Sr-Nd-Pb-Hf isotope results from ODP Leg 187: Evidence for mantle dynamics of the Australian-Antarctic Discordance and origin of the Indian MORB source

New high precision PIMMS Hf and Pb isotope data for 14–28 Ma basalts recovered during ODP Leg 187 are compared with zero-age dredge samples from the Australian-Antarctic Discordance (AAD). These new data show that combined Nd-Hf isotope systematics can be used as an effective discriminant between Indian and Pacific MORB source mantle domains. In particular, Indian mantle is displaced to lower εNd and higher εHf ratios compared to Pacific mantle. As with Pb isotope plots, there is almost no overlap between the two mantle types in Nd-Hf isotope space. On the basis of our new Nd-Hf isotope data, we demonstrate that Pacific MORB-source mantle was present near the eastern margin of the AAD from as early as 28 Ma, its boundary with Indian MORB-source mantle coinciding with the eastern edge of a basin-wide arcuate depth anomaly that is centered on the AAD. This observation rules out models requiring rapid migration of Pacific MORB mantle into the Indian Ocean basin since separation of Australia from Antarctica. Although temporal variations in isotopic composition can be discerned relative to the fracture zone boundary of the modern AAD at 127°E, the distribution of different compositional groups appears to have remained much the same relative to the position of the residual depth anomaly for the past 30 m.y. Thus significant lateral flow of mantle along the ridge axis toward the interface appears unlikely. Instead, the dynamics that maintain both the residual depth anomaly and the isotopic boundary between Indian and Pacific mantle are due to eastward migration of the Australian and Antarctic plates over a stagnated, but slowly upwelling, slab oriented roughly orthogonal to the ridge axis. Temporal and spatial variations in the compositions of Indian MORB basalts within the AAD can be explained by progressive displacement of shallower Indian MORB-source mantle by deeper mantle having a higher εHf composition ascending ahead of the upwelling slab. Models for the origin of the distinctive composition of the Indian MORB-source based on recycling of a heterogeneous enriched component that consist of ancient altered ocean crust plus<10% pelagic sediment are inconsistent with Nd-Hf isotope systematics. Instead, the data can be explained by a model in which Indian mantle includes a significant proportion of material that was processed in the mantle wedge above a subduction zone and was subsequently mixed back into unprocessed upper mantle

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

Pain after disease/damage of the nervous system is predominantly treated with opioids, but without exploration of the long-term consequences. We demonstrate that a short course of morphine after nerve injury doubles the duration of neuropathic pain. Using genetic and pharmacological interventions, and innovative Designer Receptor Exclusively Activated by Designer Drugs disruption of microglia reactivity, we demonstrate that opioid-prolonged neuropathic pain arises from spinal microglia and NOD-like receptor protein 3 inflammasome formation/activation. Inhibiting these processes permanently resets amplified pain to basal levels, an effect not previously reported. These data support the “two-hit hypothesis” of amplification of microglial activation—nerve injury being the first “hit,” morphine the second. The implications of such potent microglial “priming” has fundamental clinical implications for pain and may extend to many chronic neurological disorders

Bioactive Trace Metals and Their Isotopes as Paleoproductivity Proxies: An Assessment Using GEOTRACES-Era Data

Phytoplankton productivity and export sequester climatically significant quantities of atmospheric carbon dioxide as particulate organic carbon through a suite of processes termed the biological pump. Constraining how the biological pump operated in the past is important for understanding past atmospheric carbon dioxide concentrations and Earth\u27s climate history. However, reconstructing the history of the biological pump requires proxies. Due to their intimate association with biological processes, several bioactive trace metals and their isotopes are potential proxies for past phytoplankton productivity, including iron, zinc, copper, cadmium, molybdenum, barium, nickel, chromium, and silver. Here, we review the oceanic distributions, driving processes, and depositional archives for these nine metals and their isotopes based on GEOTRACES-era datasets. We offer an assessment of the overall maturity of each isotope system to serve as a proxy for diagnosing aspects of past ocean productivity and identify priorities for future research. This assessment reveals that cadmium, barium, nickel, and chromium isotopes offer the most promise as tracers of paleoproductivity, whereas iron, zinc, copper, and molybdenum do not. Too little is known about silver to make a confident determination. Intriguingly, the trace metals that are least sensitive to productivity may be used to track other aspects of ocean chemistry, such as nutrient sources, particle scavenging, organic complexation, and ocean redox state. These complementary sensitivities suggest new opportunities for combining perspectives from multiple proxies that will ultimately enable painting a more complete picture of marine paleoproductivity, biogeochemical cycles, and Earth\u27s climate history

Bioactive Trace Metals and Their Isotopes as Paleoproductivity Proxies: An Assessment Using GEOTRACES-Era Data

Phytoplankton productivity and export sequester climatically significant quantities of atmospheric carbon dioxide as particulate organic carbon through a suite of processes termed the biological pump. Constraining how the biological pump operated in the past is important for understanding past atmospheric carbon dioxide concentrations and Earth\u27s climate history. However, reconstructing the history of the biological pump requires proxies. Due to their intimate association with biological processes, several bioactive trace metals and their isotopes are potential proxies for past phytoplankton productivity, including iron, zinc, copper, cadmium, molybdenum, barium, nickel, chromium, and silver. Here, we review the oceanic distributions, driving processes, and depositional archives for these nine metals and their isotopes based on GEOTRACES-era datasets. We offer an assessment of the overall maturity of each isotope system to serve as a proxy for diagnosing aspects of past ocean productivity and identify priorities for future research. This assessment reveals that cadmium, barium, nickel, and chromium isotopes offer the most promise as tracers of paleoproductivity, whereas iron, zinc, copper, and molybdenum do not. Too little is known about silver to make a confident determination. Intriguingly, the trace metals that are least sensitive to productivity may be used to track other aspects of ocean chemistry, such as nutrient sources, particle scavenging, organic complexation, and ocean redox state. These complementary sensitivities suggest new opportunities for combining perspectives from multiple proxies that will ultimately enable painting a more complete picture of marine paleoproductivity, biogeochemical cycles, and Earth\u27s climate history

Bioactive Trace Metals and Their Isotopes as Paleoproductivity Proxies: An Assessment Using GEOTRACES-Era Data

86 pages, 33 figures, 2 tables, 1 appendix.-- Data Availability Statement: The majority of the dissolved data were sourced from the GEOTRACES Intermediate Data Products in 2014 (Mawji et al., 2015) and 2017 (Schlitzer et al., 2018), and citations to the primary data sources are given in the caption for each figure. Data sources for Figure 1 are given below. Figure 1: Iron: Conway & John, 2014a (Atlantic); Conway & John, 2015a (Pacific); Abadie et al., 2017 (Southern). Zinc: Conway & John, 2014b (Atlantic); Conway & John, 2015a (Pacific); R. M. Wang et al., 2019 (Southern). Copper: Little et al., 2018 (Atlantic); Takano et al., 2017 (Pacific); Boye et al., 2012 (Southern). Cadmium: Conway and John, 2015b (Atlantic); Conway & John, 2015a (Pacific); Abouchami et al., 2014 (Southern). Molybdenum: Nakagawa et al., 2012 (all basins). Barium: Bates et al., 2017 (Atlantic); Geyman et al., 2019 (Pacific); Hsieh & Henderson, 2017 (Southern). Nickel: Archer et al., 2020 (Atlantic); Takano et al., 2017 (Pacific); R. M. Wang et al., 2019 (Southern). Chromium: Goring-Harford et al., 2018 (Atlantic); Moos & Boyle, 2019 (Pacific); Rickli et al., 2019 (Southern). Silver: Fischer et al., 2018 (Pacific); Boye et al., 2012 (Southern)Phytoplankton productivity and export sequester climatically significant quantities of atmospheric carbon dioxide as particulate organic carbon through a suite of processes termed the biological pump. Constraining how the biological pump operated in the past is important for understanding past atmospheric carbon dioxide concentrations and Earth's climate history. However, reconstructing the history of the biological pump requires proxies. Due to their intimate association with biological processes, several bioactive trace metals and their isotopes are potential proxies for past phytoplankton productivity, including iron, zinc, copper, cadmium, molybdenum, barium, nickel, chromium, and silver. Here, we review the oceanic distributions, driving processes, and depositional archives for these nine metals and their isotopes based on GEOTRACES-era datasets. We offer an assessment of the overall maturity of each isotope system to serve as a proxy for diagnosing aspects of past ocean productivity and identify priorities for future research. This assessment reveals that cadmium, barium, nickel, and chromium isotopes offer the most promise as tracers of paleoproductivity, whereas iron, zinc, copper, and molybdenum do not. Too little is known about silver to make a confident determination. Intriguingly, the trace metals that are least sensitive to productivity may be used to track other aspects of ocean chemistry, such as nutrient sources, particle scavenging, organic complexation, and ocean redox state. These complementary sensitivities suggest new opportunities for combining perspectives from multiple proxies that will ultimately enable painting a more complete picture of marine paleoproductivity, biogeochemical cycles, and Earth's climate historyThis contribution grew (and grew) out of a joint workshop between GEOTRACES and Past Global Changes (PAGES) held in Aix-en-Provence in December 2018. The workshop was funded by the U.S. National Science Foundation (NSF) through the GEOTRACES program, the international PAGES project, which received support from the Swiss Academy of Sciences and NSF, and the French program Les Envelopes Fluides et l'Environnement. [...] T. J. Horner acknowledges support from NSF; S. H. Little from the UK Natural Environment Research Council (NE/P018181/1); T. M. Conway from the University of South Florida; and, J. R. Farmer from the Max Planck Society, the Tuttle Fund of the Department of Geosciences of Princeton University, the Grand Challenges Program of the Princeton Environmental Institute, and the Andlinger Center for Energy and the Environment of Princeton University. [...] With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S

Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial

IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT0292689

A modified score to identify and discriminate neuropathic pain: a study on the German version of the neuropathic pain symptom inventory (NPSI)

<p>Abstract</p> <p>Background</p> <p>Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain.</p> <p>Methods</p> <p>We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles.</p> <p>Results</p> <p>Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct.</p> <p>Conclusions</p> <p>The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain.</p