The estrogen content and relative performance of Japanese and British sewage treatment plants and their potential impact on endocrine disruption

Both the UK and Japan are densely populated islands with relatively short rivers. Therefore, both countries are likely to be highly exposed to contaminants emanating from their human populations. This review considered how effective the different sewage treatment facilities of the two countries are at removing steroid estrogens from the effluent. The methods of estrogen analysis in sewage effluent, the number and importance of different sewage treatment types, and their apparent effectiveness at removing estrogens were all considered. In both countries the activated sludge treatment was dominant in terms of people served and water discharged. The analytical techniques used by those studying estrogen concentrations in effluents in both countries were broadly similar. Activated sludge plant (ASP) effluent in the UK typically contained around 2 ng/L E2 and 8 ng/L E1, whilst Japanese ASPs typically reported E2 as below detection, and 10 ng/L E1 in their effluents. When estrogenic bioassays were used in Japan they typically record an estrogenic potency of 10 ng/L E2 equivalents. Even taking into account EE2 (not found in Japanese effluents), the overall estrogenicity of British sewage effluents would appear to be the same as that of Japanese (around 10 ng/L E2 equivalents). This suggests that the ASPs serving the large urban communities would have effluent of similar estrogenic potencies in Japan and the UK. Less information is available about the more numerous biological (trickling) filter plants (BFP) in the UK and oxygen ditches (OD) in Japan which tend to serve smaller, more rural communities. The available data would suggest that the BFPs are significantly less efficient than the ODs at removing E1. This would suggest that in similar circumstances, British headwaters (where this STP type is often found) might be more at risk from endocrine disruption than their Japanese counterparts. Overall, the higher apparent incidence of endocrine disruption in British wild fish compared to Japanese cannot be attributed to differences in the efficiency of their respective STPs

An interpretation of SPring-8 ground elevation by the empirical AT L-law approach

Starting in 1996, the coordinates of the accelerator components on the SPring-8 storage ring were continuously surveyed for over two decades. The dispersion of the elevation changes of the ground motion lang dz2rang analyzed from the aspect of the empirical ATL-law which has been intensively researched since 1990s. With the ATL-law, lang dz2rang can be expressed as products of a ground diffusion coefficient A, temporal survey spans T, and spatial scales L. The coefficient A is well known to depend on the local geology and is evaluated as (7.6 ± 1.4) × 10−6 μm2/s/m for the SPring-8 storage ring. In this paper, a transition of survey methods in the SPring-8 storage ring is reviewd and survey results both in horizontal and vertical directions are presented. Furthermore, the relevance of the ATL-law approach for the ground elevation dispersion are discussed

Radiosensitization Effect of PARP Inhibition in Cells Exposed to Low and High LET Radiation

Poly(ADP-ribose) polymerase (PARP)-1 promotes base excision repair and DNA strand break repair. Inhibitors of PARP enhance the cytotoxic effects of gamma- and X-irradiation. We investigated the impact of PARP inhibition on the responses to gamma-irradiation (low LET (liner energy transfer) radiation) and carbon-ion irradiation (high LET radiation) in the human pancreatic cancer cell line MIA PaCa-2. Cell survival was assessed by colony formation assay after combination treatment with the PARP inhibitor AZD2281 and single fraction gamma-irradiation and carbon-ion irradiation (LET 13 and 70 keV/um). The DNA damage response (DDR) was assessed by pulse field gel electrophoresis (PFGE), Western blotting and flow cytometry. Treatment with a PARP inhibitor enhanced the cytotoxic effect of gamma-, LET 13 and LET 70 carbon-ion irradiation. Moreover, the radiosensitization effect was greater for LET 70 than for LET 13 irradiation. Prolonged and increased levels of gamma-H2AX were observed both after gamma- and carbon-ion irradiation in the presence of the PARP inhibitor. Enhanced level of phosphorylated-p53 (Ser-15) was observed after gamma-irradiation but not after carbon-ion irradiation. PARP inhibitor treatment induced S phase arrest and enhanced subsequent G2/M arrest both after gamma- and carbon-ion irradiation. These results suggest that the induction of S phase arrest through an enhanced DDR and a local delay in DNA double strand break processing by PARP inhibition caused sensitization to gamma- and carbon-ion irradiation. Taken together, PARP inhibitors might be applicable to a wide therapeutic range of LET radiation through their effects on the DDR

Parg deficiency confers radio-sensitization through enhanced cell death in mouse ES cells exposed to various forms of ionizing radiation

Poly(ADP-ribose) glycohydrolase (Parg) is the main enzyme involved in poly(ADP-ribose) degradation. Here, the effects of Parg deficiency on sensitivity to low and high linear-energy-transfer (LET) radiation were investigated in mouse embryonic stem (ES) cells. Mouse Parg-/- and poly(ADP-ribose) polymerase-1 deficient (Parp-1-/-) ES cells were used and responses to low and high LET radiation were assessed by clonogenic survival and biochemical and biological analysis methods.Parg-/-cells were more sensitive to gamma-irradiation than Parp-1-/- cells. Transient accumulation of poly(ADP-ribose) was enhanced in Parg-/-cells. Augmented levels of phosphorylated H2AX (gamma-H2AX)from early phase were observed in Parg-/- ES cells. The induction level of p53 phophorylation at ser18 was similar in wild-type and Parp-1-/- cells and apoptotic cell death process was mainly observed in the both genotypes. These results suggested that the enhanced sensitivity of Parg-/- ES cells to gamma-irradiation involved defective repair of DNA double strand breaks. The effects of Parg and Parp-1 deficiency on the ES cell response to carbon-ion irradiation (LET13 and 70 keV/um) and Fe-ion irradiation (200 keV/um) were also examined. Parg-/- cells were more sensitive to LET 70 keV/um carbon-ion irradiation than Parp-1-/- cells. Enhanced apoptotic cell death also accompanied augmented levels of gamma-H2AX in a biphasic manner peaked at 1 and 24 h. The induction level of p53 phophorylation atser18 was not different between wild-type and Parg-/- cells. The augmented level of poly(ADP-ribose) accumulation was noted after carbon-ion irradiation compared to gamma-irradiation even in the wild-type cells. An enhanced poly(ADP-ribose) accumulation was further observed in Parg-/- cells. Both Parg-/- cells and Parp-1-/- cells did not show sensitization to Fe-ion irradiation. Parg deficiency sensitizes mouse ES cells to a wide therapeutic range of LET radiation through the effects on DNA double strand break repair responses and enhanced cell death

QT is longer in drug-free patients with schizophrenia compared with age-matched healthy subjects.

The potassium voltage-gated channel KCNH2 is a well-known gene in which mutations induce familial QT interval prolongation. KCNH2 is suggested to be a risk gene for schizophrenia. Additionally, the disturbance of autonomic control, which affects the QT interval, is known in schizophrenia. Therefore, we speculate that schizophrenic patients have characteristic features in terms of the QT interval in addition to the effect of antipsychotic medication. The QT interval of patients with schizophrenia not receiving antipsychotics (n = 85) was compared with that of patients with schizophrenia receiving relatively large doses of antipsychotics (n = 85) and healthy volunteers (n = 85). The QT interval was corrected using four methods (Bazett, Fridericia, Framingham or Hodges method). In ANCOVA with age and heart rate as covariates, patients not receiving antipsychotic treatment had longer QT intervals than did the healthy volunteers, but antipsychotics prolonged the QT interval regardless of the correction method used (P<0.01). Schizophrenic patients with and without medication had a significantly higher mean heart rate than did the healthy volunteers, with no obvious sex-related differences in the QT interval. The QT interval prolongation may be manifestation of a certain biological feature of schizophrenia

A comprehensive analysis of radiosensitization targets; functional inhibition of DNA methyltransferase 3B radiosensitizes by disrupting DNA damage regulation.

A comprehensive genome-wide screen of radiosensitization targets in HeLa cells was performed using a shRNA-library/functional cluster analysis and DNMT3B was identified as a candidate target. DNMT3B RNAi increased the sensitivity of HeLa, A549 and HCT116 cells to both γ-irradiation and carbon-ion beam irradiation. DNMT3B RNAi reduced the activation of DNA damage responses induced by γ-irradiation, including HP1β-, γH2AX- and Rad51-foci formation. DNMT3B RNAi impaired damage-dependent H2AX accumulation and showed a reduced level of γH2AX induction after γ-irradiation. DNMT3B interacted with HP1β in non-irradiated conditions, whereas irradiation abrogated the DNMT3B/HP1β complex but induced interaction between DNMT3B and H2AX. Consistent with radiosensitization, TP63, BAX, PUMA and NOXA expression was induced after γ-irradiation in DNMT3B knockdown cells. Together with the observation that H2AX overexpression canceled radiosensitization by DNMT3B RNAi, these results suggest that DNMT3B RNAi induced radiosensitization through impairment of damage-dependent HP1β foci formation and efficient γH2AX-induction mechanisms including H2AX accumulation. Enhanced radiosensitivity by DNMT3B RNAi was also observed in a tumor xenograft model. Taken together, the current study implies that comprehensive screening accompanied by a cluster analysis enabled the identification of radiosensitization targets. Downregulation of DNMT3B, one of the targets identified using this method, radiosensitizes cancer cells by disturbing multiple DNA damage responses

Slower titration of lamotrigine reduces the risk of rash.

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