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The microdosimetric kinetic (MK) model underestimates the cell-survival fractions for high linear energy transfer (LET) and high dose irradiations. To address the issue, some researchers previously extended the MK model to the stochastic microdosimetric kinetic (SMK) model. In the SMK model, the radiation induced cell-survival fractions were estimated from the specific energies z d and z n absorbed by a microscopic subnuclear structure domain and a cell nucleus, respectively. By taking the stochastic nature of z n as well as that of z d into account, the SMK model could reproduce the measured cell-survival fractions for radiations with wide LET and dose ranges. However, treatment planning based on the SMK model was unrealistic in clinical practice due to its long computation time and huge memory space required for the computation. In this study, we modified the SMK model to shorten the computation time and to reduce the memory space required for the computation. By using the dose-averaged cell-nucleus specific energy per event [Formula: see text] in the SMK formalism, the stochastic nature of z n was reflected onto the estimated cell-survival fractions. The accuracy of the modified SMK model was examined through the comparison between the estimated and the measured survival fractions of human salivary gland tumor cells and V79 cells. We then implemented the modified SMK model into the in-house treatment planning software for scanned charged-particle therapy to validate its applicability in clinical practice. As examples, treatment plans of helium-, carbon-, and neon-ion beams were made for an orbital tumor case. The modified SMK model could reproduce the measured cell-survival fractions more accurately compared to the MK model especially for high-LET and high-dose irradiations. In summary, the modified SMK model offers the accuracy and simplicity required in treatment planning of scanned charged-particle therapy for wide LET and dose ranges.

Background: Observational clinical studies have demonstrated that there is a U‐shaped relationship between ethanol consumption and all‐cause mortality or risk of ischemic stroke. Although the exact cause of the U‐shaped relationship is unclear, the pharmacokinetics of ethanol during the time course of chronic intake of ethanol may be involved, in relation to its cardiotoxic effects. The present study has assessed the cause of the U‐shaped relationship between the ethanol consumption and left ventricular (LV) systolic dysfunction in a pharmacokinetic way.Methods: Male Wistar rats were paired, and either ethanol or control liquid diet was chronically administered for 7 weeks. Then, these rats were subdivided into 3 groups: control liquid‐diet‐fed rats [EtOH (−)], 3 g/dL ethanol liquid‐diet‐fed rats (3%EtOH), and 5 g/dL ethanol liquid‐diet‐fed rats (5%EtOH). Ethanol's cardiotoxicity on LV systolic function was investigated by echocardiography. Ethanol concentration in blood, ethanol pharmacokinetics, and hepatic alcohol dehydrogenase (ADH) activity were evaluated simultaneously.Results: The 5%EtOH group revealed LV systolic dysfunction, associated with a higher ethanol concentration in blood, and lower hepatic ADH activity than the EtOH (−) group; however, the 3%EtOH group did not show LV systolic dysfunction. During the acute ethanol stress, LV systolic dysfunction appeared in both EtOH (−) and 5%EtOH groups, with a higher ethanol concentration in blood and lower hepatic ADH activity than the 3%EtOH group. The 3%EtOH group showed a higher ethanol washout rate, less time‐integral of ethanol concentration, and shorter mean residence time of ethanol in blood than the EtOH (−) or 5%EtOH group.Conclusions: The U‐shaped relationship between chronic ethanol consumption and LV systolic dysfunction may be closely related to the pharmacokinetic characteristics of ethanol in blood, which depends on the quantity of chronically drinking alcohol.

To summarize the results of treatment for sacral chordoma in Phase I-II and Phase II carbon ion radiotherapy trials for bone and soft-tissue sarcomas.We performed a retrospective analysis of 38 patients with medically unresectable sacral chordomas treated with the Heavy Ion Medical Accelerator in Chiba, Japan between 1996 and 2003. Of the 38 patients, 30 had not received previous treatment and 8 had locally recurrent tumor after previous resection. The applied carbon ion dose was 52.8-73.6 Gray equivalents (median, 70.4) in a total of 16 fixed fractions within 4 weeks.The median patient age was 66 years. The cranial tumor extension was S2 or greater in 31 patients. The median clinical target volume was 523 cm(3). The median follow-up period was 80 months. The 5-year overall survival rate was 86%, and the 5-year local control rate was 89%. After treatment, 27 of 30 patients with primary tumor remained ambulatory with or without supportive devices. Two patients experienced severe skin or soft-tissue complications requiring skin grafts.Carbon ion radiotherapy appears effective and safe in the treatment of patients with sacral chordoma and offers a promising alternative to surgery.

This study was conducted to develop a phase-space dataset in the International Atomic Energy Agency (IAEA) format for Monte Carlo (MC) simulations of the Leksell Gamma Knife® (LGK, Elekta Instrument AB, Stockholm, Sweden) Perfexion™ (PFX). An open-source MC code, namely, the Geant4 toolkit with a recently updated multi-threaded mode, was used to maximize the efficiency of the developed IAEA phase-space dataset. The absorbed dose profiles for single shots of the LGK PFX were calculated using the developed dataset and compared with those from radiochromic film measurements and Leksell GammaPlan® version 11.0.3 (LGP, Elekta Instruments) for verification. The mean relative absorbed dose differences in all single shots were less than 3.6% compared with the films and less than 4.0% compared with LGP. The collimator output factors were also calculated for all single shots and compared with the LGP results. The simulated collimator output factor was 0.816 ± 0.003 for a 4-mm shot and 0.903 ± 0.001 for an 8-mm shot in a spherical water phantom. The efficiency of the developed dataset was evaluated by comparing the times required for various simulations. Simulations with the phase-space dataset ran 25, 8.2 and 3.2 times faster than simulations without the phase-space dataset for 4-, 8-, and 16-mm shots, respectively. Using the dataset developed in this study, MC simulations of the LGK PFX can be performed more efficiently for various purposes, such as treatment plan verification and beam quality factor calculations.

Synovial fluid was collected from the superior articular cavity of the temporomandibular joint in patients with unilateral internal derangement and joint pain whose contralateral joint was healthy. Glycosaminoglycans were liberated by digestion with pronase E, and precipitated with cetylpyridinium chloride and ethanol. Unsaturated disaccharide isomers of chondroitin sulfate, obtained following chondroitinase ACII digestion, were analyzed by high‐performance liquid chromatography. Analytic data indicated that ΔDi‐0S and ΔDi‐6S were often found in chondroitin sulfate from the fluid of the diseased joints. The amounts of ΔDi‐0S and ΔDi‐6S differed significantly between synovial fluid samples from the diseased and healthy joints. Comparison of the relative proportions of the unsaturated disaccharides in the synovial fluid with previously reported values for several tissues, indicated that the chondroitin sulfate originated from articular cartilage, with possibly some contributions from soft connective tissues and serum present in the synovial fluid. These results suggest that chondroitin sulfate in the synovial fluid provides a useful indicator of the degree of internal derangement of the temporomandibular joint.

Urinary concentrations of coproporphyrin I and III (CP I and III) were determined by high-performance liquid chromatography in 131 male workers exposed to lead, and the relationships between lead exposure and urinary coproporphyrins were reevaluated. CP I had a statistically significant correlation with lead in the blood (Pb-B), but it was not useful as an indicator of the effect of lead on heme metabolism. On the other hand, CP III had a good correlation with Pb-B and markedly increased when Pb-B levels exceeded 40 to 50 micrograms/100 ml. Both sensitivity and specificity were more than 80% when the health-based Pb-B limit and the screening level of CP III were fixed at 50 micrograms/100 ml and 50 micrograms/g creatinine, respectively. In conclusion, measurement of CP III is sufficiently sensitive and specific enough in practice for the early detection of health effects due to lead exposure in the same way as the measurement of delta-aminolevulinic acid in urine.

The anticonvulsant effect of [(+/-)-2-[(inden-7-yloxy)methyl]morpholine (indeloxazine) HCl, a new cerebral activator, was investigated in rats against kindled seizures from the amygdala, an assumed model of secondarily generalized seizures in human. Indeloxazine (0.25-10 mg/kg, IP) dose-dependently depressed the kindled seizure and shortened the evoked amygdaloid afterdischarge. A high dose of indeloxazine (40 mg/kg, IP), however, induced generalized seizures. Comparison of the effects on the kindled seizures of indeloxazine to those of phenytoin, diazepam, ethanol, and imipramine revealed that the anticonvulsant actions of indeloxazine are similar to those of imipramine but not to those of phenytoin, ethanol, and diazepam. The results suggest that indeloxazine may exert its action through the monoaminergic system in the brain.