Kinin-B2 Receptor Mediated Neuroprotection after NMDA Excitotoxicity Is Reversed in the Presence of Kinin-B1 Receptor Agonists

Background: Kinins, with bradykinin and des-Arg 9-bradykinin being the most important ones, are pro-inflammatory peptides released after tissue injury including stroke. Although the actions of bradykinin are in general well characterized; it remains controversial whether the effects of bradykinin are beneficial or not. Kinin-B2 receptor activation participates in various physiological processes including hypotension, neurotransmission and neuronal differentiation. The bradykinin metabolite des-Arg 9-bradykinin as well as Lys-des-Arg 9-bradykinin activates the kinin-B1 receptor known to be expressed under inflammatory conditions. We have investigated the effects of kinin-B1 and B2 receptor activation on N-methyl-Daspartate (NMDA)-induced excitotoxicity measured as decreased capacity to produce synaptically evoked population spikes in the CA1 area of rat hippocampal slices. Principal Findings: Bradykinin at 10 nM and 1 mM concentrations triggered a neuroprotective cascade via kinin-B2 receptor activation which conferred protection against NMDA-induced excitotoxicity. Recovery of population spikes induced by 10 nM bradykinin was completely abolished when the peptide was co-applied with the selective kinin-B2 receptor antagonist HOE-140. Kinin-B2 receptor activation promoted survival of hippocampal neurons via phosphatidylinositol 3-kinase, while MEK/MAPK signaling was not involved in protection against NMDA-evoked excitotoxic effects. However, 100 nM Lys-des-Arg 9-bradykinin, a potent kinin-B1 receptor agonist, reversed bradykinin-induced population spik

Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

Intrinsic antioxidant defenses are important for neuronal longevity. We found that in rat neurons, synaptic activity, acting via NMDA receptor (NMDAR) signaling, boosted antioxidant defenses by making changes to the thioredoxin-peroxiredoxin (Prx) system. Synaptic activity enhanced thioredoxin activity, facilitated the reduction of overoxidized Prxs and promoted resistance to oxidative stress. Resistance was mediated by coordinated transcriptional changes; synaptic NMDAR activity inactivated a previously unknown Forkhead box O target gene, the thioredoxin inhibitor Txnip. Conversely, NMDAR blockade upregulated Txnip in vivo and in vitro, where it bound thioredoxin and promoted vulnerability to oxidative damage. Synaptic activity also upregulated the Prx reactivating genes Sesn2 (sestrin 2) and Srxn1 (sulfiredoxin), via C/EBPβ and AP-1, respectively. Mimicking these expression changes was sufficient to strengthen antioxidant defenses. Trans-synaptic stimulation of synaptic NMDARs was crucial for boosting antioxidant defenses; chronic bath activation of all (synaptic and extrasynaptic) NMDARs induced no antioxidative effects. Thus, synaptic NMDAR activity may influence the progression of pathological processes associated with oxidative damage

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021

Veteran Perspectives on Phantom Limb Pain and Non-Drug Interventions

Tonya L Rich,1,2 Hannah L Phelan,1,3 Amy A Gravely,1 Kierra J Falbo,1,2 Jacob A Finn,1,4 Mary E Matsumoto,1,5 Katherine J Muschler,1 Christine M Olney,1,2,6 Jessica E Kiecker,1 Andrew H Hansen1,2,7 1Minneapolis Veteran’s Affairs Health Care System, Minneapolis, MN, USA; 2Department of Rehabilitation Medicine, Division of Rehabilitation Science, University of Minnesota, Minneapolis, MN, USA; 3Medical College of Wisconsin, Milwaukee, WI, USA; 4Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA; 5Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN, USA; 6Department of Nursing, University of Minnesota, Minneapolis, MN, USA; 7Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USACorrespondence: Tonya L Rich, Tel +1 612-467-5463, Fax +1 612-725-2093, Email [email protected]: Phantom limb pain (PLP) commonly occurs post-amputation and can negatively affect the daily functioning of persons with amputation. Best practices for medication and non-drug management remain unclear.Objective: To better understand the PLP experience and patients’ familiarity with treatments, phone interviews were conducted at the Minneapolis Veterans Affairs Regional Amputation Center in Veterans with amputations.Methods: Fifty Veteran participants (average age 66, 96% male) with lower limb amputation were recruited for phone-based data collection of patient-reported outcomes (ie, demographics using the Trinity Amputation and Prosthesis Experience Scales-Revised (TAPES-R) and pain experience using the Phantom Phenomena Questionnaire) to characterize the population and a semi-structured interview. Notes taken during interviews were analyzed using the Krueger and Casey constant comparison analysis method.Results: Participants had an average of 15 years since amputation, and 80% reported PLP as identified with the Phantom Phenomena Questionnaire. Investigators identified several core themes from the qualitative interviews including 1) high variability in the experience of PLP, 2) acceptance and resilience, and 3) PLP treatment perceptions. The majority of participants reported trying common non-drug treatments with none endorsed consistently as highly effective.Conclusion: More research is needed to inform identification and implementation of clinical best practices for non-drug interventions for PLP and understand the factors that influence engagement in non-drug interventions. The participants in this study were largely male, so these results may not be generalizable to females.Keywords: amputation, phantom limb pain, rehabilitation, non-drug interventions, pai