47 research outputs found

    A Blueprint for the Problem Formulation Phase of EPA-Type Ecological Risk Assessments for 316(b) Determinations

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    The difference between management objectives focused on sustainability of fish populations and the indigenous aquatic community, and a management objective focused on minimizing entrainment and impingement losses accounts for much of the ongoing controversy surrounding §316(b). We describe the EPA’s ecological risk assessment framework and recommend that this framework be used to more effectively address differences in management objectives and structure §316(b) determinations. We provide a blueprint for the problem formulation phase of EPA-type ecological risk assessments for cooling-water intake structures (CWIS) at existing power plant facilities. Our management objectives, assessment endpoints, conceptual model, and generic analysis plan apply to all existing facilities. However, adapting the problem formulation process for a specific facility requires consideration of the permitting agency’s guidelines and level of regulatory concern, as well as site-specific ecological and technical differences. The facility-specific problem formulation phase is designed around the hierarchy of biolo gical levels of organization in the generic conceptual model and the sequence of cause-effect events and risk hypotheses represented by this model. Problem formulation is designed to be flexible in that it can be tailored for facilities where §316(b) regulatory concern is low or high. For some facilities, we anticipate that the assessment can be completed based on consideration of susceptibility alone. At the other extreme, a high level of regulatory concern combined with the availability of extensive information and consideration of costly CWIS mitigation options may result in the ecological risk assessment relying on analyses at all levels. Decisions on whether to extend the ecological risk assessment to additional levels should be based on whether regulatory or generator concerns merit additional analyses and whether available information is adequate to support such analyses. In making these decisions, the functional dependence between levels of analysis must be considered in making the transition to the analysis phase and risk estimation component of the ecological risk assessment. Regardless of how the generic analysis plan is modified to develop a facility-specific analysis plan, the resulting plan should be viewed as a tool for comparing representative species and alternative CWIS options by focusing on relative changes (i.e., proportional or percent changes) in various measures. The analysis plan is specifically designed to encourage consideration of multiple lines of evidence and to characterize uncertainties in each line of evidence. Multiple lines of evidence from different levels of analysis, obtained using both prospective and retrospective techniques, provide a broader perspective on the magnitude of potential effects and associated uncertainties and risks. The implications of the EPA’s recent (April 2002) proposed regulations for existing facilities on the applicability of this blueprint are briefly considered

    Does the use of the 2009 FIGO classification of endometrial cancer impact on indications of the sentinel node biopsy?

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    <p>Abstract</p> <p>Background</p> <p>Lymphadenectomy is debated in early stages endometrial cancer. Moreover, a new FIGO classification of endometrial cancer, merging stages IA and IB has been recently published. Therefore, the aims of the present study was to evaluate the relevance of the sentinel node (SN) procedure in women with endometrial cancer and to discuss whether the use of the 2009 FIGO classification could modify the indications for SN procedure.</p> <p>Methods</p> <p>Eighty-five patients with endometrial cancer underwent the SN procedure followed by pelvic lymphadenectomy. SNs were detected with a dual or single labelling method in 74 and 11 cases, respectively. All SNs were analysed by both H&E staining and immunohistochemistry. Presumed stage before surgery was assessed for all patients based on MR imaging features using the 1988 FIGO classification and the 2009 FIGO classification.</p> <p>Results</p> <p>An SN was detected in 88.2% of cases (75/85 women). Among the fourteen patients with lymph node metastases one-half were detected by serial sectioning and immunohistochemical analysis. There were no false negative case. Using the 1988 FIGO classification and the 2009 FIGO classification, the correlation between preoperative MRI staging and final histology was moderate with Kappa = 0.24 and Kappa = 0.45, respectively. None of the patients with grade 1 endometrioid carcinoma on biopsy and IA 2009 FIGO stage on MR imaging exhibited positive SN. In patients with grade 2-3 endometrioid carcinoma and stage IA on MR imaging, the rate of positive SN reached 16.6% with an incidence of micrometastases of 50%.</p> <p>Conclusions</p> <p>The present study suggests that sentinel node biopsy is an adequate technique to evaluate lymph node status. The use of the 2009 FIGO classification increases the accuracy of MR imaging to stage patients with early stages of endometrial cancer and contributes to clarify the indication of SN biopsy according to tumour grade and histological type.</p

    Screening of MAMLD1 Mutations in 70 Children with 46,XY DSD: Identification and Functional Analysis of Two New Mutations

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    More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients

    A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

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    This is the author's accepted manuscript.Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs
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