The British pharmaceutical codex, 1949.
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One- and two-dimensional 13C exchange nuclear magnetic resonance experiments under magic-angle spinning (MAS) can provide detailed information on slow segmental reorientations and chemical exchange in organic solids, including polymers and proteins. However, observations of dynamics on the time scale of seconds or longer are hampered by the competing process of dipolar 13C spin exchange (spin diffusion). In this Communication, we show that fast MAS can significantly slow down the dipolar spin exchange effect for unprotonated carbon sites. The exchange is measured quantitatively using the centerband-only detection of exchange technique, which enables the detection of exchange at any spinning speed, even in the absence of changes of isotropic chemical shifts. For chemically equivalent unprotonated 13C sites, the dipolar spin exchange rate is found to decrease slightly less than proportionally with the sample-rotation frequency, between 8 and 28 kHz. In the same range, the dipolar spin exchange rate for a glassy polymer with an inhomogeneously broadened MAS line decreases by a factor of 10. For methylene groups, no or only a minor slow-down of the exchange rate is found.
The chlorinated isocoumarin compound, ochratoxin A (OTA), together with some related derivatives (ochratoxins B, C, alpha, beta) are produced by Penicillium verrucosum and by several spp. of Aspergillus, most notably A. ochraceus. P. verrucosum is the principal source of OTA contamination of stored foods in temperate climates while Aspergillus spp. predominate in warmer countries. The major dietary sources of OTA are cereals but significant levels of contamination may be found in grape juice and red wine, coffee, cocoa, nuts, spices and dried fruits. Because of the chemical stability of OTA and long half-life in mammalian tissues, contamination may also carry over into pork and pig blood products and into beer. OTA is potently nephrotoxic and carcinogenic, the potency varying markedly between species and sexes; it is also teratogenic and immunotoxic. There have been different approaches to the risk assessment of OTA in different jurisdictions, largely arising from whether or not the carcinogenicity of OTA is considered to arise through a thresholded or non-thresholded mechanism. Consequently the tolerable intakes have variously been estimated at 100 ng/kg bw/week (JECFA), 1.5 to 5.7 ng/kg bw/day (Canada) and not more than 5 ng/kg bw/day (European Commission). These differences are also reflected in risk management measures that have been implemented or proposed with different maximum contamination levels being applied to different commodities and to the same commodity in different countries. Prevention of contamination at source is considered to be the most effective public health measure. There is also a need to harmonise the risk assessment and management processes to a greater extent than currently exist if barriers to trade are to be avoided.
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Residues on foodstuffs resulting from the use of crop-protection products are a function of many factors, e.g. environmental conditions, dissipation and application rate, some of which are linked to the physicochemical properties of the active ingredients. Residue limits (maximum residue levels (MRLs) and tolerances) of fungicides, herbicides and insecticides set by different regulatory authorities are compared, and the relationship between physicochemical properties of the active ingredients and residue limits are explored. This was carried out using simple summary statistics and artificial neural networks. US tolerances tended to be higher than European Union MRLs. Generally, fungicides had the highest residue limits followed by insecticides and herbicides. Physicochemical properties (e.g. aromatic proportion, non-carbon proportion and water solubility) and crop type explained up to 50% of the variation in residue limits. This suggests that physicochemical properties of the active ingredients may control important aspects of the processes leading to residues.
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BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, of which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are the most frequently observed. The impact of these molecular alterations on the tumor immune microenvironment remains incompletely understood. METHODS: We performed a high-parameter spatial immune phenotyping of iCCA samples with pathogenic FGFR2 or IDH1 alterations and FGFR2/IDH1 wild-type controls at the single-cell level using CO-Detection by indEXing. RESULTS: A total of 24 tumors were examined. Tumors with FGFR2 alterations were characterized by fewer CD8+ T cells and "M2-like" macrophages but higher levels of polymorphonuclear myeloid-derived suppressor cells as compared to FGFR2 wild-type tumors. Spatial relationships between polymorphonuclear myeloid-derived suppressor cells and multiple other cell types in the tumor microenvironment (including tumor cells, CD4+, and CD8+ T cells) were enriched in tumors with FGFR2 alterations. Tumors with IDH1 mutations had a trend toward more fibroblasts and were characterized by a closer proximity of tumor cells to CD4+ T cells, and between macrophages and multiple structural tumor microenvironment components as compared to other subtypes. CONCLUSIONS: iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.
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