Opioid overdose risk during and after drug treatment for heroin dependence: An incidence density case–control study nested in the VEdeTTE cohort

Introduction and Aims: To corroborate protective effects of a range of drug treatment modalities against overdose mortality risk. Design and Methods: Nested case–control study, with incidence density sampling, selecting controls retrospectively at each case event. Cases and controls came from a sub-cohort of opioid-dependent patients (n = 4444) from two Italian regions (Lazio and Piedmont). From 1998 to 2005, there were 91 overdose deaths (cases) matched to 352 controls. The primary outcome was overdose mortality and the primary exposure was drug treatment: opioid agonist treatment (OAT), opioid detoxification, residential community, psychosocial and other pharmacological treatment. Conditional logistic regression models generated intervention effects comparing mortality risk in and out of treatment, adjusting for confounding variables. Results: Overall, drug treatment reduced overdose mortality risk by 80% [adjusted odds ratio (AOR) 0.18, 95% confidence interval (CI) 0.10–0.33, P < 0.001] compared to being out of treatment. There was a particularly strong protective effect of OAT on overdose mortality (AOR 0.08, 95% CI 0.03–0.23, P < 0.001) compared to being out of treatment. There was evidence of a substantially elevated risk of overdose in the first month of leaving treatment (AOR 23.50, 95% CI 7.84–70.19, P < 0.001) compared to being in treatment. Discussion and Conclusions: The nested case–control design strengthened earlier findings that OAT in Italy has strong protective effects on overdose mortality risk, much stronger than has been previously seen in other Western European settings

Correction to: Consent requirements for research with human tissue: Swiss ethics committee members disagree.

It has come to our attention that in the original article [1] information regarding dates was omitted. The data in this study were obtained in Switzerland four years before the entering into force of the new Swiss Human Research Act in 2014, when the guidelines of the Swiss Academy of Medical Sciences (SAMS) ceased to apply. It is important for readers to know that at the time of the study there was no binding law in Switzerland, only the more open SAMS guidelines that have a different legal status. We would expect to find less variation of opinions among research ethics committee members if the study were repeated after the federal law came into force

Metabolic View on Human Healthspan: A Lipidome-Wide Association Study.

As ageing is a major risk factor for the development of non-communicable diseases, extending healthspan has become a medical and societal necessity. Precise lipid phenotyping that captures metabolic individuality could support healthspan extension strategies. This study applied 'omic-scale lipid profiling to characterise sex-specific age-related differences in the serum lipidome composition of healthy humans. A subset of the COmPLETE-Health study, composed of 73 young (25.2 ± 2.6 years, 43% female) and 77 aged (73.5 ± 2.3 years, 48% female) clinically healthy individuals, was investigated, using an untargeted liquid chromatography high-resolution mass spectrometry approach. Compared to their younger counterparts, aged females and males exhibited significant higher levels in 138 and 107 lipid species representing 15 and 13 distinct subclasses, respectively. Percentage of difference ranged from 5.8% to 61.7% (females) and from 5.3% to 46.0% (males), with sphingolipid and glycerophophospholipid species displaying the greatest amplitudes. Remarkably, specific sphingolipid and glycerophospholipid species, previously described as cardiometabolically favourable, were found elevated in aged individuals. Furthermore, specific ether-glycerophospholipid and lyso-glycerophosphocholine species displayed higher levels in aged females only, revealing a more favourable lipidome evolution in females. Altogether, age determined the circulating lipidome composition, while lipid species analysis revealed additional findings that were not observed at the subclass level

Hormonal Signal Amplification Mediates Environmental Conditions during Development and Controls an Irreversible Commitment to Adulthood

Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt one of two developmental fates (adulthood or diapause) depending on environmental conditions. The steroid hormone dafachronic acid (DA) directs development to adulthood by regulating the transcriptional activity of the nuclear hormone receptor DAF-12. The known role of DA suggests that it may be the molecular mediator of environmental condition effects on the developmental fate decision, although the mechanism is yet unknown. We used a combination of physiological and molecular biology techniques to demonstrate that commitment to reproductive adult development occurs when DA levels, produced in the neuroendocrine XXX cells, exceed a threshold. Furthermore, imaging and cell ablation experiments demonstrate that the XXX cells act as a source of DA, which, upon commitment to adult development, is amplified and propagated in the epidermis in a DAF-12 dependent manner. This positive feedback loop increases DA levels and drives adult programs in the gonad and epidermis, thus conferring the irreversibility of the decision. We show that the positive feedback loop canalizes development by ensuring that sufficient amounts of DA are dispersed throughout the body and serves as a robust fate-locking mechanism to enforce an organism-wide binary decision, despite noisy and complex environmental cues. These mechanisms are not only relevant to C. elegans but may be extended to other hormonal-based decision-making mechanisms in insects and mammals

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone