Safety Study of Photodynamic Therapy Using Talaporfin Sodium in the Pancreas and Surrounding Tissues in the Syrian Golden Hamster

Aim. To assess the safety of photodynamic therapy (PDT) using talaporfin sodium on the pancreas and surrounding organs in normal hamsters. Methods. Fluorescence microscopy documented talaporfin levels in liver, duodenum, and pancreas up to 24 hours after photosensitisation. Lesion size in liver 3 days after PDT (50 J, 5 mg/kg, variable drug-light interval (DLI)) was documented to optimise the DLI. Using optimum DLI, pancreas and surrounding organs were treated with laser fibre touching the surface and animals were killed at 3 or 21 days. Results. Peak fluorescence was seen in duodenum and pancreas at 15 mins (second lower peak at 2 hours). Liver fluorescence was consistently high (peak 1 hour) until after 4 hours. Optimum DLI was seen at 15 minutes. The pancreas was relatively resistant to direct PDT injury (small lesions at high doses) but surrounding stomach, duodenum, and liver were more susceptible with evidence of adhesions and full thickness damage (localised peritonitis and duodenal perforation at highest doses). Conclusion. The safety profile is similar to PDT with longer acting photosensitisers. The pancreas appears safe to treat, but care is required to avoid high light doses to the intestinal tract, particularly the duodenum

UK and Ireland Joint Advisory Group (JAG) consensus statements for training and certification in diagnostic endoscopic ultrasound (EUS)

Background and Aims: International endoscopy societies vary in their approach for credentialing individuals in endoscopic ultrasound (EUS) to enable independent practice; however, there is no consensus in this or its implementation. In 2019, the Joint Advisory Group on GI Endoscopy (JAG) commissioned a working group to examine the evidence relating to this process for EUS. The aim of this was to develop evidence-based recommendations for EUS training and certification in the UK.Methods: Under the oversight of the JAG quality assurance team, a modified Delphi process was conducted which included major stakeholders from the UK and Ireland. A formal literature review was made, initial questions for study were proposed and recommendations for training and certification in EUS were formulated after a rigorous assessment using the Grading of Recommendation Assessment, Development and Evaluation tool and subjected to electronic voting to identify accepted statements. These were peer reviewed by JAG and relevant stakeholder societies before consensus on the final EUS certification pathway was achieved.Results: 39 initial questions were proposed of which 33 were deemed worthy of assessment and finally formed the key recommendations. The statements covered four key domains, such as: definition of competence (13 statements), acquisition of competence (10), assessment of competence (5) and postcertification mentorship (5). Key recommendations include: (1) minimum of 250 hands-on cases before an assessment for competency can be made, (2) attendance at the JAG basic EUS course, (3) completing a minimum of one formative direct observation of procedural skills (DOPS) every 10 cases to allow the learning curve in EUS training to be adequately studied, (4) competent performance in summative DOPS assessments and (5) a period of mentorship over a 12-month period is recommended as minimum to support and mentor new service providers.Conclusions: An evidence-based certification pathway has been commissioned by JAG to support and quality assure EUS training. This will form the basis to improve quality of training and safety standards in EUS in the UK and Ireland.</p

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control

Petrological and geochemical characterisation of the sarsen stones at Stonehenge.

Little is known of the properties of the sarsen stones (or silcretes) that comprise the main architecture of Stonehenge. The only studies of rock struck from the monument date from the 19th century, while 20th century investigations have focussed on excavated debris without demonstrating a link to specific megaliths. Here, we present the first comprehensive analysis of sarsen samples taken directly from a Stonehenge megalith (Stone 58, in the centrally placed trilithon horseshoe). We apply state-of-the-art petrographic, mineralogical and geochemical techniques to two cores drilled from the stone during conservation work in 1958. Petrographic analyses demonstrate that Stone 58 is a highly indurated, grain-supported, structureless and texturally mature groundwater silcrete, comprising fine-to-medium grained quartz sand cemented by optically-continuous syntaxial quartz overgrowths. In addition to detrital quartz, trace quantities of silica-rich rock fragments, Fe-oxides/hydroxides and other minerals are present. Cathodoluminescence analyses show that the quartz cement developed as an initial <10 μm thick zone of non-luminescing quartz followed by ~16 separate quartz cement growth zones. Late-stage Fe-oxides/hydroxides and Ti-oxides line and/or infill some pores. Automated mineralogical analyses indicate that the sarsen preserves 7.2 to 9.2 area % porosity as a moderately-connected intergranular network. Geochemical data show that the sarsen is chemically pure, comprising 99.7 wt. % SiO2. The major and trace element chemistry is highly consistent within the stone, with the only magnitude variations being observed in Fe content. Non-quartz accessory minerals within the silcrete host sediments impart a trace element signature distinct from standard sedimentary and other crustal materials. 143Nd/144Nd isotope analyses suggest that these host sediments were likely derived from eroded Mesozoic rocks, and that these Mesozoic rocks incorporated much older Mesoproterozoic material. The chemistry of Stone 58 has been identified recently as representative of 50 of the 52 remaining sarsens at Stonehenge. These results are therefore representative of the main stone type used to build what is arguably the most important Late Neolithic monument in Europe

CD4陽性T細胞に発現するA20(tnfaip3) はTh2型アレルギー性気道炎症を抑制する

研究科: 千葉大学大学院医学薬学府（先端医学薬学専攻）学位記番号: 千大院医薬博甲第医1412号博士（医学）千葉大学 = Chiba Universit

The small pelagic fishery of the Pemba Channel, Tanzania: what we know and what we need to know for management under climate change

Small pelagic fish, including anchovies, sardines and sardinellas, mackerels, capelin, hilsa, sprats and herrings, are distributed widely, from the tropics to the far north Atlantic Ocean and to the southern oceans off Chile and South Africa. They are most abundant in the highly productive major eastern boundary upwelling systems and are characterised by significant natural variations in biomass. Overall, small pelagic fisheries represent about one third of global fish landings although a large proportion of the catch is processed into animal feeds. Nonetheless, in some developing countries in addition to their economic value, small pelagic fisheries also make an important contribution to human diets and the food security of many low-income households. Such is the case for many communities in the Zanzibar Archipelago and on mainland Tanzania in the Western Indian Ocean. Of great concern in this region, as elsewhere, is the potential impact of climate change on marine and coastal ecosystems in general, and on small pelagic fisheries in particular. This paper describes data and information available on Tanzania's small pelagic fisheries, including catch and effort, management protocols and socio-economic significance

Outcome and patterns of care in advanced biliary tract carcinoma (ABC): experience from two tertiary institutions in the United Kingdom

Aims and Background The ABC-02 trial has defined the standard therapy for patients with advanced biliary tract cancer (ABC); however, outcome in an unselected patient population in the UK has not been described. We aimed to investigate the outcome of a series of patients with ABC from two large UK cancer networks. Methods and Study Design We retrospectively reviewed all cases of ABC presenting to two UK cancer networks over a nine-year period. Overall survival (OS) and factors influencing OS were assessed. Results Four hundred and two patients were available for analysis. The median OS was 6.2 months. On univariate analysis, age ≥70 years (P = 0.047), advanced disease stage (P &lt;0.001), gall bladder primary (P = 0.033), poor performance status (P &lt;0.001) and lack of chemotherapy (P &lt;0.001) were associated with worse outcome. Survival was superior in the 36.4% of patients who received palliative chemotherapy (12.5 vs 4.3 months; P &lt;0.001). On multivariate analysis of patients who had chemotherapy, those who did not receive fluoropyrimidine-based regimens (HR = 5.12; P = 0.022) or gemcitabine-based regimens (HR = 5.01; P = 0.021) had a higher mortality, whereas the effect of platinum-containing regimens was of borderline significance (HR = 2.23; P = 0.086). Sites, age, and multi-agent regimens were not significant. Conclusions This is one of the largest retrospective studies reporting outcome of palliative chemotherapy for ABC. It confirms the benefit of palliative chemotherapy in an unselected group of patients. Fluoropyrimidine-based regimens appear to be as effective as gemcitabine-based treatments. </jats:sec

Outcome and patterns of care in advanced biliary tract carcinoma (ABC): experience from two tertiary institutions in the United Kingdom

Aims and background: the ABC-02 trial has defined the standard therapy for patients with advanced biliary tract cancer (ABC); however, outcome in an unselected patient population in the UK has not been described. We aimed to investigate the outcome of a series of patients with ABC from two large UK cancer networks.Methods and study design: we retrospectively reviewed all cases of ABC presenting to two UK cancer networks over a nine-year period. Overall survival (OS) and factors influencing OS were assessed.Results: four hundred and two patients were available for analysis. The median OS was 6.2 months. On univariate analysis, age ≥70 years (P = 0.047), advanced disease stage (P &lt;0.001), gall bladder primary (P = 0.033), poor performance status (P &lt;0.001) and lack of chemotherapy (P &lt;0.001) were associated with worse outcome. Survival was superior in the 36.4% of patients who received palliative chemotherapy (12.5 vs 4.3 months; P &lt;0.001). On multivariate analysis of patients who had chemotherapy, those who did not receive fluoropyrimidine-based regimens (HR = 5.12; P = 0.022) or gemcitabine-based regimens (HR = 5.01; P = 0.021) had a higher mortality, whereas the effect of platinum-containing regimens was of borderline significance (HR = 2.23; P = 0.086). Sites, age, and multi-agent regimens were not significant.Conclusions: this is one of the largest retrospective studies reporting outcome of palliative chemotherapy for ABC. It confirms the benefit of palliative chemotherapy in an unselected group of patients. Fluoropyrimidine-based regimens appear to be as effective as gemcitabine-based treatments