The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Altered Cl^-homeostasis and GABAergic function are associated with nociceptive input hypersensitivity. This study investigated the role of two major intracellular Cl^-regulatory proteins, Na⁺-K⁺-Cl^-cotransporter 1 (NKCC1) and K⁺-Cl^-cotransporter 2 (KCC2), in neuropathic pain following spinal cord injury (SCI).</p> <p>Results</p> <p>Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI. Thermal hyperalgesia (TH) was determined by a decrease in hindpaw thermal withdrawal latency time (WLT) between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH) or NKCC1 inhibitor bumetanide (BU, 30 mg/kg, i.p.) in vehicle. TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p < 0.05). The group administered with the vehicle alone showed no anti-hyperalgesic effects. Moreover, an increase in NKCC1 protein expression occurred in the lesion epicenter of the spinal cord during day 2–14 post-SCI and peaked on day 14 post-SCI (p < 0.05). Concurrently, a down-regulation of KCC2 protein was detected during day 2–14 post-SCI. The rats with TH exhibited a sustained loss of KCC2 protein during post-SCI days 21–42. No significant changes of these proteins were detected in the rostral region of the spinal cord.</p> <p>Conclusion</p> <p>Taken together, expression of NKCC1 and KCC2 proteins was differentially altered following SCI. The anti-hyperalgesic effect of NKCC1 inhibition suggests that normal or elevated NKCC1 function and loss of KCC2 function play a role in the development and maintenance of SCI-induced neuropathic pain.</p

Palaeolimnological evidence for an east-west climate see-saw in the Mediterranean since AD 900

During the period of instrumental records, the North Atlantic Oscillation (NAO) has strongly influenced inter-annual precipitation variations in the western Mediterranean, while some eastern parts of the basin have shown an anti-phase relationship in precipitation and atmospheric pressure. Here we explore how the NAO and other atmospheric circulation modes operated over the longer timescales of the Medieval Climate Anomaly (MCA) and Little Ice Age (LIA). High-resolution palaeolimnological evidence from opposite ends of the Mediterranean basin, supplemented by other palaeoclimate data, is used to track shifts in regional hydro-climatic conditions. Multiple geochemical, sedimentological, isotopic and palaeoecological proxies from Estanya and Montcortés lakes in northeast Spain and Nar lake in central Turkey have been cross-correlated at decadal time intervals since AD 900. These dryland lakes capture sensitively changes in precipitation/evaporation (P/E) balance by adjustments in water level and salinity, and are especially valuable for reconstructing variability over decadal-centennial timescales. Iberian lakes show lower water levels and higher salinities during the 11th to 13th centuries synchronous with the MCA and generally more humid conditions during the 'LIA' (15th-19th centuries). This pattern is also clearly evident in tree-ring records from Morocco and from marine cores in the western Mediterranean Sea. In the eastern Mediterranean, palaeoclimatic records from Turkey, Greece and the Levant show generally drier hydro-climatic conditions during the LIA and a wetter phase during the MCA. This implies that a bipolar climate see-saw has operated in the Mediterranean for the last 1100. years. However, while western Mediterranean aridity appears consistent with persistent positive NAO state during the MCA, the pattern is less clear in the eastern Mediterranean. Here the strongest evidence for higher winter season precipitation during the MCA comes from central Turkey in the northeastern sector of the Mediterranean basin. This in turn implies that the LIA/MCA hydro-climatic pattern in the Mediterranean was determined by a combination of different climate modes along with major physical geographical controls, and not by NAO forcing alone, or that the character of the NAO and its teleconnections have been non-stationary. © 2011 Elsevier B.V

A Trait‐Based Framework for Assessing the Vulnerability of Marine Species to Human Impacts

Marine species and ecosystems are widely affected by anthropogenic stressors, ranging from pollution and fishing to climate change. Comprehensive assessments of how species and ecosystems are impacted by anthropogenic stressors are critical for guiding conservation and management investments. Previous global risk or vulnerability assessments have focused on marine habitats, or on limited taxa or specific regions. However, information about the susceptibility of marine species across a range of taxa to different stressors everywhere is required to predict how marine biodiversity will respond to human pressures. We present a novel framework that uses life-history traits to assess species’ vulnerability to a stressor, which we compare across more than 44,000 species from 12 taxonomic groups (classes). Using expert elicitation and literature review, we assessed every combination of each of 42 traits and 22 anthropogenic stressors to calculate each species’ or representative species group’s sensitivity and adaptive capacity to stressors, and then used these assessments to derive their overall relative vulnerability. The stressors with the greatest potential impact were related to biomass removal (e.g., fisheries), pollution, and climate change. The taxa with the highest vulnerabilities across the range of stressors were mollusks, corals, and echinoderms, while elasmobranchs had the highest vulnerability to fishing-related stressors. Traits likely to confer vulnerability to climate change stressors were related to the presence of calcium carbonate structures, and whether a species exists across the interface of marine, terrestrial, and atmospheric realms. Traits likely to confer vulnerability to pollution stressors were related to planktonic state, organism size, and respiration. Such a replicable, broadly applicable method is useful for informing ocean conservation and management decisions at a range of scales, and the framework is amenable to further testing and improvement. Our framework for assessing the vulnerability of marine species is the first critical step toward generating cumulative human impact maps based on comprehensive assessments of species, rather than habitats

The relationship between gambling event frequency, motor response inhibition, arousal, and dissociative experience

Speed of play has been identified as a key structural characteristic in gambling behaviour, where games involving higher playing speeds enhance the experience of gambling. Of interest in the present study is the consistent finding that games with higher event frequencies are preferred by problem gamblers and are associated with more negative gambling outcomes, such as difficulty quitting the game and increased monetary loss. The present study investigated the impact of gambling speed of play on executive control functioning, focusing on how increased speeds of play impact motor response inhibition, and the potential mediating role arousal and dissociative experience play in this relationship. Fifty regular non-problem gamblers took part in a repeated-measures experiment where they gambled with real money on a simulated slot machine across five speed of play conditions. Response inhibition was measured using an embedded Go/No-Go task, where participants had to withhold motor responses, rather than operating the spin button on the slot machine when a specific colour cue was present. Results indicated that response inhibition performance was significantly worse during faster speeds of play, and that the role of arousal in this relationship was independent of any motor priming affect. The implications of these findings for gambling legislation and gambling harm-minimisation approaches are discussed

Thorough assessment of DNA preservation from fossil bone and sediments excavated from a late Pleistocenee-Holocene cave deposit on Kangaroo Island, South Australia

Fossils and sediments preserved in caves are an excellent source of information for investigating impacts of past environmental changes on biodiversity. Until recently studies have relied on morphology-based palaeontological approaches, but recent advances in molecular analytical methods offer excellent potential for extracting a greater array of biological information from these sites. This study presents a thorough assessment of DNA preservation from late Pleistocene-Holocene vertebrate fossils and sediments from Kelly Hill Cave Kangaroo Island, South Australia. Using a combination of extraction techniques and sequencing technologies, ancient DNA was characterised from over 70 bones and 20 sediment samples from 15 stratigraphic layers ranging in age from >20 ka to ~6.8 ka. A combination of primers targeting marsupial and placental mammals, reptiles and two universal plant primers were used to reveal genetic biodiversity for comparison with the mainland and with the morphological fossil record for Kelly Hill Cave. We demonstrate that Kelly Hill Cave has excellent long-term DNA preservation, back to at least 20 ka. This contrasts with the majority of Australian cave sites thus far explored for ancient DNA preservation, and highlights the great promise Kangaroo Island caves hold for yielding the hitherto-elusive DNA of extinct Australian Pleistocene species

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation &lt;92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p&lt;0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p&lt;0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research