Contribution of Monocarboxylate Transporter 6 to the Pharmacokinetics and Pharmacodynamics of Bumetanide in Mice.

Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiologic pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (SLC22A) have been extensively studied in terms of their importance in transporting bumetanide to its primary site of action in the kidney. The contribution of one of the less-studied bumetanide transporters, monocarboxylate transporter 6 (MCT6; SLC16A5), to bumetanide pharmacokinetics (PK) and pharmacodynamics (PD) has yet to be characterized. The affinity of bumetanide for murine Mct6 was evaluated using Mct6-transfected Xenopus laevis oocytes. Furthermore, bumetanide was intravenously and orally administered to wild-type mice (Mct6+/+) and homozygous Mct6 knockout mice (Mct6-/-) to elucidate the contribution of Mct6 to bumetanide PK/PD in vivo. We demonstrated that murine Mct6 transports bumetanide at a similar affinity compared with human MCT6 (78 and 84 µM, respectively, at pH 7.4). After bumetanide administration, there were no significant differences in plasma PK. Additionally, diuresis was significantly decreased by ∼55% after intravenous bumetanide administration in Mct6-/- mice. Kidney cortex concentrations of bumetanide were decreased, suggesting decreased Mct6-mediated bumetanide transport to its site of action in the kidney. Overall, these results suggest that Mct6 does not play a major role in the plasma PK of bumetanide in mice; however, it significantly contributes to bumetanide's pharmacodynamics due to changes in kidney concentrations. SIGNIFICANCE STATEMENT: Previous evidence suggested that MCT6 transports bumetanide in vitro; however, no studies to date have evaluated the in vivo contribution of this transporter. In vitro studies indicated that mouse and human MCT6 transport bumetanide with similar affinities. Using Mct6 knockout mice, we demonstrated that murine Mct6 does not play a major role in the plasma pharmacokinetics of bumetanide; however, the pharmacodynamic effect of diuresis was attenuated in the knockout mice, likely because of the decreased bumetanide concentrations in the kidney.

Assessing near infrared optical properties of ceramic orthodontic brackets using cross-polarization optical coherence tomography.

Secondary decay (caries) under ceramic orthodontic brackets remains a significant dental problem and near infrared cross-polarization optical coherence tomography (CP-OCT) has the potential to detect underlying demineralization. The purpose of this study was to determine the effect of crystalline structure and chemical composition of ceramic brackets on CP-OCT imaging. Four ceramic brackets types, which were divided into monocrystalline and polycrystalline, were examined using CP-OCT. The results of this study demonstrated that the crystallinity of the ceramic brackets affected the 1310 nm CP-OCT imaging with the greatest attenuation seen in polycrystalline alumina brackets. The alumina polycrystalline bracket materials had significantly higher attenuation and scattering than alumina monocrystalline brackets (p < 0.05, ANOVA, Bonferroni). Additionally, bracket base morphology and composition affected NIR light attenuation. There was considerable attenuation in bracket bases that contained additive zirconium spheres (∼30 µm) and this alteration was significantly greater than the jagged alumina crystallographic alterations found in the other bracket systems (p < 0.05, ANOVA, Bonferroni). Noninvasive, near infrared (NIR) cross-polarization optical coherence tomography (CP-OCT) has potential to effectively image through portions of ceramic brackets; however, further investigation into the optical effects of resin integration in the base portion of the brackets is warranted.

Outcomes of anti-bullying intervention for adults with intellectual disabilities.

Although existing research is scarce, evidence suggests that children and adults with intellectual disabilities may be at increased risk of being bullied (as they are for maltreatment generally) and possibly more likely than those without disabilities to also engage in bullying behavior. Despite significant clinical interest in bullying, we could find no published research on the outcomes of bullying intervention for individuals with intellectual disabilities. Adults with intellectual disabilities in three work center settings participated in one of two interventions for perpetrators and/or victims of bullying: (a) psychoeducational intervention with a cognitive behavioral orientation (n=20), or (b) the same intervention but with additional involvement of community stakeholders such as parents, the police, and local schools (n=22). A third work center (n=18) acted as a waiting list control comparison. Pre-intervention, 43% of participants reported that they had been bullied within the preceding three months and 28% identified themselves as having bullied others. Reports of being bullied decreased significantly within the two intervention groups over time but not in the control group. There were no differences between the two intervention groups, and no statistically significant reduction in self-reported bullying behavior. Initial data on this intervention suggest that its effects might be clinically meaningful with an associated Numbers Needed to Treat for reduction in exposure to bullying of 5.55.