Nicotine- and methamphetamine-induced dopamine release evaluated with in-vivo binding of radiolabelled raclopride to dopamine D2 receptors: comparison with in-vivo microdialysis data

The effect of substances which alter extracellular dopamine (DA) concentration has been studied by measuring changes in the binding of radiolabelled raclopride, a DA D2 receptor ligand that is sensitive to endogenous DA. To better characterize the relationship between extracellular DA concentration and DA D2 receptor binding of raclopride, we compared the changes of extracellular DA concentration (measured using in-vivo microdialysis) and in-vivo [3H]raclopride binding induced by different doses of methamphetamine (Meth) and nicotine, drugs that enhance DA release with and without blocking DA transporters (DATs), respectively, in rat striatum. Nicotine elicited a modest increase of striatal extrasynaptic extracellular DA, while Meth produced a marked increase of striatal extrasynaptic DA in a dose-dependent manner. There was a close correlation between the decrease in [3H]raclopride in-vivo binding and the increase in extrasynaptic DA concentration induced by both nicotine (r2=0.95, p<0.001) and Meth (r2=0.98, p=0.001), supporting the usefulness of the radiolabelled raclopride-binding measurement for the non-invasive assessment of DA release following interventions in the living brain. However, the linear regression analysis revealed that the ratio of percent DA increase to percent [3H]raclopride binding reduction was 25-fold higher for Meth (34.8:1) than for nicotine (1.4:1). The apparent discrepancy in the extrasynaptic DA-[3H]raclopride binding relationship between the DA-enhancing drugs with and without DAT-blocking property indicates that the competition between endogenous DA and radiolabelled raclopride takes place at the intrasynaptic rather than extrasynaptic DA D2 receptors and reflects synaptic concentration of DA

Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus

Home blood pressure measurement for hypertension management in the real world: Do not just measure, but share with your physician

IntroductionStudies of the effectiveness of home blood pressure (BP) measurement on the treatment of hypertension in the real world are sparse, and the results are controversial. There is an efficacy-effectiveness gap in the treatment of hypertension using home BP measurements. We aimed to investigate the effect of reporting home BP to physicians on ambulatory BP control as a factor contributing to the efficacy-effectiveness gap in treating patients with hypertension.MethodsWe recruited patients ≥20 years of age taking antihypertensive drugs. Office and 24-h ambulatory BP were measured. A questionnaire to the measurement of home BP was conducted. Participants were divided into an HBPM(−) group, home BP was not measured (n = 467); HBPM(+)-R(−) group, home BP was measured but not reported (n = 81); and HBPM(+)-R(+) group, home BP was measured and reported (n = 125).ResultsThe HBPM(+)-R(+) group had significantly lower office systolic BP (SBP, p = 0.035), 24-h SBP (p = 0.009), and daytime SBP (p = 0.016) than the HBPM(−) group, and lower nighttime SBP (p = 0.005) and diastolic BP (DBP, p = 0.008) than the HBPM(+)-R(−) group. In the multivariate analysis, the differences in 24-h SBP, daytime SBP, and nighttime DBP remained significant. There was a significant difference between groups in the target achievement rate of 24-h SBP (p = 0.046), nighttime SBP (p = 0.021), and nighttime DBP (p = 0.023). The nighttime SBP and DBP target achievement rates in the HBPM(+)-R(+) group were higher than those in the HBPM(+)-R(−) group (p = 0.006 and 0.010, respectively). Among patients measuring home BP, the adjusted odds ratio for 24-h and nighttime BP target achievement in the HBPM(+)-R(+) group were 2.233 and 3.658, respectively.ConclusionHome BP measurements should be reported to the treating physician to effectively manage hypertension.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT03868384

Supplementation of H1N1pdm09 Split Vaccine with Heterologous Tandem Repeat M2e5x Virus-like Particles Confers Improved Cross-Protection in Ferrets

Current influenza vaccines induce strain-specific immunity to the highly variable hemagglutinin (HA) protein. It is therefore a high priority to develop vaccines that induce broadly cross-protective immunity to different strains of influenza. Since influenza A M2 proteins are highly conserved among different strains, five tandem repeats of the extracellular peptide of M2 in a membrane-anchored form on virus- like particles (VLPs) have been suggested to be a promising candidate for universal influenza vaccine. In this study, ferrets were intramuscularly immunized with 2009 H1N1 split HA vaccine (“Split”) alone, influenza split vaccine supplemented with M2e5x VLP (“Split+M2e5x”), M2e5x VLP alone (“M2e5x”), or mock immunized. Vaccine efficacy was measured serologically and by protection against a sero- logically distinct viral challenge. Ferrets immunized with Split+M2e5x induced HA strain specific and conserved M2e immunity. Supplementation of M2e5x VLP to split vaccination significantly increased the immunogenicity of split vaccine compared to split alone. The Split+M2e5x ferret group showed evidence of cross-reactive protection, including faster recovery from weight loss, and reduced inflammation, as inferred from changes in peripheral leukocyte subsets, compared to mock-immunized animals. In addi- tion, ferrets immunized with Split+M2e5x shed lower viral nasal-wash titers than the other groups. Ferrets immunized with M2e5x alone also show some protective effects, while those immunized with split vaccine alone induced no protective effects compared to mock-immunized ferrets. These stud- ies suggest that supplementation of split vaccine with M2e5x-VLP may provide broader and improved cross-protection than split vaccine alone