Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to re-evaluate the safety in use of vitamin D and to provide, if necessary, revised Tolerable Upper Intake Levels (ULs) of vitamin D for all relevant population groups. The ULs for adults including pregnant and lactating women, children and adolescents were revised. For adults, hypercalcaemia was selected as the indicator of toxicity. In two studies in men, intakes between 234 and 275 µg/day were not associated with hypercalcaemia, and a no observed adverse effect level (NOAEL) of 250 µg/day was established. Taking into account uncertainties associated with these studies, the UL for adults including pregnant and lactating women was set at 100 µg/day. Despite a continuing paucity of data for high vitamin D intakes in children and adolescents, the UL was adapted to 100 µg/day for ages 11-17 years, considering that owing to phases of rapid bone formation and growth this age group is unlikely to have a lower tolerance for vitamin D compared to adults. The same applies also to children aged 1-10 years, but taking into account their smaller body size, a UL of 50 µg/day is proposed. For infants, the UL of 25 µg/day based on previously available data relating high vitamin D intakes to impaired growth and hypercalcaemia was retained as limited additional evidence has emerged since the previous risk assessment. Data on vitamin D intakes from surveys in 14 European countries indicate that intakes in high consumers are below the revised ULs for vitamin D for all population groups.
tolerance data 2012 en francais 45
Opioid receptors (OR) are part of the class A of G-protein coupled receptors and the target of the opiates, the most powerful analgesic molecules used in clinic. During a protracted use, a tolerance to analgesic effect develops resulting in a reduction of the effectiveness. So understanding mechanisms of tolerance is a great challenge and may help to find new strategies to tackle this side effect. This review will summarize receptor-related mechanisms that could underlie tolerance especially receptor desensitization. We will focus on the latest data obtained on molecular mechanisms involved in opioid receptor desensitization: phosphorylation, receptor uncoupling, internalization, and post-endocytic fate of the receptor.
Figure 2. Schematic illustration of mechanisms involved in opioid receptor desensitization by biased agonists. (A) MOR are differentially phosphorylated by different kinases upon either DAMGO or morphine exposure (Doll et al., 2011). This results in binding of arrestins to MOR upon DAMGO while this interaction is weakly detectable for morphine when a GRK is over-expressed (Groer et al., 2007). In such conditions, acute DAMGO exposure promotes G protein uncoupling from MOR while morphine does not (Whistler and Von Zastrow, 1998). However, MOR phosphorylation at S375 induced by morphine is able to promote desensitization but not internalization (Schulz et al., 2004). Some reports rather suggest that under morphine exposure, MOR is not desensitized and this continuous signaling promotes tolerance (Finn and Whistler, 2001). Even if it's now well-admitted that morphine is able to promote MOR internalization (Haberstock-Debic et al., 2005; Nowoczyn et al., 2013), DAMGO induces a stronger internalization compared to morphine (Whistler and Von Zastrow, 1998; Schulz et al., 2004). MOR is dephosphorylated by phosphatase proteins (Doll et al., 2012) then undergoes an active recycling (Tanowitz and Von Zastrow, 2003). Other proteins such as arrestins, dynamin, or GRK could participate MOR trafficking (Dang et al., 2011). In contrast, as morphine is a poor inducer of MOR internalization, receptor is maintained in a phosphorylation state at S375 for longer time compared to DAMGO. (B) Different kinases are involved in the regulation of hDOR (Marie et al., 2008): GRK2 plays a major role in receptor phosphorylation on S363 upon DPDPE and etorphine while other kinases are also implicated. Etorphine-induced desensitization requires arrestins but not receptor internalization. In contrast, an arrestin is involved in hDOR internalization but not desensitization upon DPDPE (Aguila et al., 2012). Once sequestrated by etorphine, hDOR is dephosphorylated and recycled back to the cell surface (Hasbi et al., 2000; Marie et al., 2003b) while upon DPDPE exposure, the receptor is mainly targeted to lysosomes for degradation (Marie et al., 2003b) probably by a mechanism involving GASP (Whistler et al., 2002).
Observed global changes in the water cycle, including precipitation, are more uncertain than observed changes in temperature (Hartmann et al., 2013; Stocker et al., 2013)95. There is high confidence that mean precipitation over the mid-latitude land areas of the Northern Hemisphere has increased since 1951 (Hartmann et al., 2013)96. For other latitudinal zones, area-averaged long-term positive or negative trends have low confidence because of poor data quality, incomplete data or disagreement amongst available estimates (Hartmann et al., 2013)97. There is, in particular, low confidence regarding observed trends in precipitation in monsoon regions, according to the SREX report (Seneviratne et al., 2012)98 and AR5 (Hartmann et al., 2013)99, as well as more recent publications (Singh et al., 2014; Taylor et al., 2017; Bichet and Diedhiou, 2018;100 see Supplementary Material 3.SM.2).
There is a lack of precise, quantitative studies of projected impacts of SLR at 1.5C and 2C. Small islands are projected to be at risk and very sensitive to coastal climate change and other stressors (high confidence) (Nurse et al., 2014; Benjamin and Thomas, 2016; Ourbak and Magnan, 2017; Brown et al., 2018a; Nicholls et al., 2018; Rasmussen et al., 2018;777 AR5 Sections 29.3 and 29.4), such as oceanic warming, SLR (resulting in salinization, flooding and erosion), cyclones and mass coral bleaching and mortality (Section 3.4.4, Boxes 3.4 and 3.5). These impacts can have significant socio-economic and ecological implications, such as on health, agriculture and water resources, which in turn have impacts on livelihoods (Sovacool, 2012; Mycoo, 2014, 2017; Nurse et al., 2014)778. Combinations of drivers causing adverse impacts are important. For example, Storlazzi et al. (2018)779 found that the impacts of SLR and wave-induced flooding (within a temperature horizon equivalent of 1.5C), could affect freshwater availability on Roi-Namur, Marshall Islands, but is also dependent on other extreme weather events. Freshwater resources may also be affected by a 0.40 m rise in sea level (which may be experienced with a 1.5C warming) in other Pacific atolls (Terry and Chui, 2012)780. Whilst SLR is a major hazard for atolls, islands reaching higher elevations are also threatened given that there is often a lot of infrastructure located near the coast (high confidence) (Kumar and Taylor, 2015; Nicholls et al., 2018)781. Tens of thousands of people on small islands are exposed to SLR (Rasmussen et al., 2018)782. Giardino et al. (2018)783 found that hard defence structures on the island of Ebeye in the Marshall Islands were effective in reducing damage due to SLR at 1.5C and 2C. Additionally, damage was also reduced under mitigation scenarios compared with non-mitigation scenarios. In Jamaica and St Lucia, SLR and extreme sea levels are projected to threaten transport system infrastructure at 1.5C unless further adaptation is undertaken (Monioudi et al., 2018)784. Slower rates of SLR will provide a greater opportunity for adaptation to be successful (medium confidence), but this may not be substantial enough on islands with a very low mean elevation. Migration and/or relocation may be an adaptation option (Section 3.4.10). Thomas and Benjamin (2017)785 highlight three areas of concern in the context of loss and damage at 1.5C: a lack of data, gaps in financial assessments, and a lack of targeted policies or mechanisms to address these issues (Cross-Chapter Box 12 in Chapter 5). Small islands are projected to remain vulnerable to SLR (high confidence). 2ff7e9595c