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Background: Although a causal relationship between mesothelioma and asbestos exposure is well known, few studies have shown a relationship to non-occupational exposure, including neighborhood exposure, most likely because of the large effect size of occupational exposure. The aim of this study was to quantify the risk of malignant mesothelioma death associated with neighborhood asbestos exposure due to a large-scale asbestos-cement (AC) plant in Amagasaki, Japan, by properly adjusting for occupational exposure. Methods: We conducted a nested case-control study in which a fixed population of 143,929 residents who had been living in Amagasaki City between 1975 and 2002 were followed from 2002 to 2015. All 133 cases and 403 matched controls were interviewed about their occupational, domestic, household, and neighborhood asbestos exposures. Odds ratios (ORs) for mesothelioma death associated with neighborhood exposure were estimated by a conditional logistic-regression model that adjusted for other asbestos exposures. We adopted cumulative indices that considered residence-specific asbestos (crocidolite) concentrations and durations during the potential exposure period of 1957-1975 to evaluate individual neighborhood exposures.Results: There was an increasing, dose-dependent risk of mesothelioma death associated with neighborhood exposure, demonstrated by ORs in the highest quintile category that were 21.4 (95% CI: 5.8 - 79.2) for all, 23.7 (95% CI: 3.8 -147.2) for males, and 26.0 (95% CI: 2.8 - 237.5) for females, compared to the lowest quintile, respectively. These results clearly demonstrated no substantial differences between males and females in relation to the magnitude of risk from neighborhood exposure.Conclusions: By adjusting for occupational and other asbestos exposures, a dose-dependent relationship was demonstrated between mesothelioma death and neighborhood asbestos exposure from a large-scale AC plant. Our findings suggest that the risk of mesothelioma death associated with neighborhood exposure persists and will not be diminished for many years, even though it has been decades since the AC plant closed.

Occupational asbestos exposure occurs in many workplaces and is a well‐known cause of mesothelioma and lung cancer. However, the association between nonoccupational asbestos exposure and those diseases is not clearly described. The aim of this study was to investigate cause‐specific mortality among the residents of Amagasaki, a city in Japan with many asbestos factories, and evaluate the potential excess mortality due to established and suspected asbestos‐related diseases. The study population consisted of 143 929 residents in Amagasaki City before 1975 until 2002, aged 40 years or older on January 1, 2002. Follow‐up was carried out from 2002 to 2015. Standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated by sex, using the mortality rate of the Japanese population as reference. A total of 38 546 deaths (including 303 from mesothelioma and 2683 from lung cancer) were observed. The SMRs in the long‐term residents’ cohort were as follows: death due to all causes, 1.12 (95% CI, 1.10‐1.13) in men and 1.07 (95% CI, 1.06‐1.09) in women; lung cancer, 1.28 (95% CI, 1.23‐1.34) in men and 1.23 (95% CI, 1.14‐1.32) in women; and mesothelioma, 6.75 (95% CI, 5.83‐7.78) in men and 14.99 (95% CI, 12.34‐18.06) in women. These SMRs were significantly higher than expected. The increased SMR of mesothelioma suggests the impact of occupational asbestos exposure among men and nonoccupational asbestos exposure among women in the long‐term residents’ cohort. In addition, the high level of excess mortality from mesothelioma has persisted, despite the mixture of crocidolite and chrysotile no longer being used for three or four decades.

Zinc (Zn)-depletion inhibits the second step of RNA splicing, namely exon-ligation. To investigate the effects of cadmium (Cd) and other metal ions on RNA splicing inhibited by Zn-depletion, we measured in vitro splicing activities in the presence of these metals. Zn-depletion in the splicing reaction mixture was achieved by addition of a Zn-chelator, 1,10-phenanthroline. Cd(II) at 1, 5 and 10 microM restored the splicing activity to 2, 24 and 72% of that in the control reaction mixture, while higher concentrations of Cd(II) decreased the splicing activity, and more than 50 microM Cd(II) showed a complete absence of spliced products. Hg(II) also restored the splicing activity, albeit to a lesser extent, since 5 and 10 microM Hg(II) restored the splicing activity to 3 and 4% of the control value. The other metal ions examined in this study, Co(II), Cu(II), Mg(II) and Mn(II), did not show any restoration of the splicing activity. We concluded that Cd(II) could restore the in vitro splicing activity inhibited by Zn-depletion, although higher concentrations of Cd(II) prevented progress of the RNA splicing reaction. These results suggest that Cd(II) has a bifunctional property regarding RNA splicing, and is stimulatory at low concentrations and inhibitory at high concentrations.

The dominant C96Y mutation of one of the two murine insulin genes, Ins2, causes diabetes mellitus in 'Akita' mice. Here we established pancreatic islet beta cell lines from heterozygous mice (Ins2+/Akita). Western blot analysis of endoplasmic reticulum (ER) molecular chaperones indicated that Grp78, Grp94 and Orp150 are significantly increased in Ins2+/Akita cells compared with wild-type (Ins2+/+) cells. Reporter gene assays using the human GRP78 promoter with or without the ER stress response element (ERSE) showed that Ins2+/Akita cells exhibit significantly stronger ERSE-dependent transcriptional activity than Ins2+/+ cells. Transient over-expression of the Ins2 C96Y mutant in wild-type beta cells induces a stronger ERSE-dependent stress response than does wild-type Ins2 over-expression. The ERSE-binding transcription factor ATF6 is strongly activated in Ins2+/Akita cells. The activity of a reporter containing the specific binding sequence of another ERSE-binding transcription factor, XBP1, is also enhanced in Ins2+/Akita cells. Levels of active forms of XBP1 mRNA and protein are both markedly elevated in Ins2+/Akita cells. These results indicate that this cell line is subject to continuous ER stress and that the Ins2 C96Y mutation induces the expression of ER chaperones through the activation of ATF6 and XBP1.

The effect of painting on alcoholic liver dysfunction was investigated. The subjects were male workers engaged in small-scale enterprises under contract to with heavy industries. Painting involved metal cleaning and painting, and the air concentrations of organic solvents were frequently high. The study population consisted of 1,157 male workers over 40 yr of age. Of them, 85 were painters engaged for a mean duration of 20.9 +/- 9.8 yr. There was no significant difference in GOT and GPT between painters who did not drink and non-painters who did not drink, but GOT and GPT were significantly higher in painters drinking several days a week than in non-painters. A past history of hepatitis affected GOT, GPT and gamma-GTP. Painting, daily alcohol consumption, drinking frequency and body mass index affected gamma-GTP. A questionnaire survey of hepatitis was also conducted in 206 male workers (age range 18-67 yr). Of them, 134 were painters (mean duration of painting, 16.8 +/- 10.4 yr). This questionnaire survey showed that 13 painters (9.6% of the painters) and two non-painters (2.6% of the non-painters) had a history of hepatitis. Of the 13 painters, five painters had a history of hepatitis C and four had a history of alcoholic hepatitis. All of these 13 painters had the habit of drinking. This study indicated that painting had little effect on the liver function in painters not drinking, but increased alcoholic liver dysfunction in painters with the drinking habit.

Phosphodiesterase I/nucleotide pyrophosphatase is a widely expressed membrane-bound enzyme that cleaves diester bonds of a variety of substrates. We have cloned brain-type cDNA for this enzyme from rat brain and designated it PD-I alpha (M. Narita, J. Goji, H. Nakamura, and K. Sano, 1994, J. Biol. Chem. 269: 28235-28242). In this study we have isolated cDNA and genomic DNA encoding human PD-I alpha. Human PD-I alpha cDNA, designated PDNP2 in HGMW nomenclature, has a 2589-nucleotide open reading frame encoding a polypeptide of 863 amino acids with a calculated M(r) of 99,034. Northern blot analysis revealed that human PD-I alpha transcript was present in brain, lung, placenta, and kidney. The database analysis showed that human PD-I alpha was identical with human autotaxin (ATX), a novel tumor motility-stimulating factor, except that human PD-I alpha lacks 156 nucleotides and 52 amino acids of human ATX. Human PD-I alpha and human ATX are likely to be alternative splicing products from the same gene. The 5' region of the human PDNP2 gene contains four putative binding sites of transcription factor Sp1 without typical TATA or CAAT boxes, and there is a potential octamer binding motif in intron 2. From the results of fluorescence in situ hybridization, the human PDNP2 gene is located at chromosome 8q24.1.

We here report a unique case of a young boy with an intrathoracic tumor which consisted of neurogenic and myogenic elements. The initial pathological diagnosis was alveolar rhabdomyosarcoma. The tumor tissue from surgical resection was composed of three parts, each showing a different histological appearance, i.e. a monotonous small cell area, an alveolar area, and an area consisting of pleomorphic rhabdomyoblasts. The small round cells in the monotonous area were immunoreactive with the antibodies for Leu7, neuron-specific enolase (NSE), neurofilament proteins (NFP), and beta 2 microglobulin, but not with the antibody for desmin. These cells also had dense core granules. The tumor cells in the alveolar area were immunoreactive with the antibodies for Leu7 and desmin, but not with the antibody for NFP. Pleomorphic rhabdomyoblasts were immunoreactive with the antibody for desmin, but not with the antibodies for Leu7 and NFP. These findings imply that this tumor consisted of neurogenic and myogenic elements and is considered to be a special type of rhabdomyosarcoma.

The majority of existing literature reports that cadmium (Cd) is toxic to humans and most living organisms. This paper reports the results of our study that measured Cd levels in the livers and kidneys of humans and other 50 mammalian species under normal conditions in Japan. The study tests the differences in the Cd concentrations across different mammalian species and sexes. Our results revealed that (1) there is a strong correlation between the Cd levels in the livers and kidneys across all examined species, (2) humans exhibit the highest Cd accumulation level in both organs, (3) primates also show a high Cd concentration at a level close to humans, (4) mice and rats show low Cd levels in both organs, indicating that humans accumulate about a few thousand times more Cd than mice and rats, and (5) the Cd concentration of female mammals is more than double of males for both organs. Our results indicate that these cross-sex as well as cross-species discrepancies cannot be explained by the difference in daily Cd intake. While further research is necessary to determine any potential role of Cd accumulation, we speculate that Cd plays some physiological function in the renal cortex of humans and primates.

We present a case of childhood T-cell lymphoblastic lymphoma (T-LBL) with a translocation (10;12)(q24;q15) as a main clonal abnormality, which to our knowledge is the first reported karyotype of this malignancy. The patient's peripheral blood and bone marrow showed marked leukocytosis mostly myeloid lineage cells, at diagnosis. The enlarged lymph node consisted of two different cell populations: CD2+/CD7+ prothymic lymphoblasts and a cluster of peroxidase-positive myeloid cells around vessels. This case might represent a rare but distinct clinical entity of LBL.

A 66-year-old male patient was admitted with dyspnea; physical examination revealed petechiae and systemic lymphadenopathy. Laboratory findings showed leukemia. The blasts in the peripheral blood were negative for cytochemical myeloperoxidase, and had condensed nuclear chromatin with a nucleolus. The histological diagnosis of the biopsied neck lymph node was lymphoblastic lymphoma. The leukemia cells expressed CD2, CD6, CD7, CD13low, CD56, beta chain of IL-2 receptorlow (IL-2R beta), and HLA-DR antigens, but not other pan-T (CD5, CD3, CD4, and CD8); pan-B (CD10, CD19, CD20, and CD24); natural killer (NK) (CD16, CD57); or myeloid (CD33) antigens. Electronmicroscopy revealed convoluted nuclei with conspicuous nucleoli and peripherally condensed heterochromatin. Membrane-bound granules containing an electron dense matrix were observed in the cytoplasm, indicating the NK cell nature of the neoplastic cells. While terminal deoxynucleotidyl transferase (TdT) and cytoplasmic CD3 were not detected by immunofluorescence on fixed smears, Northern blot analysis revealed the gene expression of CD3 epsilon, CD3 zeta, and TdT. Gene rearrangement analysis revealed that the beta, gamma, and delta chains of T-cell receptor (TCR) and immunoglobulin heavy chain (IgH) were of germline genotype. While the overall interpretation of the phenotype and genotype was difficult, the derivation of an immature stage of NK lineage was strongly suggested, based predominantly on the electronmicroscopic features. Despite initially successful chemotherapy, the patient died 14 months after initial presentation.