192 research outputs found
Whole-exome and HLA sequencing in Febrile infection-related epilepsy syndrome
Febrile infectionârelated epilepsy syndrome (FIRES) is a devastating epilepsy characterized by newâonset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in 50 individuals with FIRES, including 27 patientâparent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors
Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy
Small fibre neuropathy (SFN) has been demonstrated in sarcoidosis. However, a systematic analysis of neuropathic pain and autonomic symptoms, key features of SFN, has not been performed. Clinimetric evaluation of pain and autonomic symptoms using the neuropathic pain scale (NPS) and the modified Composite Autonomic Symptoms Scale (mCOMPASS) was used in sarcoidosis patients for this study. A total of 91 sarcoidosis patients (n = 23 without SFN symptoms, n = 43 with SFN symptoms but normal intraepidermal nerve fibre density (IENFD), n = 25 with SFN symptoms and reduced IENFD) were examined. NPS and mCOMPASS were assessed twice (reliability studies). Severity of pain was compared between the subgroups. Correlation between NPS and a visual analogue pain scale (VAS) was assessed (validity studies). Healthy controls (n = 105) completed the mCOMPASS for comparison with patientsâ scores. Patients with sarcoidosis, SFN complaints, and reduced IENFD demonstrated more severe pain scores on the NPS. The mCOMPASS differentiated between subjects with and without SFN symptoms. A significant correlation was obtained between the NPS and VAS, indicating good construct validity. Good reliability values were obtained for all scales. The use of the NPS to evaluate SFN symptoms is suggested, as it shows differences between patients with SFN symptoms with normal or reduced IENFD values. The mCOMPASS might be used to select patients for further testing
Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (<5 years) with Dravet syndrome: A critical period for early neurodevelopment
OBJECTIVE: To evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)-self-regulation-in preschool-aged children with Dravet syndrome (DS). METHODS: Children with DS received placebo or FFA in one of two phase III studies (first study: placebo, FFA 0.2 mg/kg/day, or FFA 0.7 mg/kg/day added to stiripentol-free standard-of-care regimens; second study: placebo or FFA 0.4 mg/kg/day added to stiripentol-inclusive regimens). Everyday EF was evaluated at baseline and Week 14-15 for children aged 2-4 years with parent ratings on the Behavior Rating Inventory of Executive FunctionÂź-Preschool (BRIEFÂź-P); raw scores were transformed to T-scores and summarized in Inhibitory Self-Control Index (ISCI), Flexibility Index (FI), Emergent Metacognition Index (EMI), and Global Executive Composite (GEC). Clinically meaningful improvement and worsening were defined using RCI â„ 90% and RCI â„ 80% certainty, respectively. The associations between placebo vs FFA combined (0.2, 0.4, and 0.7 mg/kg/day) or individual treatment groups and the likelihood of clinically meaningful change in BRIEFÂź-P indexes/composite T-scores were evaluated using Somers'd; pairwise comparisons were calculated by 2-sided Fisher's Exact tests (p â€Â 0.05) and CramĂ©r's V. RESULTS: Data were analyzed for 61 evaluable children of median age 3 years (placebo, n = 22; FFA 0.2 mg/kg/day, n = 15; 0.4 mg/kg/day [with stiripentol], n = 10; 0.7 mg/kg/day, n = 14 [total FFA, n = 39]). Elevated or problematic T-scores (T â„ 65) were reported in 55% to 86% of patients at baseline for ISCI, EMI, and GEC, and in âŒ33% for FI. Seventeen of the 61 children (28%) showed reliable, clinically meaningful improvement (RCI â„ 90% certainty) in at least one BRIEFÂź-P index/composite, including a majority of the children in the FFA 0.7 mg/kg/day group (9/14, 64%). Only 53% of these children (9/17) also experienced clinically meaningful reduction (â„50%) in monthly convulsive seizure frequency, including 6/14 patients in the FFA 0.7 mg/kg/day group. Overall, there were positive associations between the four individual treatment groups and the likelihood of reliable, clinically meaningful improvement in all BRIEFÂź-P indexes/composite (ISCI, p = 0.001; FI, p = 0.005; EMI, p = 0.040; GEC, p = 0.002). The FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than placebo in ISCI (50% vs 5%; p = 0.003), FI (36% vs 0%; p = 0.005), and GEC (36% vs 0%; p = 0.005). For EMI, the FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than the FFA 0.2 mg/kg/day group (29% vs 0%; p = 0.040), but did not meet the significance threshold compared with placebo (29% vs 5%; p = 0.064). There were no significant associations between treatment and the likelihood of reliable, clinically meaningful worsening (p > 0.05). SIGNIFICANCE: In this preschool-aged DS population with high baseline everyday EF impairment, FFA treatment for 14-15 weeks was associated with dose-dependent, clinically meaningful improvements in regulating behavior, emotion, cognition, and overall everyday EF. These clinically meaningful improvements in everyday EF were not entirely due to seizure frequency reduction, suggesting that FFA may have direct effects on everyday EF during the early formative years of neurodevelopment
High Precision Femtosecond Laser Ablation ICPâMS Measurement of Benthic Foraminiferal MnâIncorporation for Paleoenvironmental Reconstruction: A Case Study From the PlioâPleistocene Caribbean Sea
Closure of the Central American Seaway (CAS) and hydrology of the Caribbean Sea triggered Northern Hemisphere Glaciation and played an important role in the Pliocene to modern-day climate re-establishing the deep and surface ocean currents. New data on Mn/Ca obtained with femtosecond laser ablation inductively coupled plasma mass spectrometry on well-preserved tests of the epibenthic foraminifer Cibicidoides wuellerstorfi and infaunal C. mundulus contribute to the interpretation of paleoenvironmental conditions of the Caribbean Sea between 5.2 and 2.2 Ma (million years) across the closure of the CAS. Hydrothermal activity at the Lesser Antilles may be a primary source of Mn in the well-oxygenated Plio-Pleistocene Caribbean Sea. Incorporation of Mn in the benthic foraminifer shell carbonate is assumed to be affected by surface ocean nutrient cycling, and may hence be an indicator of paleoproductivity.
Key Points
- Femtosecond-laser ablation inductively coupled plasma mass spectrometry provides a new approach on distinguishing Mn of the ontogenetic shell calcite from Mn of the authigenic coatings
- Ontogenetic Mn within the foraminifer shell calcite may result from the regional nutrient cycle
- Mn in the deep eastern Caribbean Sea may mainly derive from hydrothermal sources along the Antilles Island Ar
Trace Metals and Their Isotopes in the Tropical Atlantic Ocean - Cruise No. M81/1, February 04 â March 08, 2010, Las Palmas (Canary Islands, Spain) â Port of Spain (Trinidad & Tobago)
Summary
Meteor Cruise M81/1 was dedicated to the investigation of the distribution of dissolved and
particulate trace metals and their isotopic compositions (TEIs) in the full water column of the
tropical Atlantic Ocean and their driving factors including main external inputs and internal
cycling and ocean circulation. The research program is embedded in the international
GEOTRACES program (e.g. Henderson et al., 2007), which this cruise was an official part of
and thus corresponds to GEOTRACES cruise GA11. This cruise was completely dedicated to the
trace metal clean and contamination-free sampling of waters and particulates for subsequent
analyses of the TEIs in the home laboratories of the national and international participants.
Besides a standard rosette for the less contaminant prone metals, trace metal clean sampling was
realized by using a dedicated and coated trace metal clean rosette equipped with Teflon-coated
GO-FLO bottles operated via a polyester coated cable from a mobile winch that was thankfully
made available by the U.S. partners of the GEOTRACES program for this cruise. The particulate
samples were also collected under trace metal clean conditions using established in-situ pump
systems. The cruise track led the cruise southward from the Canary Islands to 11°S and then
continued northwestward along the northern margin of South America until it reached Port of
Spain, Trinidad & Tobago. The track crossed areas of major external inputs including exchange
with the volcanic Canary Islands, the Saharan dust plume, as well as the plume of the Amazon
outflow. In terms of internal cycling the equatorial high biological productivity band, as well as
increased productivity associated with the Amazon Plume were covered. All major water masses
contributing the Atlantic Meridional Overturning Circulation, as well as the distinct narrow
equatorial surface and subsurface east-west current bands were sampled. A total of 17 deep
stations were sampled for the different dissolved TEIs, which were in most cases accompanied
by particulate sampling. In addition, surface waters were continuously sampled under trace metal
clean conditions using a towed fish
How and when plume zonation appeared during the 132 Myr evolution of the Tristan Hotspot
Increasingly, spatial geochemical zonation, present as geographically distinct, subparallel
trends, is observed along hotspot tracks, such as Hawaii and the Galapagos. The origin of this
zonation is currently unclear. Recently zonation was found along the last B70 Myr of the
Tristan-Gough hotspot track. Here we present new SrâNdâPbâHf isotope data from the older
parts of this hotspot track (Walvis Ridge and Rio Grande Rise) and re-evaluate published data
from the Etendeka and Parana flood basalts erupted at the initiation of the hotspot track. We
show that only the enriched Gough, but not the less-enriched Tristan, component is present in
the earlier (70â132 Ma) history of the hotspot. Here we present a model that can explain the
temporal evolution and origin of plume zonation for both the Tristan-Gough and Hawaiian
hotspots, two end member types of zoned plumes, through processes taking place in the
plume sources at the base of the lower mantle
Nature of the Earth's earliest crust from hafnium isotopes in single detrital zircons
Continental crust forms from, and thus chemically depletes, the Earth's mantle. Evidence that the Earth's mantle was already chemically depleted by melting before the formation of today's oldest surviving crust has been presented in the form of Sm-Nd isotope studies of 3.8-4.0 billion years old rocks from Greenland(1-5) and Canada(5-7). But this interpretation has been questioned because of the possibility that subsequent perturbations may have re-equilibrated the neodymium-isotope compositions of these rocks(8). Independent and more robust evidence for the origin of the earliest crust and depletion of the Archaean mantle can potentially be provided by hafnium-isotope compositions of zircon, a mineral whose age can be precisely determined by U-Pb dating, and which can survive metamorphisms(4). But the amounts of hafnium in single zircon grains are too small for the isotopic composition to be precisely analysed by conventional methods. Here we report hafnium-isotope data, obtained using the new technique of multiple-collector plasma-source mass spectrometry(9), for 37 individual grains of the oldest known terrestrial zircons (from the Narryer Gneiss Complex, Australia, with U-Pb ages of up to 4.14 Gyr (refs 10-13)). We find that none of the grains has a depleted mantle signature, but that many were derived from a source with a hafnium-isotope composition similar to that of chondritic meteorites. Furthermore, more than half of the analysed grains seem to have formed by remelting of significantly older crust, indicating that crustal preservation and subsequent reworking might have been important processes from earliest times.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62681/1/399252a0.pd
Same task rules, different responses:Goal neglect, stimulus-response mapping and response modalities
To complete complex tasks, individuals must actively maintain task rules to direct behavior correctly. Failure to use task rules appropriately, termed goal neglect, has been shown across both vocal and manual response modalities. However, previous goal maintenance studies have differed not only in the response modality that they require, but also in the complexity of the stimulusâresponse mappings that participants must use during the task. The present study examines the effects of both response modality and stimulusâresponse mapping complexity, separately, on the rate of goal neglect in a modification of a classic goal maintenance task. Seventy-two younger adults were administered a shape-monitoring task, with three between-subjects response conditions: a vocal response with a simple stimulusâresponse mapping, a vocal response with a complex stimulusâresponse mapping, and a manual response with a complex stimulusâresponse mapping. Contrasting the rate at which task rules were neglected between response conditions showed that participants using complex stimulusâresponse mappings committed more frequent goal neglect than those using simple mappings, but that participants using vocal or manual responses did not differ in their rate of goal neglect once both responses required complex mappings. This suggests that the need to represent novel and complex stimulusâresponse mappings, of any modality, at the same time as novel task rules within working memory leads to some task rules being insufficiently maintained
Topical NSAIDs for acute pain: a meta-analysis
BACKGROUND: A previous systematic review reported that topical NSAIDs were effective in relieving pain in acute conditions like sprains and strains, with differences between individual drugs for efficacy. More trials, a better understanding of trial quality and bias, and a reclassification of certain drugs necessitate a new review. METHODS: Studies were identified by searching electronic databases and writing to manufacturers. We selected randomised double blind trials comparing topical NSAID with either placebo or another active treatment in adults with acute pain, and extracted dichotomous information approximating to a 50% reduction in pain at one week, together with details of adverse events and withdrawals. Relative benefit and number-needed-to-treat (NNT), and relative risk and number-needed-to-harm (NNH) were calculated, with sensitivity analyses where appropriate to investigate differences between individual drugs and aspects of trial design. RESULTS: Twenty-six double blind placebo controlled trials had information from 2,853 patients for evaluation of efficacy. Topical NSAID was significantly better than placebo in 19 of the 26 trials, with a pooled relative benefit of 1.6 (95% confidence interval 1.4 to 1.7), and NNT of 3.8 (95% confidence interval 3.4 to 4.4) compared with placebo for the outcome of half pain relief at seven days. Results were not affected by outcome reported, or condition treated, but smaller trials yielded a larger estimate of efficacy. Indirect comparisons of individual topical NSAIDs showed that ketoprofen was significantly better than all other topical NSAIDs, while indomethacin was barely distinguished from placebo. Three trials, with 433 patients, compared topical with oral NSAID (two trials compared the same drug, one compared different drugs) and found no difference in efficacy. Local adverse events, systemic adverse events, or withdrawals due to an adverse event were rare, and no different between topical NSAID and placebo. CONCLUSIONS: Topical NSAIDs were effective and safe in treating acute painful conditions for one week
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