B lymphocyte-induced maturation protein 1 (Blimp-1) is a key regulator for plasma cell differentiation. Prior to the terminal differentiation into plasma cells, Blimp-1 expression is suppressed in B cells by transcription repressors BTB and CNC homology 2 (Bach2) and B cell lymphoma 6 (Bcl6). Bach2 binds to the Maf recognition element (MARE) of the promoter upstream region of the Blimp-1 gene (Prdm1) by forming a heterodimer with MafK. Bach2 and Bcl6 were found to interact with each other in B cells. While both Bach2 and Bcl6 possess the BTB domain which mediates protein-protein interactions, they interacted in a BTB-independent manner. Bcl6 is known to repress Prdm1 through a Bcl6 recognition element 1 in the intron 5, in which a putative, evolutionarily conserved MARE was identified. Both repressed the expression of a reporter gene containing the intron 5 region depending on the presence of the respective binding sites in 18-81 pre-B cells. Co-expression of Bach2 and Bcl6 resulted in further repression of the reporter plasmid. Chromatin immunoprecipitation assays showed MafK to bind to the intron MARE in various B cell lines, thus suggesting that it binds as a heterodimer with Bach2. Therefore, the interaction between Bach2 and Bcl6 might be crucial for the proper repression of Prdm1 in B cells.

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The CYP2D6 genotype but not the CYP2B6 and CYP3A5 genotypes affected the plasma concentrations of O- and N-desmethyltramadol through alteration of the tramadol metabolic pathway. The serum IL-6 level was associated with N-demethylation activity and tramadol tolerability.

BackgroundThis study aimed to develop a simultaneous determination method for tramadol and its desmethylates in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and to validate it for pharmacokinetic evaluation in patients with cancer pain or non-cancer pain.MethodsThe pretreatments for human plasma involved protein precipitation using acetonitrile and methanol under basic conditions. Tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were separated on an octadecylsilyl column filled with 3-μm particles using isocratic mixture of methanol and 0.15 % formic acid in water (35:65, v/v). The mass spectrometer was run in positive ion multiple reaction monitoring mode. This method was applied to the determination of plasma samples in patients treated with oral tramadol.ResultsThe chromatographic total run time was 10 min. The calibration curves in human plasma of tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were linear over the concentration ranges of 12.5–1600, 2.5–320, 2.5–320, and 2.5–320 ng/mL, respectively. The lower limits of quantitation of tramadol and its desmethylates in human plasma were 12.5 and 2.5 ng/mL. Their extraction recoveries were 85.5–106.3 %. The intra-day and inter-day precisions and accuracies were 1.6–10.2 % and 89.2–106.2 % for all analytes. The plasma concentration ranges of tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were 18.2–564, 11.8–137, 4.9–250, and 6.1–147 ng/mL in cancer patients, and 32.8–670, 7.0–84.8, 5.1–317, and 6.7–85.2 ng/mL, respectively, in non-cancer patients.ConclusionsThe present method with acceptable analytical performance can be helpful for evaluating the pharmacokinetics of oral tramadol, including the determination of its desmethylates, for patients with cancer pain or non-cancer pain in clinical settings.

This article presents some progress in the development for preclinical trials of an artificial anal sphincter using shape memory alloys. The novel device has been proposed and developed by the author's group at Tohoku University. It has two dominant features different from other systems, which are either clinically available or still under development. One is that a solid driving element, a combination of shape memory alloy (SMA) ribbons and silicone elastomer sheets with a layered structure, is adopted for the opening and closing functions of the artificial sphincter. The other is a sandwich mechanism for the closing of bowel to reduce the risk of buckling induced ischemia which has been reported in hydraulically driven artificial sphincters with a radial squeezing mechanism. The device has fewer parts inside the body and therefore be implanted more easily. A new design eliminating the risk of heat burns enables long-term implantation and brings the device closer to practical use. Functionality and safety of the device have been proved in three-month animal experiments.