4 research outputs found
Amphetamine and Methamphetamine Differentially Affect Dopamine Transporters in Vitro and in Vivo*S⃞
The psychostimulants d-amphetamine (AMPH) and methamphetamine
(METH) release excess dopamine (DA) into the synaptic clefts of dopaminergic
neurons. Abnormal DA release is thought to occur by reverse transport through
the DA transporter (DAT), and it is believed to underlie the severe behavioral
effects of these drugs. Here we compare structurally similar AMPH and METH on
DAT function in a heterologous expression system and in an animal model. In
the in vitro expression system, DAT-mediated whole-cell currents were
greater for METH stimulation than for AMPH. At the same voltage and
concentration, METH released five times more DA than AMPH and did so at
physiological membrane potentials. At maximally effective concentrations, METH
released twice as much [Ca2+]i from internal
stores compared with AMPH. [Ca2+]i responses to
both drugs were independent of membrane voltage but inhibited by DAT
antagonists. Intact phosphorylation sites in the N-terminal domain of DAT were
required for the AMPH- and METH-induced increase in
[Ca2+]i and for the enhanced effects of METH on
[Ca2+]i elevation. Calmodulin-dependent protein
kinase II and protein kinase C inhibitors alone or in combination also blocked
AMPH- or METH-induced Ca2+ responses. Finally, in the rat nucleus
accumbens, in vivo voltammetry showed that systemic application of
METH inhibited DAT-mediated DA clearance more efficiently than AMPH, resulting
in excess external DA. Together these data demonstrate that METH has a
stronger effect on DAT-mediated cell physiology than AMPH, which may
contribute to the euphoric and addictive properties of METH compared with
AMPH
The politics of law in a post-conflict UN protectorate: privatisation and property rights in Kosovo (1999–2008)
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Risk of COVID-19 after natural infection or vaccinationResearch in context
Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health
Risk of COVID-19 after natural infection or vaccinationResearch in context
Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health