Modeling principles of protective thyroid blocking.

PURPOSE: In the case of a nuclear incident, the release of radioiodine must be expected. Radioiodine accumulates in the thyroid and by irradiation enhances the risk of cancer. Large doses of stable (non-radioactive) iodine may inhibit radioiodine accumulation and protect the thyroid ('thyroid blocking'). Protection is based on a competition at the active carrier site in the cellular membrane and an additional temporary inhibition of the organification of iodide (Wolff-Chaikoff effect). Alternatively, other agents like e.g. perchlorate that compete with iodide for the uptake into the thyrocytes may also confer thyroidal protection against radioiodine exposure.Biokinetic models for radioiodine mostly describe exchanges between compartments by first order kinetics. This leads to correct predictions only for low (radio)iodide concentrations. These models are not suited to describe the kinetics of iodine if administered at the dosages recommended for thyroid blocking and moreover does not permit to simulate either the protective competition mechanism at the membrane or the Wolff-Chaikoff effect. Models adapted for this purpose must be used. Such models may use a mathematical relation between the serum iodide concentration and a relative uptake suppression or a dependent rate constant determining total thyroidal radioiodine accumulation. Alternatively, the thyroidal uptake rate constant may be modeled as a function of the total iodine content of the gland relative to a saturation amount. Newer models integrate a carrier-mechanism described by Michalis-Menten kinetics in the membrane and in analogy to enzyme kinetics apply the rate law for monomolecular irreversible enzyme reactions with competing substrates to model the competition mechanism. An additional total iodide uptake block, independent on competition but limited in time, is used to simulate the Wolff-Chaikoff effect. CONCLUSION: The selection of the best model depends on the issue to be studied. Most models cannot quantify the relative contributions of the competition mechanism at the membrane and the Wolff-Chaikoff effect. This makes it impossible or exceedingly difficult to simulate prolonged radioiodine exposure and the effect of repetitive administrations of stable iodine. The newer thyroid blocking models with a separate modeling of competition and Wolff-Chaikoff effect allow better quantitative mechanistic insights and offer the possibility to simulate complex radioiodine exposure scenarios and various protective dosage schemes of stable iodine relatively easily. Moreover, they permit to study the protective effects of other competitors at the membrane carrier site, like e.g. perchlorate, and to draw conclusions on their protective efficacy in comparison to stable iodine.

Ascorbic acid-2 glucoside mitigates intestinal damage during pelvic radiotherapy in a rat bladder tumor model.

PURPOSE: Ascorbic acid is a strong antioxidant and has potent radioprotective effects on radiation injuries. Ascorbic acid 2-glucoside (AA2G) is a stabilized derivative of ascorbic acid and rapidly hydrolyzed into ascorbic acid and glucose. Since there is the possibility that AA2G treatment interferes with the antitumor activity of radiotherapy, we investigated the effect of AA2G treatment during radiotherapy on acute radiation enteritis and antitumor activity of radiotherapy in rats. MATERIALS AND METHODS: AY-27 rat bladder tumor cells were used to induce bladder tumors in rats. Two weeks after inoculation rats received fractionated pelvic radiotherapy in eight fractions for 4 weeks totaling 40 Gy. During radiotherapy, one group of rats received per os AA2G (ascorbic acid: 250 mg/kg/day) and its bolus engulfment (ascorbic acid: 250 mg/kg) 8 h before each X-irradiation fraction. Seven days after the last X-irradiation, we studied histology, DNA double strand break (DSB) damage (by 53BP1 foci staining), and the M1/M2 macrophage response by immunohistochemistry of paraffin-fixed bladder and intestinal tissues. RESULTS: AA2G treatment reduced the intestinal damage (shortening of villi) but did not reduce antitumor effectiveness of radiotherapy against bladder tumors. Like the controls, AA2G-treated rats showed no residual tumor lesions in the bladder after X-irradiation. Both AA2G-treated and control groups showed similar persistent DSB damage (53BP1 foci) both in bladders and ilea seven days after radiotherapy. Radiotherapy tended to reduce CD163+ M2 macrophages, which are considered as an anti-inflammatory subtype favoring tissue repair, in the bladders. X-irradiation also reduced the occurrence of M2 macrophages in the ilea. AA2G treatment significantly increased CD163+/CD68+ macrophage ratio in the ilea of rats after pelvic irradiation in comparison to the sham irradiated control rats. AA2G treatment increased, albeit not significantly, the CD163+/CD68+ macrophage ratio in the irradiated bladders relative to the control irradiated rats. On the other hand, bladders and ilea of the irradiated rats with and without AA2G treatment showed similar frequencies of CD68+ macrophages. CONCLUSIONS: AA2G treatment mitigated radiation-induced intestinal damage without reducing antitumor activity after fractionated pelvic radiotherapy against bladder tumors in rats. The beneficial effect of AA2G treatment seems to promote a restoration of the M2 answer as well as tissue remodeling and wound healing. Similar residual DNA damage in bladders and ilea seven days post-irradiation is consistent with tumor control in both groups.

A comparison of thyroidal protection by stable iodine or perchlorate in the case of acute or prolonged radioiodine exposure.

In the case of a nuclear power plant accident, repetitive/prolonged radioiodine release may occur. Radioiodine accumulates in the thyroid and by irradiation enhances the risk of cancer. Large doses of non-radioactive iodine may protect the thyroid by inhibiting radioiodine uptake into the gland (iodine blockade). Protection is based on a competition at the active carrier site in the cellular membrane and the Wolff-Chaikoff effect, the latter being, however, only transient (24-48 h). Perchlorate may alternatively provide protection by a carrier competition mechanism only. Perchlorate has, however, a stronger affinity to the carrier than iodide. Based on an established biokinetic-dosimetric model developed to study iodine blockade, and after its extension to describe perchlorate pharmacokinetics and the inhibition of iodine transport through the carrier, we computed the protective efficacies that can be achieved by stable iodine or perchlorate in the case of an acute or prolonged radioiodine exposure. In the case of acute radioiodine exposure, perchlorate is less potent than stable iodine considering its ED50. A dose of 100 mg stable iodine has roughly the same protective efficacy as 1000 mg perchlorate. For prolonged exposures, single doses of protective agents, whether stable iodine or perchlorate, offer substantially lower protection than after acute radioiodine exposure, and thus repetitive administrations seem necessary. In case of prolonged exposure, the higher affinity of perchlorate for the carrier in combination with the fading Wolff-Chaikoff effect of iodine confers perchlorate a higher protective efficacy compared to stable iodine. Taking into account the frequency and seriousness of adverse effects, iodine and perchlorate at equieffective dosages seem to be alternatives in case of short-term acute radioiodine exposure, whereas preference should be given to perchlorate in view of its higher protective efficacy in the case of longer lasting radioiodine exposures.

Development of New Biokinetic-Dosimetric Models for the Simulation of Iodine Blockade in the Case of Radioiodine Exposure in Man.

In the case of nuclear incidents, radioiodine may be liberated. After incorporation it accumulates in the thyroid and by internal irradiation enhances the risk of cancer occurrence. By administering a large dose of non-radioactive iodine the uptake of radioiodine into the gland can be inhibited ("iodine blockade"). Biokinetic models using first order kinetics are not suited to simulate iodine blockade, as the uptake into the gland is mediated by a saturable active transport. Therefore, we integrated an uptake mechanism described by a Michaelis-Menten kinetic into a simple ICRP biokinetic model. We moreover added a total uptake blocking mechanism representing the Wolff-Chaikoff effect becoming active when the gland is saturated with iodine. The validity of the model was ascertained by comparison with IMBA software. The competition of radioiodine and stable iodine at the membrane carrier site was modeled according to the rate law for monomolecular reactions for competing substrates. Our simulations show that competition for the uptake at the membrane carrier site accounts for about 60% and the saturation of the gland with iodine for over 35% of the total protective efficacy that exceeds 95%. Following acute radioiodine exposure, it is preferable to administer a single large dose of stable iodine. In the case of continuous radioiodine exposure, a single dose of stable iodine is less effective than after an acute exposure and splitting the total available dose and shortening the dosage intervals enhance efficacy. Model-based simulations may be a useful tool to develop antidote dosage schemes for uncommon emergencies.

Treatment of irradiated mice with high-dose ascorbic acid reduced lethality.

Ascorbic acid is an effective antioxidant and free radical scavenger. Therefore, it is expected that ascorbic acid should act as a radioprotectant. We investigated the effects of post-radiation treatment with ascorbic acid on mouse survival. Mice received whole body irradiation (WBI) followed by intraperitoneal administration of ascorbic acid. Administration of 3 g/kg of ascorbic acid immediately after exposure significantly increased mouse survival after WBI at 7 to 8 Gy. However, administration of less than 3 g/kg of ascorbic acid was ineffective, and 4 or more g/kg was harmful to the mice. Post-exposure treatment with 3 g/kg of ascorbic acid reduced radiation-induced apoptosis in bone marrow cells and restored hematopoietic function. Treatment with ascorbic acid (3 g/kg) up to 24 h (1, 6, 12, or 24 h) after WBI at 7.5 Gy effectively improved mouse survival; however, treatments beyond 36 h were ineffective. Two treatments with ascorbic acid (1.5 g/kg × 2, immediately and 24 h after radiation, 3 g/kg in total) also improved mouse survival after WBI at 7.5 Gy, accompanied with suppression of radiation-induced free radical metabolites. In conclusion, administration of high-dose ascorbic acid might reduce radiation lethality in mice even after exposure.

Decreased plasma brain-derived neurotrophic factor and vascular endothelial growth factor concentrations during military training.

Decreased concentrations of plasma brain-derived neurotrophic factor (BDNF) and serum BDNF have been proposed to be a state marker of depression and a biological indicator of loaded psychosocial stress. Stress evaluations of participants in military mission are critically important and appropriate objective biological parameters that evaluate stress are needed. In military circumstances, there are several problems to adopt plasma BDNF concentration as a stress biomarker. First, in addition to psychosocial stress, military missions inevitably involve physical exercise that increases plasma BDNF concentrations. Second, most participants in the mission do not have adequate quality or quantity of sleep, and sleep deprivation has also been reported to increase plasma BDNF concentration. We evaluated plasma BDNF concentrations in 52 participants on a 9-week military mission. The present study revealed that plasma BDNF concentration significantly decreased despite elevated serum enzymes that escaped from muscle and decreased quantity and quality of sleep, as detected by a wearable watch-type sensor. In addition, we observed a significant decrease in plasma vascular endothelial growth factor (VEGF) during the mission. VEGF is also neurotrophic and its expression in the brain has been reported to be up-regulated by antidepressive treatments and down-regulated by stress. This is the first report of decreased plasma VEGF concentrations by stress. We conclude that decreased plasma concentrations of neurotrophins can be candidates for mental stress indicators in actual stressful environments that include physical exercise and limited sleep.

A combination of pre- and post-exposure ascorbic acid rescues mice from radiation-induced lethal gastrointestinal damage.

The development of an effective therapy for radiation-induced gastrointestinal damage is important, because it is currently a major complication of treatment and there are few effective therapies available. Although we have recently demonstrated that pretreatment with ascorbic acid attenuates lethal gastrointestinal damage in irradiated mice, more than half of mice eventually died, thus indicating that better approach was needed. We then investigated a more effective therapy for radiation-induced gastrointestinal damage. Mice receiving abdominal radiation at 13 Gy were orally administered ascorbic acid (250 mg/kg/day) for three days before radiation (pretreatment), one shot of engulfment (250 mg/kg) at 8 h before radiation, or were administered the agent for seven days after radiation (post-treatment). None of the control mice survived the abdominal radiation at 13 Gy due to severe gastrointestinal damage (without bone marrow damage). Neither pretreatment with ascorbic acid (20% survival), engulfment (20%), nor post-treatment (0%) was effective in irradiated mice. However, combination therapy using ascorbic acid, including pretreatment, engulfment and post-treatment, rescued all of the mice from lethal abdominal radiation, and was accompanied by remarkable improvements in the gastrointestinal damage (100% survival). Omitting post-treatment from the combination therapy with ascorbic acid markedly reduced the mouse survival (20% survival), suggesting the importance of post-treatment with ascorbic acid. Combination therapy with ascorbic acid may be a potent therapeutic tool for radiation-induced gastrointestinal damage.

Quality of gastric cancer care in designated cancer care hospitals in Japan.

OBJECTIVE: To develop a set of process-of-care quality indicators (QIs) that would cover a wide range of gastric cancer care modalities and to examine the current state of the quality of care provided by designated cancer care hospitals in Japan. DESIGN: A retrospective medical record review. SETTING: Eighteen designated cancer care hospitals throughout Japan. PARTICIPANTS: A total of 1685 patients diagnosed with gastric cancer in 2007. MAIN OUTCOME MEASURES: Provision of care to eligible patients as described in the 29 QIs, which were developed using an adaptation of the RAND/UCLA (University of California, Los Angeles) appropriateness method by a panel of nationally recognized experts in Japan. RESULTS: Overall, the patients received 68.3% of the care processes recommended by the QIs. While 'deep venous thrombosis prophylaxis before major surgery' was performed for 99% of the cases, 'documentation before endoscopic resection' was completed for only 12% of the cases. The chemotherapy care was less likely to meet the QI standards (61%) than pre-therapeutic care (76%), surgical treatment (66%) and endoscopic resection (71%; overall difference: P < 0.001). A comparison based on the types of care showed that documentation and patient explanation were performed less frequently (60 and 53%, respectively) than were diagnostic and therapeutic processes as recommended in the QIs (85%; overall P < 0.001). CONCLUSIONS: Although many required care processes were provided, some areas with room for improvement were revealed, especially with respect to chemotherapy, documentation and patient explanation. Continuous efforts to improve the quality and develop a system to monitor this progress would be beneficial in Japan.

Prevalence of organic colonic lesions in patients meeting Rome III criteria for diagnosis of IBS: a prospective multi-center study utilizing colonoscopy.

BACKGROUND: It remains unknown whether the Rome III criteria can exclude organic colonic lesions prior to the diagnosis of irritable bowel syndrome (IBS). We evaluated the colonoscopy results of patients meeting the Rome III criteria for the diagnosis of IBS to determine the presence of organic colonic lesions. METHODS: This study was prospectively conducted at 17 centers in Japan. We enrolled 4528 patients who underwent diagnostic colonoscopy examinations. The diagnosis of IBS was evaluated by questionnaire results according to the Rome III criteria. RESULTS: We evaluated 4178 patients (350 were excluded because of incomplete data or previous colonic surgery), of whom 203 met the Rome III criteria (mean age 57.9 years; range 14-87 years) prior to the diagnostic colonoscopy examination. We identified organic colonic diseases in 21 of these 203 patients (10.3 %) , and these disease were also identified in 338 (8.5 %) of 3975 patients who did not fulfill the Rome III criteria. There were no differences in regard to the prevalence of organic colonic diseases between patients who did and did not fulfill the Rome III criteria. CONCLUSIONS: The prevalence of organic colonic diseases in patients who met the Rome III criteria was at an acceptably low level, indicating that the Rome III criteria are adequately specific for the diagnosis of IBS without performing a colonoscopy examination.

Survival of geriatric patients after percutaneous endoscopic gastrostomy in Japan.

AIM: To examine the long term survival of geriatric patients treated with percutaneous endoscopic gastrostomy (PEG) in Japan. METHODS: We retrospectively included 46 Japanese community and tertiary hospitals to investigate 931 consecutive geriatric patients (≥ 65 years old) with swallowing difficulty and newly performed PEG between Jan 1st 2005 and Dec 31st 2008. We set death as an outcome and explored the associations among patient's characteristics at PEG using log-rank tests and Cox proportional hazard models. RESULTS: Nine hundred and thirty one patients were followed up for a median of 468 d. A total of 502 deaths were observed (mortality 53%). However, 99%, 95%, 88%, 75% and 66% of 931 patients survived more than 7, 30, 60 d, a half year and one year, respectively. In addition, 50% and 25% of the patients survived 753 and 1647 d, respectively. Eight deaths were considered as PEG-related, and were associated with lower serum albumin levels (P = 0.002). On the other hand, among 28 surviving patients (6.5%), PEG was removed. In a multivariate hazard model, older age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.00-1.03; P = 0.009], higher C-reactive protein (HR, 1.04; 95% CI: 1.01-1.07; P = 0.005), and higher blood urea nitrogen (HR, 1.01; 95% CI: 1.00-1.02; P = 0.003) were significant poor prognostic factors, whereas higher albumin (HR, 0.67; 95% CI: 0.52-0.85; P = 0.001), female gender (HR, 0.60; 95% CI: 0.48-0.75; P < 0.001) and no previous history of ischemic heart disease (HR, 0.69; 95% CI: 0.54-0.88, P = 0.003) were markedly better prognostic factors. CONCLUSION: These results suggest that more than half of geriatric patients with PEG may survive longer than 2 years. The analysis elucidated prognostic factors.

Pretreatment with ascorbic acid prevents lethal gastrointestinal syndrome in mice receiving a massive amount of radiation.

While bone marrow or stem cell transplantation can rescue bone marrow aplasia in patients accidentally exposed to a lethal radiation dose, radiation-induced irreversible gastrointestinal damage (GI syndrome) is fatal. We investigated the effects of ascorbic acid on radiation-induced GI syndrome in mice. Ascorbic acid (150 mg/kg/day) was orally administered to mice for 3 days, and then the mice underwent whole body irradiation (WBI). Bone marrow transplantation (BMT) 24 h after irradiation rescued mice receiving a WBI dose of less than 12 Gy. No mice receiving 14 Gy-WBI survived, because of radiation-induced GI syndrome, even if they received BMT. However, pretreatment with ascorbic acid significantly suppressed radiation-induced DNA damage in the crypt cells and prevented denudation of intestinal mucosa; therefore, ascorbic acid in combination with BMT rescued mice after 14 Gy-WBI. DNA microarray analysis demonstrated that irradiation up-regulated expressions of apoptosis-related genes in the small intestine, including those related to the caspase-9-mediated intrinsic pathway as well as the caspase-8-mediated extrinsic pathway, and down-regulated expressions of these genes in ascorbic acid-pretreated mice. Thus, pretreatment with ascorbic acid may effectively prevent radiation-induced GI syndrome.

Zinc, cadmium, and mercury 1,2-benzenedithiolates with intramolecular NH...S hydrogen bonds.

Mononuclear Zn, Cd, and Hg 1,2-benzenedithiolates with intramolecular NH...S hydrogen bonds, [M(II){1,2-S2-3,6-(RCONH)2C6H2}2](2-) (R = CH 3, t-Bu; M = Zn, Cd, Hg), were synthesized and characterized by X-ray analysis and spectral measurements. The presence of intramolecular NH...S hydrogen bonds was established by the IR spectra. (199)Hg and (113)Cd nuclear magnetic resonance showed a stabilized four-thiolate coordinated structure and suggested the influence of the NH...S hydrogen bonds to ppi(Hg)-ppi(S) interactions. The NH stretching bands show that the NH...S hydrogen bonds in Cd and Hg complexes are stronger than those in the corresponding Zn complex. These results are supported by theoretical calculations. The experimental and theoretical results suggested that the NH...S hydrogen bond influences the efficient capture of toxic Cd and Hg ions by metallothioneins.

Vitamin K2 inhibits the proliferation of HepG2 cells by up-regulating the transcription of p21 gene.

AIM: Vitamin K2 has been reported to inhibit the growth of human hepatocellular carcinoma (HCC) in vitro and suppress hepatocarcinogenesis in vivo. However, its inhibitory mechanism has not yet been clarified. METHODS: Different concentrations of vitamin K2 (30, 10, 1, 0.1 and 0.01 muM) were added to the HCC cell line HepG2 to assess effects on cell growth. The effect of vitamin K2 on cell cycle progression was determined by flow-cytometric analysis. The expression of cell cycle regulatory proteins p21 and p27 was then examined by Western blot. Whether vitamin K2 regulates the gene expression through action on the p21 promoter region was investigated by luciferase assay. RESULTS: Vitamin K2 inhibited the growth of HepG2 cells dose-dependently, and its inhibitory rate reached approximately 50% at the dose of 30 muM after 96 h treatment. After treatment with vitamin K2, the proportion of cells in G0-G1 phase increased, and in S phase decreased. Apoptotic cells were not detected. The expression of cell cycle regulatory protein p21 was induced by vitamin K2 treatment, but p27 was not. By the luciferase assay, vitamin K2 significantly activated the promoter of p21. Knock-down of p21 by siRNA reversed the growth inhibition of HepG2 cells by vitamin K2. CONCLUSIONS: The findings suggest that vitamin K2 suppresses the proliferation of HCC cells by blocking the cell cycle G1/S progression through the transcriptional induction of p21.

Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis.

UNLABELLED: The predictive role of antinuclear antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end-point, positive anti-gp210 antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuer's stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive anti-centromere antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti-gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere antibodies was most significantly associated with more severe ductular reaction. CONCLUSION: These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive-anti-gp210 and positive-anticentromere antibodies, respectively.

Chemoprevention of spontaneous development of hepatocellular carcinomas in fatty liver Shionogi mice by a cyclooxygenase-2 inhibitor.

Cyclooxygenase 2 (COX-2) and retinoid X receptor alpha (RXRalpha) are suggested to have roles in carcinogenesis. COX-2 inhibitors have been reported to suppress growth of hepatocellular carcinoma (HCC) cell lines in vitro. However, little is known about the preventive effect of these drugs on spontaneous hepatocarcinogenesis in vivo. Etodolac exists in a racemic mixture containing S- and R-etodolac. S-etodolac is responsible for COX-2 inhibitory activity and R-etodolac is related to the downregulation of RXRalpha. Here, the effect of etodolac on spontaneous development of HCC in fatty liver Shionogi mice is evaluated. Etodolac was administered at a low (2 mg/kg) or high (10 mg/kg) dose three times a week for 16 months starting at the age of 3 months. The development of HCC was suppressed slightly in the high-dose group, and suppressed markedly in the low-dose group, although the development of fatty liver was not inhibited in either group. Plasma prostaglandin E2 levels were also decreased significantly in the low-dose group, consistent with the suppression of HCC. The expression of RXRalpha and proliferating cell nuclear antigen in non-tumorous liver tissues was decreased significantly in both the low-dose and high-dose groups. These findings show that etodolac treatment at an optimum dose suppresses hepatocarcinogenesis in vivo, and may be useful for preventing the development of HCC in humans.

Hemochromatosis with mutation of the ferroportin 1 (IREG1) gene.

The HFE, H ferritin, TFR2, and ferroportin 1 genes of a Japanese patient diagnosed as having hemochromatosis were amplified by PCR and sequenced. A novel mutation in the ferroportin 1 was found in the patient. It was located in the noncoding region of the ferroportin 1; nucleotide 117 adenine was changed to guanine, 7 nucleotides downstream the iron responsive element (IRE) region. This mutation was not found in the patient's son or daughter, or in 50 healthy individuals. It was suggested that the mutation in the ferroportin 1 may be related to hemochromatosis of this patient.

[A questionnaire about radiation safety management of the draining-water system at nuclear medicine facilities].

We conducted a questionnaire survey about radiation-safety management condition in Japanese nuclear medicine facilities to make materials of proposition for more reasonable management of medical radioactive waste. We distributed a questionnaire to institutions equipped with Nuclear Medicine facilities. Of 1,125 institutions, 642 institutes (52.8%) returned effective answers. The questionnaire covered the following areas: 1) scale of an institution, 2) presence of enforcement of radiotherapy, 3) system of a tank, 4) size and number of each tank, 5) a form of draining-water system, 6) a displacement in a radioactive rays management area, 7) a measurement method of the concentration of medical radioactive waste in draining water system, 8) planned and used quantity of radioisotopes for medical examination and treatment, 9) an average displacement of hospital for one month. In most institutions, a ratio of dose limitation of radioisotope in draining-water system was less than 1.0, defined as an upper limitation in ordinance. In 499 hospitals without facilities of hospitalization for unsealed radioisotope therapy, 473 hospitals reported that sum of ratios of dose limits in a draining-water system was less than 1.0. It was calculated by used dose of radioisotope and monthly displacement from hospital, on the premise that all used radioisotope entered in the general draining-water system. When a drainage including radioactivity from a controlled area join with that from other area before it flows out of a institution, it may be diluted and its radioactive concentration should be less than its upper limitation defined in the rule. Especially, in all institutions with a monthly displacement of more than 25,000 m3, the sum of ratio of the concentration of each radionuclide to the concentration limit dose calculated by used dose of radioisotope, indicated less than 1.0.

Evaluation of interleukin-12-induced interferon-y production in vitro by peripheral blood mononuclear cells in patients with chronic liver disease.

BACKGROUND/AIMS: Interleukin-12 plays an important role in anti-tumor immune response by induction of interferon-gamma production by T cells and NK cells, and by activation of cytotoxic T cells and NK cells. We evaluated interleukin-12-induced interferon-gamma production as one of the immunological markers of patients with chronic liver diseases. METHODOLOGY: Interleukin-12-induced interferon-gamma production was measured in vitro in peripheral blood mononuclear cells from 28 hepatocellular carcinoma patients, 10 liver cirrhosis patients, 14 chronic hepatitis patients and 16 healthy individuals. RESULTS: The hepatocellular carcinoma patients exhibited a reduced interleukin-12 responsiveness for interferon-gamma production compared to the liver cirrhosis patients, the chronic hepatitis patients and the healthy individuals. The reduced interferon-gamma production seemed to roughly reflect clinical stage in the hepatocellular carcinoma patients. The interferon-gamma production correlated with neither alpha-fetoprotein nor protein induced by vitamin K absence II. CONCLUSIONS: The level of interleukin-12-induced interferon-gamma production by peripheral blood mononuclear cells in the patients with hepatocellular carcinoma was significantly lower than that in the patients with liver cirrhosis which is thought to be a premalignant state. The measurement of interferon-gamma production may be useful in evaluating severity of chronic liver disease from an immunological point of view.

Bronchopulmonary foregut malformation: a large bronchogenic cyst communicating with an esophageal duplication cyst.

A 1-year-old boy with a bronchopulmonary foregut malformation presented with a large mediastinal bronchogenic cyst associated with pulmonary sequestration, a cervical esophageal duplication cyst, a bronchial communication between these cysts, and 2 small bronchogenic cysts around the communication. These lesions were resected followed by an uneventful recovery.

Phenotypes and phosphatidylinositol glycan-class A gene abnormalities during cell differentiation and maturation from precursor cells to mature granulocytes in patients with paroxysmal nocturnal hemoglobinuria.

To define the phosphatidylinositol glycan-class A (PIG-A) gene abnormality in precursor cells and the changes of expression of glycosylphosphatidylinositol-anchored protein and contribution of paroxysmal nocturnal hemoglobinuria (PNH) clones with PIG-A gene abnormalities among various cell lineages during differentiation and maturation, we investigated CD59 expression on bone marrow CD34(+) cells and peripheral granulocytes from 3 patients with PNH and the PIG-A gene abnormalities in the CD59(-), CD59(+/-), and CD59(+) populations by nucleotide sequence analyses. We also performed clonogeneic assays of CD34(+)CD59(+) and CD34(+)CD59(-) cells from 2 of the patients and examined the PIG-A gene abnormalities in the cultured cells. In case 1, the CD34(+) cells and granulocytes consisted of CD59(-) and CD59(+) populations and CD59(-), CD59(+/-), and CD59(+) populations, respectively. Sequence analyses indicated that mutation 1-2 was in the CD59(+/-) granulocyte population (20 of 20) and the CD34(+)CD59(-) population (2 of 38). In cases 2 and 3, the CD34(+) cells and granulocytes consisted of CD59(+) and CD59(-) cells. Sequence analyses in case 3 showed that mutation 3-2 was not in CD34(+)CD59(-) cells and was present in the CD59(-) granulocyte population. However, PIG-A gene analysis of cultured CD34(+)CD59(-) cells showed that they had the mutation. This analysis also revealed that there were some other mutations, which were not found in CD34(+)CD59(-) cells and CD59(-) or CD59(+/-) granulocytes in vivo, and that sometimes they were distributed specifically among different cell lineages. In conclusion, our findings suggest that PNH clones might contribute qualitatively and quantitatively differentially to specific blood cell lineages during differentiation and maturation of hematopoietic stem cells.