by applying the Kassis rule. Two schemes are applied to calculate the transition energies: 1) a simple (Z + 1)/Z scheme, and 2) accurate calculation solving the relativistic Dirac equations. It is shown that using the extended set of relaxation probabilities leads to generation of many additional low-energy Auger and CK electrons if the (Z + 1)/Z rule is applied. On the other hand, the emissions of almost all these electrons are rejected if their energies are calculated solving the Dirac equations taking into consideration realistic electron vacancies.

Hairpins involving both inverted and direct repeats are associated with homoplasious indels in non-coding chloroplast DNA of Taraxacum (Lactuceae: Asteraceae).

Sequence variation in 2.2 kb of non-coding regions of the chloroplast genome of eight dandelions (Taraxacum: Lactuceae) from Asia and Europe is interpreted in the light of the phylogenetic signal of base substitutions vs. indels (insertions-deletions). The four non-coding regions displayed a total of approximately 30 structural mutations of which 9 are potentially phylogenetically informative. Insertions, deletions, and an inversion were found that involved consecutive stretches of up to 172 bases. When compared to phylogenetic relationships of the chloroplast genomes based on nucleotide substitutions only, many homoplasious indels (33%) were detected that differed considerably in length and did not comprise simple sequence repeats typically associated with replication slippage. Though many indels in the intergenic spacers were associated with direct repeats, frequently, the variable stretches participated in inverted repeat stabilized hairpins. In each intergenic spacer or intron examined, nucleotide stretches ranging from 30 to 60 bp were able to fold into stabilized secondary structures. When these indels were homoplasious, they always ranked among the most stabilized hairpins in the non-coding regions. The association of higher order structures that involve both classes of repeats and parallel structural mutations in hot spot regions of the chloroplast genome can be used to differentiate among mutations that differ in phylogenetic reliability.

Methods to determine the fluorescence and Auger spectra due to decay of radionuclides or due to a single atomic-subshell ionization and comparisons with experiments.

The aim of this work is to describe methods of determining the fluorescence and Auger spectra due to decay of radionuclides or a single atomic-subshell ionization. First discussed is the electron vacancy generation in an atomic subshell by ionization, internal-conversion decay, or electron-capture decay. Later discussed is the status of electron vacancy following emission of fluorescence x rays and Auger electrons. Special attention is given to the relaxation probabilities and the procedures to calculate energies of released electrons. Also discussed are the Monte Carlo and deterministic methods to calculate vacancy cascades.

Physics study of microbeam radiation therapy with PSI-version of Monte Carlo code GEANT as a new computational tool.

Microbeam radiation therapy (MRT) is a currently experimental method of radiotherapy which is mediated by an array of parallel microbeams of synchrotron-wiggler-generated x-rays. Suitably selected, nominally supralethal doses of x-rays delivered to parallel microslices of tumor-bearing tissues in rats can be either palliative or curative while causing little or no serious damage to contiguous normal tissues. Although the pathogenesis of MRT-mediated tumor regression is not understood, as in all radiotherapy such understanding will be based ultimately on our understanding of the relationships among the following three factors: (1) microdosimetry, (2) damage to normal tissues, and (3) therapeutic efficacy. Although physical microdosimetry is feasible, published information on MRT microdosimetry to date is computational. This report describes Monte Carlo-based computational MRT microdosimetry using photon and/or electron scattering and photoionization cross-section data in the 1 eV through 100 GeV range distributed publicly by the U.S. Lawrence Livermore National Laboratory (LLNL) in the 1990s. These are compared with Monte Carlo-based microdosimetric computations using a code and physical data available in the 1980s. With the aim of using the PSI-version of GEANT Monte Carlo code for future macro- and micro/nano-dosimetric studies of Microbeam Radiation Therapy (MRT) a comparison of this code is made with the INHOM(EGS4) (version 1990), Dilmanian-CPE and Persliden-CPE Monte Carlo photon-electron codes (both version 1990) with which the absorbed dose distributions were calculated in 1990 and 1991 considering, (a) a single cylindrical microbeam, (b) multiple cylindrical microbeams in an orthogonal square bundle, and (c) multiple planar microbeams. It is shown that the PSI-version of GEANT can potentially deliver more accurate results (a) using presently the most advanced atomic data, and especially (b) employing "Single-collision" electron transport instead of only the "Condensed-history" electron transport as in code INHOM(EGS4). In contrast Dilmanian-CPE and Persliden-CPE codes deposit the electron energy locally instead of transporting it to the correct position.

[Acute febrile state]. / Akuter Status febrilis.

A 34 year old airline pilot, who had spent nine days in Cameroon (Westafrica) presented for his yearly physical examination two weeks later. The physical examination and routine laboratory tests were within normal limits. The patient complained about mild pain of joints and extremities and about not feeling quite well. The same evening (a few hours after the physical examination) he experienced chills and fever (up to 39.5 degrees Celsius). He was seen subsequently by a tropical medicine specialist, who diagnosed Plasmodium falciparum on blood smears. The patient was immediately placed on Riamet, fever and symptoms disappeared completely within a few days.

Cluster models in cellular level electron dose calculations.

A program for calculating absorbed dose was developed for radioimmunotherapy (RIT) purposes. It was used to determine the difference in the therapeutic effect of (111)In electrons when using a close-packed cubic geometry and a cell cluster model developed in this project. Our cluster model piles the cells individually. The cells were modelled as spheres of diameters of 12 (tumour) and 30 (healthy) microm. Both models were used to generate clusters with spherical tumours inside healthy tissue. The program uses Monte Carlo-based dose kernels. The radiation spectra were calculated from the Auger and x-ray transition strengths and fluorescence yields of (111)In. The results show the importance of the cluster model in cellular level dose calculations. Near the tumour/healthy tissue interface in particular, the doses differ because of geometrical differences. In the case of a small cluster with tumour and total diameters of 30 and 150 microm, the ratio of the therapeutic effects is 20.

Altitude-related illnesses.

Altitude-related illnesses are a frequent cause of morbidity and occasional mortality in travelers to high altitudes in the United States and throughout the world. The primary altitude illnesses are acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. The pathogenesis of these syndromes remains unclear despite considerable research. Altitude also has potential deleterious effects on common medical conditions including coronary artery disease, pulmonary disease, hemoglobinopathies, and pregnancy. Most of these problems are primarily preventable with appropriate information before travel. Education should include information about rate of ascent, diet, alcohol intake, physical activity, and preventive medications, including acetazolamide, nifedipine, and dexamethasone in selected circumstances.