A number of studies have examined the ability of different opioids to induce µ-opioid receptor desensitization as a measure of tolerance. Desensitization is typically measured as a decrease in K+ or Ca2+ currents that occur during continuous opioid exposure. This rapid loss of receptor sensitivity occurs much more quickly (several minutes) than the development of tolerance to the antinociceptive effects of opioids (days to weeks), so the relevance to tolerance remains unclear (see above). When both signalling efficacy and this acute desensitization have been directly measured in the same heterologous expression systems (Borgland, 2001), the ability to produce desensitization was directly correlated with receptor-signalling efficacy, albeit rightward shifted. This finding contrasts with the behavioural data described above showing that high-efficacy µ-opioid receptor agonists produce less tolerance than low-efficacy agonists (Madia et al., 2009). In other words, high-efficacy µ-opioid receptor agonists produce the least tolerance, but the greatest desensitization (Table 4). For example, morphine produces rapid tolerance, but relatively little desensitization to inhibition of GIRK currents in locus coeruleus neurons (Dang and Williams, 2005). These data suggest that acute desensitization may not be a good predictor of tolerance to the antinociceptive effects of opioids. Of course, this conclusion may depend on the signalling pathway involved. Several studies indicate that different mechanisms underlie shot-term tolerance to high- and low-efficacy agonists (Hull et al., 2010; Melief et al., 2010). Thus, a causal relationship between acute desensitization and tolerance may yet be established. One possibility is that desensitization contributes to tolerance to high-, but not low-efficacy agonists.
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The effect of central catheter infection on the outcome of ITI was analyzed in 93 of 99 subjects with a CVAD and adequate data. No difference was found in the number of infected subjects with catheters who achieved tolerance (44%; 9 of 19 LD and 9 of 22 HD) compared with those never infected (48%; 13 of 26 LD and 12 of 26 HD). Furthermore, there was no significant difference in the time taken by infected or noninfected subjects to reach phase 2 of ITI (7.6 vs 5.7 months), phase 3 (9.3 vs 9.4 months), or phase 4 of ITI (tolerance; 15.3 vs 14.9 months).
We also report the first prospectively collected data on the loss of previously normalized pharmacokinetics during the first year after successful tolerance, defined in this study as relapse. Four of 37 (11%) tolerized subjects exhibited a nonrecovered loss of normalized pharmacokinetics at variable times during the prophylaxis phase of study, becoming partial responders. Pharmacokinetics in this group were indistinguishable from the group as a whole when they were originally considered tolerant. Although the NAITR reported a 12% relapse rate as part of its retrospective analysis, those patients had completely lost FVIII responsiveness and thus are not comparable.38
We were surprised to discover a significantly greater number of bleeds with LD compared with HD ITI. Furthermore, significantly more LD subjects required hospitalization for bleeding and significantly fewer experienced a bleed-free course on ITI compared with their HD counterparts. The increased number of bleeds was caused by an increase in bleeding rate and not by the greater duration of phase 1 LD ITI or the disproportionate use of bypass therapy prophylaxis during HD ITI. The difference in bleed rate between arms was most marked during phase 1 of ITI, when 85% of bleeding occurred and when the FVIII half-life was presumably the shortest. During phase 2 and 3, the bleeding rate declined dramatically in both arms. This pattern was seen for hemarthrosis, muscle bleeds, and soft tissue bleeding. These data imply that both HD and LD regimens provide some degree of protection from intercurrent bleeding when the inhibitor has fallen to a low level. More bleeding was observed in LD than in HD subjects throughout the study, and this persisted through prophylaxis.
Transcripts of a calcium-binding protein containing three EF-hands with high similarity to plant calmodulins (Xv-CAM) increased significantly upon initial drying, with the protein itself becoming evident (through use of western blot analysis) below water contents of 55 % (Conrad 2005; Abdalla and Rafudeen 2012). The protein remains highly expressed until the early stages of rehydration (40 % RWC) after which little protein was detected (Conrad 2005). Ca2+-mediated signalling in response to abiotic stresses is a well reported phenomenon and overexpression of rice calmodulin (Os MSR2) enables enhanced drought tolerance in Arabidopsis thaliana (Xu et al. 2011). While the molecular and physiological functions of such proteins are not completely understood, it is widely thought that they regulate calcium levels through a tight networks of sensory proteins, membrane pumps and ion channels, which inter alia allow for the spatial and temporal management of the resultant calcium signal with consequent down-stream ABA signalling and protectant effects (McAinsh and Hetherington 1998; Pittman and Hirschi 2003; Hirschi 2004).
During the LRD there is further decline in proteins associated with photosynthesis (particularly psbP and components of the luminal oxygen evolving complex (OEC) of PSII (Ingle et al. 2008) further minimizing potential ROS generation from photosynthetic activity. However, drying below 55 % RWC results in ROS formation from ongoing respiration and perturbation of other metabolisms as a consequence of the considerably reduced aqueous environment within tissues (Mundree and Farrant 2000; Walters et al. 2002). In general, protein housekeeping antioxidants do not show a further increase in activity during LRD, and some, like catalase and ascorbate peroxidase decline in activity at this stage. Interestingly, however, enzyme antioxidants that are present remain un-denatured during drying and retain the ability to detoxify ROS during the LRD and early rehydration, as evidenced by in vitro analysis of extracted proteins (Sherwin and Farrant 1996; Mundree and Farrant 2000; Farrant et al. 2007). Transcripts of GDP-l-galactose phosphorylase (Xv VTC2; the first committed enzyme in the synthesis of ascorbate) increase by 1000-fold during LRD, but protein expression and ascorbate concentrations remain un-elevated until the early stages of rehydration after which considerable increases in both occur (Bresler 2010). These data collectively suggest that maintenance (however this is achieved) of housekeeping antioxidant potential during drying and early rehydration is important to survival of extreme water loss. But it is clear that other antioxidant systems, not usually upregulated in desiccation-sensitive material, are also required for survival of desiccation. For example, there is significant upregulation of a nucleus-associated antioxidant 1-Cys peroxiredoxin (XvPer1, Mowla et al. 2002), to date reported to be specific to desiccation-tolerant seed tissues (Leprince and Buitink 2010). There is also an increase in transcript and protein of a type II peroxiredoxin (XvPrx2), a chloroplast-targeted protein that reduces peroxide substrates to the corresponding alcohol and water (Govender 2006; Dietz 2011). Increased polyphenol content during late drying have also been implicated in antioxidant defence as their relative antioxidant potential as determined by FRAP (ferric reducing/antioxidant power) and DPPH (2,2-diphenyl-1-picrylhydrazyl) shows higher activity in X. viscosa (and other resurrection plants) than in related desiccation-sensitive species (Farrant et al. 2007, 2012). Given the complexity involved in redox balancing (Foyer and Noctor 2005, 2009) it is probable that these are only a few of the components involved in antioxidant metabolism during LRD, with cytoplasmic vitrification, which progressively occurs during this stage (see below), further contributing to ROS stasis.
Although precise functions of most Late Embryogenesis abundant (LEA) proteins are still largely unknown, many have been implicated in tolerance of water deficit stress (reviewed in Cuming 1999; Illing et al. 2005; Leprince and Buitink 2010; Tunnacliffe and Wise 2007; Tunnacliffe et al. 2010; Farrant et al. 2012). Unpublished data from our laboratory indicate the presence of 21 LEA-like proteins in the genome of X. viscosa, only two of which (XvT6 and XvT8, both Type II or dehydrin-like proteins) have been functionally characterized (Mundree and Farrant 2000; Ndima et al. 2001). Transcripts and proteins are ABA inducible and become evident upon drying below 40 % RWC, expression declining rapidly during rehydration in a pattern typical of desiccation-tolerant plant tissues (Illing et al. 2005; Leprince and Buitink 2010). Dehydrins are induced in response to water deficit in several desiccation-tolerant systems (Ingram and Bartels 1996; Close 1997) and are constitutively expressed in the moss Tortula ruralis (Bewley et al. 1993). Because such proteins are mostly unfolded in aqueous solutions, it is experimentally difficult to assign to them a structure and function and thus the predicted roles for LEA proteins have been based largely on RNA sequence information. These include (1) water replacement molecules and/or hydration buffers; (2) ion sequesters; (3) chaperonins and/or heat shields; (4) protein/membrane anti-aggregants and membrane stabilizers; and (5) promoters of vitrification (Bray 1997; Hoekstra et al. 2001; Wise and Tunnacliffe 2004; Bartels 2005; Goyal et al. 2005; Mtwisha et al. 2006; Berjak et al. 2007; Chakrabortee et al. 2007; Tunnacliffe and Wise 2007; Farrant et al. 2012). All these functions can be visualized to be of relevance to maintenance of subcellular structural integrity in water-deprived environments and indeed in the ultimate promotion of metabolic quiescence in the dry state. Interestingly, there is also transcriptional upregulation of a rehydrin protein (RHXv) (Mundree and Farrant 2000), induced in response to rehydration of the desiccation-tolerant moss, Tortula ruralis (Oliver et al. 2005) and it is proposed that it has a dehydrin-like function, potentially protecting membranes and/or facilitating lipid transport for reconstitution of damaged membranes during rehydration. 2ff7e9595c
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