The synthetic peptide SNX-111 corresponding to the sequence of the omega-conopeptide MVIIA from the venom of the marine snail Conus magus is a highly potent and selective antagonist of N-type calcium channels. We have synthesized and characterized a large number of analogs of SNX-111 in order to elucidate the structural features of the peptide involved in blocking N-type calcium channels. Comparison of the binding of SNX-111 and its analogs to rat brain synaptosomal membranes rich in N-type channels revealed that, among the four lysines and two arginines in the molecule, lysine in position 2 and arginines at position 10 and 21 are important for the interaction of SNX-111 with N-type channels. The importance of the middle segment from residues 9 through 14 for this binding interaction was revealed by substitution of the individual residues as well as by the construction of hybrid peptides in which the residues 9-12 in SNX-111 and another conopeptide, SNX-183, corresponding to a peptide SVIB from Conus striatus, were interchanged. Introduction of the sequence SRLM from SNX-111 in place of RKTS in position 9-12 in SNX-183 resulted in a 38-fold increase in affinity.
The plasma concentrations and urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were measured in eight normal subjects, eight patients with mild liver disease and seven patients with severe liver disease following an oral dose of 1.5 g of paracetamol. The mean plasma paracetamol half-life was similar in normal subjects (2.43 h +/- 0.19) but was significantly prolonged in all patients with severe liver disease (4.25 h +/- 1.15:p = less than 0.001). Prolongation of the paracetamol half-life was related to reduced plasma albumin and increased prothrombin time. The mean ratios of plasma concentrations of unchanged paracetamol to paracetamol glucoronide and sulphate were significantly greater in patients with sever liver disease than the normal subjects. There were no significant differences in the overall 24-h urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates in the three groups. The glutathione conjugation of paracetamol did not seem to be impaired in patients with severe liver disease as evidence by the production of normal amounts of the cysteine and mercapturic acid conjugates. There is thus no evidence that they are at increased risk of hepatotoxicity when given a single therapeutic dose of paracetamol.
In this article, we reflect on our evolving ideas regarding a dialogical approach to refugee care. Broadening the predominant phased trauma care model and its engaging of directive expertise in symptom reduction, meaning making, and rebuilding connectedness, these developing dialogical notions involve the negotiation of silencing and disclosure, meaning and absurdity, hope and hopelessness in a therapeutic dialogue that accepts its encounter of cultural and social difference. In locating therapeutic practice within these divergent approaches, we argue an orientation on collaborative dialogue may operate together with notions from the phased trauma care model as heuristic background in engaging a polyphonic understanding of coping with individual and family sequelae of forced displacement. This locating of therapeutic practice, as informed by each perspective, invites us to remain present to fragments of therapeutic positioning that resonate power imbalance or appropriation in a therapeutic encounter imbued with a social context that silences refugees' suffering. In a clinical case analysis, we further explore these relational complexities of negotiating directive expertise and collaborative dialogue in the therapeutic encounter with refugee clients.
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