An extremely energetic cosmic ray observed by a surface detector array.

Cosmic rays are energetic charged particles from extraterrestrial sources, with the highest-energy events thought to come from extragalactic sources. Their arrival is infrequent, so detection requires instruments with large collecting areas. In this work, we report the detection of an extremely energetic particle recorded by the surface detector array of the Telescope Array experiment. We calculate the particle's energy as [Formula: see text] (~40 joules). Its arrival direction points back to a void in the large-scale structure of the Universe. Possible explanations include a large deflection by the foreground magnetic field, an unidentified source in the local extragalactic neighborhood, or an incomplete knowledge of particle physics.

Radioactive Doses - Predicted and Actual - and Likely Health Effects.

Five years have passed since the nuclear accident at Fukushima Daiichi Nuclear Power Stations on 11 March 2011. Here we refer to reports from international organisations as sources of predicted values obtained from environmental monitoring and dose estimation models, and reports from various institutes in Japan are used as sources of individual actual values. The World Health Organization, based on information available up to 11 September 2011 (and published in 2012), reported that characteristic effective doses in the first year after the accident, to all age groups, were estimated to be in the 10-50 mSv dose band in example locations in evacuation areas. Estimated characteristic thyroid doses to infants in Namie Town were within the 100-200 mSv dose band. A report from the United Nations Scientific Committee on the Effects of Atomic Radiation published in 2014 shows that the effective dose received by adults in evacuation areas during the first year after the accident was 1.1-13 mSv. The absorbed dose to the thyroid in evacuated settlements was 7.2-35 mSv in adults and 15-83 mSv in 1-year-old infants. Individual external radiation exposure in the initial 4 months after the accident, estimated by superimposing individual behaviour data on to a daily dose rate map, was less than 3 mSv in 93.9% of residents (maximum 15 mSv) in evacuation areas. Actual individual thyroid equivalent doses were less than 15 mSv in 98.8% of children (maximum 25 mSv) in evacuation areas. When uncertainty exists in dose estimation models, it may be sensible to err on the side of caution, and final estimated doses are often much greater than actual radiation doses. However, overestimation of the dose at the time of an accident has a great influence on the psychology of residents. More than 100 000 residents have not returned to the evacuation areas 5 years after the Fukushima accident because of the social and mental effects during the initial period of the disaster. Estimates of radiation doses placed in the public domain must be based on scientific evidence, and the way such information is communicated to residents should be carefully considered to avoid psychosocial effects that may have a greater bearing on health than the radiation itself.

Antibodies to GAD in Japanese patients classified as Type 2 diabetes at diagnosis. High titre of GAD Ab is a predictive marker for early insulin treatment--report of west Japan (Kyushu, Yamaguchi, Osaka) study for GAD Ab(+) diabetes.

AIM: We evaluated the prevalence of GAD Ab in Japanese Type 2 diabetic patients treated with oral hypoglycaemic agents (OHA) and/or diet and followed GAD Ab(+) patients to assess the usefulness of GAD Ab as a marker for future insulin treatment prospectively. METHODS: A total of 2658 Japanese Type 2 diabetic patients treated by OHA and/or diet were randomly selected between April 1996 and December 1998. The clinical characteristics at entry were assessed and patients were followed for 1-3 years. RESULTS: The overall prevalence of GAD Ab among Type 2 diabetic patients was 2.0%. Forty-five had a history of diabetes of < or = 5 years (short history) while those with duration > 5 years (long history) totalled nine. Among them, 47% of patients with a short history did not require insulin in the follow-up period. However, none of those with a long history required insulin treatment within 2 years. Comparison of patients based on GAD titre in those with short history showed that 33% of patients in the high-titre group (> or = 20 U) required no insulin treatment in the first year of follow-up. In contrast, this proportion was 80% in the first and 67% in the second year in the low-titre group (< 20 U). CONCLUSIONS: The prevalence of GAD Ab in Japanese patients with a short and long history of diabetes was 2.8% and 0.9%, respectively. The presence of GAD Ab in Japanese Type 2 diabetic patients with a short history of diabetes is a marker for early insulin treatment.

15 years after Chernobyl: new evidence of thyroid cancer.

The Chernobyl nuclear power plant accident happened on April 26, 1986. We investigated the cause of the striking increase in frequency of thyroid cancer in children who lived within a 150 km radius of Chernobyl and who were born before and after the accident. No thyroid cancer was seen in 9472 children born in 1987-89, whereas one and 31 thyroid cancers were recorded in 2409 children born April 27, 1986, to Dec 31, 1986, and 9720 born Jan 1, 1983, to April 26, 1986, respectively. Short-lived radioactive fallout caused by the Chernobyl accident probably induced thyroid cancer in children living near Chernobyl.

[Ocular complications in patients infected with human immunodeficiency virus seen at the Acquired Immunodeficiency Syndrome Clinical Center].

PURPOSE: To examine the ocular complications in patients infected with human immunodeficiency virus(HIV) in Japan. METHODS: The medical records of 322 patients seen at the acquired immunodeficiency syndrome(AIDS) Clinical Center from July 1, 1997 through December 31, 1998 were reviewed, and the HIV-associated ocular complications were correlated with serum CD 4+ T-lymphocyte counts. RESULTS: Ocular complications were found in 51 patients: 35 cases with retinal microvasculopathy, 17 cases with cytomegalovirus retinitis(9 quiescent, 6 active, and 2 recurrent), and 1 case each with tuberculous uveitis, phthisis bulbi after necrotizing herpetic retinopathy, conjunctival Kaposi's sarcoma, papilledema, divergence palsy, hemianopia, and abducens palsy. Retinal microvasculopathy was present in patients with CD 4+ T-lymphocyte counts above 500/mm3, but was more common in patients with cell counts below 200/mm3. Among 6 patients with active cytomegalovirus retinitis, 5 patients had a CD 4+ T-lymphocyte count below 50/mm3 at the onset of retinitis, while one patient developed retinitis after the cell count increased to over 200/mm3 with highly active antiretroviral therapy. CONCLUSION: Cytomegalovirus retinopathy may occur in patients with a CD 4+ T-lymphocyte count of more than 200/mm3.

Gene Targeting to Hepatomas (AFP).

Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis worldwide, especially in eastern Asia and Africa (1). Recent advances in delivering genes to mammalian cells stimulate the possibility of gene therapy for human diseases, including cancer gene therapy (2). One approach of gene therapy for cancers is the transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene in tumor cells, because the killing effect of the HSV-tk product on the virus-infected cells is seen in only proliferating cells (3). HSV-tk can efficiently phosphorylate nucleoside analogs, and the phosphorylated products act as a chain terminator of DNA synthesis, leading to cell death (4). In addition, successful application of suicide gene therapy for cancer, in part, relies on the bystander effect, where the active chemotherapeutic agent produced in target cells diffuses from cells to neighboring malignant cells in sufficient concentrations to induce growth inhibition (5).

Autoantibodies to multiple islet autoantigens in patients with abrupt onset type 1 diabetes and diabetes diagnosed with urinary glucose screening.

It has been reported that there is a heterogeneity in the clinical course of Japanese patients with type 1 diabetes. To elucidate the associations of expression of autoantibodies to multiple islet antigens with age of onset and mode of diagnosis of diabetes in Japanese patients with type 1 diabetes, autoantibodies against the protein tyrosine phosphatase-like molecules ICA512 (IA-2) and phogrin (IA-2beta) (ICA512/phogrin-A), GAD (GADA), insulin (IAA), and islet cell cytoplasm (ICA) were determined in sera from 73 Japanese patients with type 1 diabetes obtained within 14 days of diagnosis. Patients were divided into groups based on the age of onset (10 years, n=49) or the mode of onset (abrupt onset, n=59 and urinary screening identified, n=14). Of 73 new-onset patients with type 1 diabetes, 43 (59%) and 32 (44%) had ICA512A and phogrin-A levels exceeding the 99th percentile of 184 normal control subjects, respectively. Forty-five patients (62%) were positive for either ICA512A or phogrin-A. The frequencies for other autoantibodies were 71% for GADA, 48% for IAA, and 62% for ICA. The frequency of ICA512/phogrin-A was significantly higher in patients with an age of onset less than 10 years (83%) than in patients aged >10 years (51%, P<0.01). The positivity of ICA512/phogrin-A was less in patients whose diabetes was diagnosed by the urine glucose screening test (21%, P<0.001) than in abrupt onset patients (71%). Combined analysis (>/=1 antibody) of GADA, IAA, and ICA512/phogrin-A detected 88% of abrupt onset and 93% of screening-positive patients vs. 70% and 29%, respectively, for ICA (P<0.0005). These results indicate that the expression of ICA512/phogrin-A and cytoplasmic ICA is less in patients identified by urinary glucose testing but indicate that with combined autoantibody testing 90% of patients can be identified independent of the mode of diagnosis.

Significance of glutathione-dependent antioxidant system in diabetes-induced embryonic malformations.

Hyperglycemia-induced embryonic malformations may be due to an increase in radical formation and depletion of intracellular glutathione (GSH) in embryonic tissues. In the past, we have investigated the role of the glutathione-dependent antioxidant system and GSH on diabetes-related embryonic malformations. Embryos from streptozotocin-induced diabetic rats on gestational day 11 showed a significantly higher frequency of embryonic malformations (neural lesions 21.5 vs. 2.8%, P<0.001; nonneural lesions 47.4 vs. 6.4%, P<0.001) and growth retardation than those of normal mothers. The formation of intracellular reactive oxygen species (ROS), estimated by flow cytometry, was increased in isolated embryonic cells of diabetic rats on gestational day 11. The concentration of intracellular GSH in embryonic tissues of diabetic pregnant rats on day 11 was significantly lower than that of normal rats. The activity of y-glutamylcysteine synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme, in embryos of diabetic rats was significantly low, associated with reduced expression of gamma-GCS mRNA. Administration of buthionine sulfoxamine (BSO), a specific inhibitor of gamma-GCS, to diabetic rats during the period of maximal teratogenic susceptibility (days 6-11 of gestation) reduced GSH by 46.7% and increased the frequency of neural lesions (62.1 vs. 21.5%, P<0.01) and nonneural lesions (79.3 vs. 47.4%, P<0.01). Administration of GSH ester to diabetic rats restored GSH concentration in the embryos and reduced the formation of ROS, leading to normalization of neural lesions (1.9 vs. 21.5%) and improvement in nonneural lesions (26.7 vs. 47.4%) and growth retardation. Administration of insulin in another group of pregnant rats during the same period resulted in complete normalization of neural lesions (4.3 vs. 21.5%), nonneural lesions (4.3 vs. 47.4%), and growth retardation with the restoration of GSH contents. Our results indicate that GSH depletion and impaired responsiveness of GSH-synthesizing enzyme to oxidative stress during organogenesis may have important roles in the development of embryonic malformations in diabetes.

Specificity of omega-conotoxin MVIIC-binding and -blocking calcium channel antibodies in Lambert-Eaton myasthenic syndrome.

An immunoprecipitation assay was used to measure omega-conotoxin MVIIC (P/Q-type) binding and blocking calcium channel antibodies in 67 patients with Lambert-Eaton myasthenic syndrome (LEMS) and in a large control population. We first showed the presence of omega-conotoxin MVIIC-blocking antibody in LEMS patients. Binding antibodies were detected in 55 of 67 (82.1%) LEMS patients and in 2 of 296 (0.7%) controls. In contrast, blocking antibodies were positive in 14 of 67 (20.9%) LEMS patients and 8 of 171 (4.7%) controls. No LEMS patient had negative binding antibodies and positive blocking antibodies. The immunoprecipitation assay detected no antibodies against the whole P/Q-type calcium channel in either the paraneoplastic cerebellar degeneration or the amyotrophic lateral sclerosis sera. Neither the omega-conotoxin MVIIC-binding nor the -blocking calcium channel antibodies were correlated with clinical severity across the individuals, but longitudinal studies of some LEMS patients showed an inverse relation between binding antibody titre and disease severity. We concluded that the 125I-omega-conotoxin MVIIC assay for anti-P/Q-type voltage-gated calcium channel antibodies is highly specific for LEMS and that this sensitive binding antibody assay could be more valuable than the blocking antibody assay in the diagnosis of LEMS.

Expression and function of Fas and Fas ligand on peripheral blood lymphocytes in normal subjects.

We investigated the expression and function of Fas and Fas ligand (FasL) on peripheral blood lymphocytes (PBLs). The cells were stimulated with various cytokines or 12-0-tetradecanoyl phorbol 13-acetate (PMA) plus ionomycin. About 30% of unstimulated PBLs expressed Fas, and the expression was augmented by interleukin-1beta (IL-1beta), IL-2, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or PMA plus ionomycin. Although only minimal FasL expression was detected on unstimulated PBLs, FasL expression was markedly induced by IL-2 or PMA plus ionomycin, suggesting that Fas and FasL were both expressed on IL-2-stimulated or PMA-plus-ionomycin-stimulated PBLs. Although IL-2-stimulated or PMA-plus-ionomycin-stimulated PBLs were positive for both Fas and FasL, no significant increase in apoptosis was demonstrated in these activated PBLs. In addition, treatment of PBLs with IL-2 or PMA plus ionomycin did not change anti-Fas-induced apoptosis, although these activated PBLs expressed Fas strongly when compared with unstimulated PBLs. Only IL-2-stimulated or PMA-plus-ionomycin-stimulated PBLs killed Fas+ target cells efficiently via the interaction of Fas on target cells with FasL of PBLs. Bcl-2 was constitutively expressed on unstimulated PBLs, but its expression was significantly augmented by IL-2 or PMA plus ionomycin. The expression of Bax was clearly induced only on IL-2-stimulated or PMA-plus-ionomycin-stimulated PBLs and that of other Bcl-2 family proteins such as Bcl-x and Bad could not be detected on human PBLs, including IL-2-stimulated or PMA-plus-ionomycin-stimulated PBLs. Our results suggest that PBLs activated by IL-2 or PMA plus ionomycin express both Fas and FasL and that they kill Fas+ target cells by using FasL on the surface. The resistance of these activated PBLs to Fas-mediated apoptosis may be due to the augmented Bcl-2 expression or the presence of Bcl-2:Bax heterodimers on these cells.

[An autopsy case of rheumatoid arthritis accompanied with acute exacerbation of interstitial pneumonia].

An autopsy case of rheumatoid arthritis (RA) with acute exacerbation of interstitial pneumonia is reported. A 57-year-old woman with longstanding RA was admitted to our hospital because of progressive dyspnea. On chest roentogenogram, diffuse interstitial shadow was confirmed in both lungs. Chest computed tomography (CT) showed diffuse lesion of elevated density of CT level in both lung. She was diagnosed as an acute exacerbation of interstitial pneumonia, and treated by methylpredonisolone pulse therapy (1,000 mg/day). Although cyclosporin A (2 mg/kg/day) was combined to steroid therapy, she was died of progressive respiratory failure. The histological findings of the lung showed extensive fibrosis with alveolar damage associated with hyaline membranes, edema and hemorrhage in alveolar space.

Childhood thyroid cancer: comparison of Japan and Belarus.

The high incidence of childhood thyroid cancer in Belarus is suspected to be due to radiation exposure after the Chernobyl reactor accident. To clarify the clinical and histological characteristics of childhood thyroid cancer in Belarus, we therefore compared these patients to a radiation non-exposed control series in Japan. In Belarus, 26 thyroid cancers in subjects aged 15 or younger were diagnosed among 25,000 screened between 1991 and 1995 by Chernobyl-Sasakawa Health and Medical Cooperation Project. The clinical and morphologic features of these 26 cases were compared to 37 childhood thyroid cancers in Japan diagnosed between 1962 and 1995. The age distribution at operation in Belarus showed a peak at 10 years old, with a subsequent fall in numbers. In contrast, the age distribution at operation in Japan showed a smooth increase between the ages of 8 and 14. The mean tumor diameter was smaller in Belarus than that in Japan (1.4 +/- 0.7 vs. 4.1 +/- 1.7 cm, P < 0.001). The sex ratio, regional lymph node metastasis, extension to surrounding tissues or lung metastasis did not differ significantly. Histologically, all cases in Belarus were papillary and in Japan 33 cases were papillary and 4 cases were follicular carcinomas. Among papillary carcinomas, the frequency of a solid growth pattern, a criteria for classifying a tumor as poorly differentiated, was higher in Belarus than that in Japan (61.5 vs. 18.2%, P < 0.001). The difference between the features of childhood thyroid cancer in Japan and Belarus may be due to the difference in the process of carcinogenesis, but more direct evidence and further analysis by molecular epidemiology are needed in Belarussian cases.

Preoperative treatment of growth hormone-producing pituitary adenoma with continuous subcutaneous infusion of octreotide.

Preoperative therapy with octreotide, a long-acting somatostatin analog, suppresses GH hypersecretion, shrinks GH-producing tumors and leads to an improvement in subsequent surgical remission in acromegalic patients. A continuous infusion of octreotide has demonstrated more persistent suppression of GH secretion than intermittent injections, and only a few studies were reported on the effect of the tumor shrinkage with a continuous infusion of a small dose of octreotide. We therefore investigated the preoperative effects of small doses of octreotide (120-240 micrograms/day) administered continuously (with a subcutaneous infusion pump) over a short period (2 or 4 weeks) in nine untreated acromegalic patients. Octreotide therapy resulted in suppression of serum GH and IGF-1 concentrations in 8 out of 9 patients and reduction in pituitary tumor size measured by MRI in all patients (by 7.9 to 38.5%). In particular, considerable reduction in tumor size (more than 20%) occurred in 6 of 9 patients. In three patients assessed serially throughout the preoperative period, reduction in tumor size was noted within only one week after the start of octreotide therapy and reduction rate more than 20% was obtained within the first two weeks. In one patient, suprasellar tumor expansion totally disappeared after such therapy. Our results indicate that short-term continuous subcutaneous infusion of a small dose of octreotide results in not only inhibition of GH hypersecretion but also shrinkage of tumor size prior to surgery.

Regulation of alkaline phosphatase gene expression in human hepatoma cells by bile acids.

Bile acid-dependent secretion and the translationally regulated synthesis of alkaline phosphatase (ALP) in rat liver cell culture and by bile duct ligation has already been demonstrated. With the advent of ALP cDNA cloned sequences, the mechanism of the effect of bile acids on ALP activity and the expression of the ALP gene in different hepatoma cells was investigated. The HuH7 and HepG2 cells were treated with taurine-conjugated cholic acid (CA), chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) at 0-1 mmol/L and the numbers of viable cells were counted at 24, 48 and 72 h after treatment. A [3H]-thymidine incorporation study was performed with different bile acids at a concentration of 1 mmol/L for 48 h. The cellular activity of ALP in HuH7 and HepG2 cells by bile acids was measured by a substrate-specific enzymatic assay. To elucidate the effects of bile acids on ALP gene expression, a northern blotting experiment using hybridization with mouse placental ALP cDNA was performed. Cellular ALP activity was time- and dose-dependently increased in both HuH7 and HepG2 cells treated by CA and CDCA; however, no change in ALP activity was observed following treatment with UDCA compared with controls. Induction of ALP activity was dominant in HepG2 cells and independent of cell growth and proliferation. The addition of UDCA synergistically reduced the increased activity of ALP produced by CA and CDCA in both HuH7 and HepG2 cells. By northern blot analysis, the level of ALP mRNA was elevated by CA and CDCA; however, levels of ALP mRNA were suppressed by UDCA. In conclusion, CA and CDCA cause up-regulation of ALP mRNA and UDCA leads to down-regulation of ALP mRNA by its interaction with either CA or CDCA. We assume that increased ALP synthesis in hepatoma cells after bile acid treatment results from an enhanced rate of transcription rather than translation of mRNA.

Onset age-dependent variations of three islet specific autoantibodies in Japanese IDDM patients.

The age related incidence rate of insulin-dependent diabetes mellitus shows a bimodal distribution, not only in Caucasians but also in Japanese. To evaluate the onset age-related autoimmune profile at presentation in insulin-dependent diabetes mellitus (IDDM), glutamic acid decarboxylase (GAD) autoantibody, islet cell antibody (ICA), and insulin autoantibody (IAA) were measured in 137 newly diagnosed Japanese IDDM patients with onset ages between 0-29 years. The prevalence of GAD autoantibody was significantly increased from the lowest (32%) in the 0-5 years onset age group to 75% in the 13-19 years onset age group (P < 0.05), whereas the IAA prevalence significantly decreased from the peak (48%) in the 6-12 years onset age group to 10% in the 20-29 years onset age group (P < 0.05). The ICA prevalence was increased from the lowest (32%) in the 0-5 years onset age group to the highest (53%) in the 20-29 years onset age group similar to that for the GAD autoantibody. Such results demonstrate that there was age-related autoimmune characteristics at presentation of IDDM in Japanese as well as in Caucasians.

ret rearrangements in Japanese pediatric and adult papillary thyroid cancers.

Oncogenic rearrangements of the ret proto-oncogene (ret/PTC) are found uniquely in papillary thyroid carcinomas. The prevalence of ret/PTC in these tumors varies widely, from 0% to 87%, among patient series from different geographical regions. The differences in the prevalence of ret rearrangement have been ascribed to age, genetic, and/or environmental factors. The very high prevalence of ret/PTC in tumors arising in children after the Chernobyl nuclear accident has generated speculation that this oncogene may be an indicator of overt or inadvertent radiation exposure. In Japan, the prevalence of ret activation is reportedly quite low (0% to 9%). Here we examined the frequency of ret rearrangements in papillary carcinomas from Japanese adults and children by means of reverse transcription polymerase chain reaction (RT-PCR) followed by Southern hybridization. Ret rearrangements were detected in 4 of 11 (36%) tumors from the adult population, and in 3 of 10 (30%) pediatric tumors. One child with a solid variant papillary carcinoma had a ret-PTC3 rearrangement, further supporting the association between the solid variant histotype and this particular rearrangement of ret. The present data do not support a major geographic difference in the prevalence of ret/PTC rearrangements in papillary carcinomas between Japan, the United States, and Italy.