Design of ridge filters for spread-out Bragg peaks with Monte Carlo simulation in carbon ion therapy.

Spread-out Bragg peaks made by ridge filters or wheel range modulators are used in charged particle therapy with passive methods to achieve uniform biological responses in irradiated tumors. Following the biological responses needed to design the ridge filters, which were developed at the National Institute of Radiological Sciences in Japan, new ridge filters were designed using recent developments in heavy-ion reactions and dosimetry. The Monte Carlo code of Geant4 was used to calculate the qualities of carbon ion beams in a water phantom. The results obtained from the simulation were corrected so that they agreed with the measurements of depth dose distributions. The calculations of biological responses to fragments other than carbon ions were assumed to be for helium ions. The measured dose distributions with the designed ridge filters were compared to the calculated distributions. A beam modifying system using this adaptable method was successively applied to carbon ion therapy at Gunma University.

The compact electron cyclotron resonance ion source KeiGM for the carbon ion therapy facility at Gunma University.

A high-energy carbon-ion radiotherapy facility is under construction at Gunma University Heavy Ion Medical Centre (GHMC). Its design was based on a study of the heavy ion radiotherapy at the National Institute of Radiological Sciences (NIRS) in order to reduce the size and construction cost of the facility. A compact electron cyclotron resonance ion source (ECRIS) for Gunma University, called KeiGM, was installed in 2008. It is almost a copy of the prototype ECRIS Kei2 which was developed by NIRS; meanwhile this prototype produced over 1 e mA of C(4+) using C(2)H(2) gas (660 W and 40 kV). The beam intensity of C(4+) was 600 e microA with CH(4) gas (250 W and 30 kV). The beam intensity satisfies the required value of 300 e microA.

Study on tobacco components involved in the pyrolytic generation of selected smoke constituents.

The aim of this study was to investigate the contribution of various tobacco components to the generation of smoke constituents using a tobacco pyrolysis model. We analyzed the amounts of primary tobacco components (sugars, protein, polyphenols, alkaloids, organic acids, inorganics etc.) in flue-cured and burley tobacco leaves. Each of the components was added to the tobacco leaves at the 0.5-fold and 1.0-fold amount naturally present in the leaves. The treated tobacco samples were pyrolyzed at 800 degrees C in a nitrogen atmosphere with an infrared image furnace, and the selected smoke constituents (benzo[a]pyrene, hydrogen cyanide, carbonyl compounds, aromatic amines, volatile organic compounds and phenolics) were quantitatively analyzed by several methods, including high performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC-MS). The contribution of each tobacco component to the generation of selected smoke constituents was estimated from a regression line determined by the three yields (no addition, 0.5-fold addition, and 1.0-fold addition). The results of this study can provide useful and comprehensive information on the relationship between tobacco components and selected smoke constituents during pyrolysis.

Effects of temperature, atmosphere and pH on the generation of smoke compounds during tobacco pyrolysis.

The pyrolysis of tobacco under a variety of conditions was performed to examine the generation profiles of 29 known toxic compounds in tobacco smoke (hydrogen cyanide, benzo[a]pyrene, aldehydes, volatile organic compounds, phenolics, aromatic amines, etc.). The generation profiles of smoke compounds varied according to three conditions: the pyrolysis temperature (300-1000 degrees C), the pyrolysis atmosphere (in nitrogen and air) and pH of the tobacco leaf (2.89-7.07). Most of the smoke compounds (28 compounds) were generated primarily at temperatures less than 800 degrees C. More than half of the smoke compounds (17 compounds) were unaffected by the type of atmosphere, and seven compounds were significantly affected by pH. These results can provide basic and useful information to further study on the formation mechanisms and the technology involved in the control of smoke generation.

Toxic dose of a simple phenolic antioxidant, protocatechuic acid, attenuates the glutathione level in ICR mouse liver and kidney.

It has previously been reported that a toxic dose of protocatechuic acid (PA), a naturally occurring simple phenolic antioxidant in dietary plant foodstuff, has a potential to enhance tumorigenesis and induce contact hypersensitivity in mouse skin. In this study, the modifying effect of a toxic dose of PA on the glutathione (GSH) level in mouse liver and kidney was examined. Intraperitoneal administration of PA (500 mg/kg) caused significant hepatic and nephrotic GSH depletion. Interestingly, slight but significant hepatotoxicity and nephrotoxicity, characterized by the enhancement of plasmic alanine aminotrasferase (ALT) activity and urea level, respectively, were also observed. The subchronic administration of PA (0.1% in drinking water) for 60 days showed not only a significant decrease in the GSH level in kidney but also a significant enhancement of ALT activity in plasma. The protective role of GSH for acute hepatotoxicity using GSH-depleted mice administered a GSH synthesis inhibitor buthionine sulfoximine was also demonstrated. Thus, it is suggested that overdoses of PA can disturb the detoxification of other electrophilic toxicants including ultimate carcinogens.

A catechol antioxidant protocatechuic acid potentiates inflammatory leukocyte-derived oxidative stress in mouse skin via a tyrosinase bioactivation pathway.

The modifying effects of topical application of a catechol antioxidant protocatechuic acid (PA) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory responses in mouse skin were investigated. Treatment with a high dose (20,000 nmol) of PA, based on time of application, modifies inflammatory responses in the skin of the B6C3F(1) mouse, a resistant strain to inflammatory response induction by TPA, but shows much higher tyrosinase expression than that of an albino mouse. The responsibility of a large amount of PA-induced leukocyte infiltration to an inflamed region in a B6C3F(1) mouse is more sensitive than that of an ICR albino mouse. When ICR mice were treated with TPA (1.6 nmol) twice weekly for 5 weeks to induce chronic inflammatory responses, pretreatment with 1600 nmol PA 30 min prior to each TPA treatment significantly enhanced the inflammatory responses including edema formation, leukocyte infiltration, and the level of thiobarbituric acid-reacting substances. The dose-dependency was closely parallel to the results of a tumor promotion study of PA previously reported. Further, the treatment of PA alone resulted in tyrosinase-dependent contact hypersensitivity in ICR mouse skin. In addition, the in vitro study of cytotoxicity demonstrated that bioactivation by tyrosinase but not myeloperoxidase of PA significantly enhanced cytotoxicity and intracellular glutathione consumption. We conclude that the tyrosinase-derived reactive quinone intermediate(s) of PA, which binds nucleophilic residues of proteins including sulfhydryl group and conjugates of which are recognized as haptens, was partially involved in alteration of the cellular immune functions including oxygen radical-generating leukocytes migration to inflamed regions.

Radiation therapy for life- or function-threatening infant hemangioma.

PURPOSE: To assess the effectiveness and long-term results of radiation therapy in infants with life- or function-threatening hemangiomas. MATERIALS AND METHODS: Thirteen patients with life- or function-threatening hemangiomas (eight male, five female; age range, 0-8 months; median age, 2 months) were treated with radiation therapy. Life-threatening hemangiomas were treated with five fractions of radiation per week, and function-threatening hemangiomas were treated with two fractions per week. A median dose of 10 Gy was delivered to each hemangioma. The presence of residual hemangiomas, skin changes, functional problems, and growth delay was evaluated. RESULTS: All patients with Kasabach-Merritt syndrome (KMS) showed regression of the hemangioma and an increase in platelet counts to greater than 100,000 per cubic millimeter (1.0 x 10(11) per liter) within 40 days after radiation therapy. The treatment field was inadequate in two patients who required reirradiation or a change of treatment portal. With the exception of the patients with KMS, all but one patient experienced relief from symptoms in 40 days. Severe long-term radiation-related morbidity was noted in one patient who required reirradiation for a relapsed hemangioma. CONCLUSION: Radiation therapy (in doses of < or = 10 Gy in 2-Gy fractions) is indicated for life-threatening hemangiomas and for some function-threatening hemangiomas.

Epidemiological study of vancomycin-resistant enterococcus isolated from a single medical university hospital in Japan.

Since 1998 more than 50 reports have described the isolation of high-level vancomycin-resistant enterococci (VRE) in Japan. Here, we report on our clinical isolates of VRE and an epidemiological study carried out using chemical and genetic techniques. VRE isolates were screened for high resistance to vancomycin (VCM) with a cutoff value of 6 microg/ml and VCM-resistant gene was confirmed by polymerase chain reaction (PCR). The epidemiological studies used pulsed-field gel electrophoresis (PFGE) and plasmid analysis. Six strains of VRE were isolated from six different patients on two wards during a 3-months period. All of the isolates possessed vanA on their plasmid, and the isolates were divided into two similar groups. Furthermore, three different patterns were defined by PFGE. Although all of the asymptomatic carriers were hospitalized for more than 3 months, we were able to prevent an outbreak of VRE in our hospital by using our guidelines for infection control, which are stricter than those for methicillin-resistant Staphylococcus aurens. From the results of this epidemiological study, we propose that there was a possibility of contamination in this hospital, and that three of the six isolates may have acquired vanA independently. In this study, we demonstrated that infection control, according to appropriate prevention guidelines, as well as regular surveillance for VRE, are essential for designing interventions to prevent the further spread of VRE.

KL-6 as a novel marker for activities of interstitial pneumonia in connective tissue diseases.

The objective of this study was to determine the role of serum KL-6 levels as a marker for the activity of interstitial pneumonia in patients with connective tissue diseases. The serum concentrations of KL-6, a glycoprotein produced mainly by pulmonary type II epithelial cells, were measured in 21 patients with connective tissue disease. The activity of interstitial pneumonia was compared with the associated serum KL-6 concentrations. Serum KL-6 concentrations in patients with interstitial pneumonia were significantly higher than those in the controls. Among patients with active interstitial pneumonia, serum KL-6 concentrations following the treatment (after improvement) were significantly lower than the pretreatment values. The extent of the pulmonary fibrosis correlated positively with the serum KL-6 concentrations during the inactive phase of the interstitial pneumonia. These results suggest that sequential measurement of serum KL-6 levels is a new and useful means for the evaluation of interstitial pneumonia in patients with connective tissue diseases.

Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice.

The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-gamma in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 micromol)/TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P < 0.001) and 75.7% (P < 0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.

A simple phenolic antioxidant protocatechuic acid enhances tumor promotion and oxidative stress in female ICR mouse skin: dose-and timing-dependent enhancement and involvement of bioactivation by tyrosinase.

The modifying effects of topical application of the phenolic antioxidant protocatechuic acid (PA) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tumor promotion were investigated. Dimethylbenz[a]anthracene-initiated female ICR mice were treated with TPA (1.6 nmol) twice weekly for 20 weeks to promote papilloma formation. Pre-treatment with 16nmol PA 30 min prior to each TPA treatment significantly inhibited the number of papillomas per mouse by 52% (P < 0.05). On the other hand, PA pre-treatment at a high dose (1600 nmol) significantly enhanced tumor numbers by 38% (P < 0.05). Interestingly, in the group treated with a quite high dose (20000 nmol) of PA 5 min prior to each TPA application, the average number of tumors per mouse was reduced by 38%, whereas the same PA dose 3 h before TPA treatment significantly enhanced tumor numbers by 84% (P < 0.01). These results suggested that topically applied PA was converted to compound(s) lacking antioxidative properties and/or rather possessing the potential to enhance tumor development. A similar tendency was also observed in the short-term experiment of TPA-induced inflammation and oxidative stress; i.e. two groups pre-treated with PA at 20000 nmol, 30min and 3h before TPA treatment, did not show suppression or even significantly enhanced TPA-induced leukocyte infiltration, H(2)O(2) generation, thiobarbituric acid-reacting substances level and proliferating cell nuclear antigen index, while PA treatment together with TPA significantly suppressed these parameters. Treatment with a high dose (20000 nmol) of PA alone for 3h enhanced oxidative stress by reducing glutathione levels in mouse skin, which was counteracted by the tyrosinase inhibitor arbutin. Oxidative stress responses such as leukocyte infiltration and H(2)O(2) generation were also counteracted by arbutin. These results suggested that tyrosinase-dependent oxidative metabolism of PA was at least partially involved in the enhanced effects of PA on TPA-induced inflammatory responses and thus tumor promotion.

Kurosu, a traditional vinegar produced from unpolished rice, suppresses lipid peroxidation in vitro and in mouse skin.

The in vitro antioxidative activities of various kinds of vinegar were investigated by using a linoleic acid autoxidation model detected by the thiobarbituric acid (TBA) method and the 1,1-diphenyl-2-picrylhydrazyl radical system. An ethyl acetate extract of Kurosu (EK), a vinegar made from unpolished rice, exhibited the highest antioxidative activity in both systems. EK (5 mg) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema formation (14%) and myeloperoxidase activity (52%, P< 0.01) in female ICR mouse skin. Furthermore, EK significantly suppressed double TPA application-induced H2O2 generation (53%, P< 0.01) and lipid peroxidation determined by the TBA-reacting substance level (95 %, P< 0.01). In a two-stage carcinogenesis experiment with dimethylbenz[a]anthracene/TPA, EK significantly reduced the number of tumors per mouse by 36% (P<0.05) at 15 weeks after promotion. These results suggest that the antitumor-promoting effect may be partially due to the antioxidative properties of EK such as the decomposition of free radicals and interference with free radical-generating leukocytes.

Early and delayed Tc-99m ECD brain SPECT in SLE patients with CNS involvement.

We compared early and delayed Tc-99m ECD SPECT scans in 32 SLE patients (Group 1, definite neuropsychiatric disorders; Group 2, minor neurologic symptoms or normal) with those of normal controls by visual inspection and semi-quantitative evaluation. With visual interpretation, 13 out of 14 patients in Group 1 (93%) and 7 out of 18 patients in Group 2 (39%) had diffuse uneven decrease in early scans. Seven patients in Group 2 (39%) who had normal early scans demonstrated focal decrease in the medial frontal lobe in delayed scans. With cerebral region to cerebellar ratios, in early scans, the medial frontal lobe in Group 1 and Group 2 was significantly lower than in normal controls, and lateral frontal lobe and occipital lobes in Group 1 were significantly lower than in normal controls. Nevertheless, in delayed scans, every cortical region except for the parietal lobe in Groups 1 and 2 was significantly lower than in normal controls. The retention rates in all regions in SLE patients were significantly lower than in normal controls. No case showed SPECT improvement on follow-up studies in either group in spite of clinical improvement. Delayed Tc-99m ECD brain SPECT of high sensitivity might be useful in detecting CNS involvement. Although the SPECT findings did not correlate with the neuropsychiatric symptoms, early and delayed Tc-99m ECD SPECT seems to provide useful objective diagnostic information in SLE patients.

An avocado constituent, persenone A, suppresses expression of inducible forms of nitric oxide synthase and cyclooxygenase in macrophages, and hydrogen peroxide generation in mouse skin.

We investigated the suppressive effects of an avocado constituent, persenone A, on lipopolysaccharide- and interferon-y-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in a mouse macrophage cell line RAW 264.7. Persenone A at concentration of 20 microM almost completely suppressed both iNOS and COX-2 protein expression. In mouse skin, double treatments with persenone A (810 nmol) significantly suppressed double 12-O-tetradecanoylphorbol-13-acetate (TPA, 8.1 nmol) application-induced hydrogen peroxide (H2O2) generation. Treatment with persenone A before the second TPA treatment was sufficient to inhibit H2O2 generation, while the first treatment was not. This study thus suggests that persenone A is a possible agent to prevent inflammation-associated diseases including cancer.

[A case of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) related glomerulonephritis associated with systemic sclerosis treated by steroid pulse therapy: a case report].

A 57-year-old woman had been diagnosed as systemic sclerosis (SSc) with Raynaud's phenomenon, acrosclerosis and polyarthritis since 1995. She admitted to our hospital in July 1996 because of general fatigue, hemosputa and progressive renal insufficiency. On admission, the blood pressure was normal and laboratory findings showed elevation of the serum creatinin level and a high titer of the myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) (> 1000 EU). The renal biopsy revealed crescentic glomerulonephritis. Both renal insufficiency and high titers of MPO-ANCA improved remarkably after methylpredonisolone pulse therapy. This case was suggestive of elucidating the pathogenesis of SSc and MPO-ANCA related glomerulonephritis.

Alteration of the cellular response to interleukin-1 beta by SV40 large T antigen in rheumatoid synovial fibroblasts.

The large T antigen of SV40 (LT) has been widely used to immortalize primary cells for various studies. In this study, synovial fibroblasts of a patient from rheumatoid arthritis (RA) were transformed with LT gene to analyze the effect of SV40-mediated transformation on the production of cytokines, such as IL-6, IL-8, and GM-CSF, that are under the control of interleukin-1 beta (IL-1 beta), a physiological inducer of nuclear factor kappa B (NF-kappa B). It was noted that the basal levels of GM-CSF and IL-8 were upregulated, whereas that of IL-6 was downregulated. Moreover, the extents of induction of these cytokines in response to IL-1 beta were markedly downregulated in synovial fibroblasts transformed by LT as compared from parental cells. Although IL-1 beta could translocate NF-kappa B to the nucleus in all cells, some of the transformed cells exhibited nuclear translocation of NF-kappa B even before the stimulation with IL-1 beta, suggesting that transformation of LT resulted in the constitutive activation of NF-kappa B, either directly or indirectly. In order to examine whether LT downregulate the kappa B-dependent gene expression, we performed the transient luciferase gene expression assay. We found that cotransfection of LT did not downregulate the kappa B-dependent gene expression that was stimulated with L-1 beta. These observations suggest that the apparent inhibitory effect of LT on the IL-1-induced expression of cytokines may not be through its direct action on the NF-kappa B transactivation.