Abstract Background Congenital muscular dystrophy is a clinically and genetically heterogeneous group of myopathies. Congenital muscular dystrophy related to lamin A/C is rare and characterized by ...early-onset hypotonia with axial muscle weakness typically presenting with a loss in motor acquisitions within the first year of life and a dropped-head phenotype. Methods Here we report the clinical and histological characteristics of four unrelated Brazilian patients with dropped-head syndrome and mutations in the LMNA gene. Results All patients had previously described mutations (p.E358K, p.R249W, and p.N39S) and showed pronounced cervical muscle weakness, elevation of serum creatine kinase, dystrophic pattern on muscle biopsy, and respiratory insufficiency requiring ventilatory support. Three of the patients manifested cardiac arrhythmias, and one demonstrated a neuropathic pattern on nerve conduction study. Conclusion Although lamin A/C–related congenital muscular dystrophy is a clinically distinct and recognizable phenotype, genotype/phenotype correlation, ability to anticipate onset of respiratory and cardiac involvement, and need for nutritional support remain difficult.
Acid and metalliferous release occurring when sulfide (principally pyrite)-containing rock from mining activities and from natural environments is exposed to the elements is acknowledged as a major ...environmental problem. Acid rock drainage (ARD) management is both challenging and costly for operating and legacy mine sites. Current technological solutions are expensive and focused on treating ARD on release rather than preventing it at source. We describe here a viable, practical mechanism for reduced ARD through the formation of silicate-stabilized iron oxyhydroxide surface layers. Without silicate, oxidized pyrite particles form an overlayer of crystalline goethite or lepidocrocite with porous structure. With silicate addition, a smooth, continuous, coherent and apparently amorphous iron oxyhydroxide surface layer is observed, with consequent pyrite dissolution rates reduced by more than 90% at neutral pH. Silicate is structurally incorporated within this layer and inhibits the phase transformation from amorphous iron (oxy)hydroxide to goethite, resulting in pyrite surface passivation. This is confirmed by computational simulation, suggesting that silicate-doping of a pseudoamorphous iron oxyhydroxide (ferrihydrite structure) is thermodynamically more stable than the equivalent undoped structure. This mechanism and its controlling factors are described. As a consequence of the greatly reduced acid generation rate, neutralization from on-site available reactive silicate minerals may be used to maintain neutral pH, after initial limestone addition to achieve neutral pH, thus maintaining the integrity of these layers for effective ARD management.
Summary Background Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered ...humanised anti-CGRP antibody, for migraine prevention. Methods In this randomised, double-blind, placebo-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18–55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked to treatment allocation during the study. The primary objective was to assess safety at 12 weeks after infusion. The primary efficacy endpoint was the change from baseline to weeks 5–8 in the frequency of migraine days, as recorded in patient electronic diaries. Patients were followed up until 24 weeks for exploratory safety and efficacy analyses. Safety and efficacy analyses were done by intention to treat. This study is registered with ClinicalTrials.gov , NCT01772524. Findings Between Jan 28, 2013, and Dec 23, 2013, of 174 patients randomly assigned at 26 centres in the USA, 163 received either ALD403 (n=81) or placebo (n=82). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. The most frequent adverse events were upper respiratory tract infection (placebo 6 7% patients vs ALD403 7 9% patients), urinary tract infection (4 5% vs 1 1%), fatigue (3 4% vs 3 4%), back pain (4 5% vs 3 4%), arthralgia (4 5% vs 1 1%), and nausea and vomiting (2 2% vs 3 4%). Six serious adverse events were reported by three patients and were judged to be unrelated to study drug: in the ALD403 group, one patient had four serious adverse events and one had one serious adverse event, and in the placebo group, one patient had one serious adverse event. There were no differences in vital signs or laboratory safety data between the two treatment groups. The mean change in migraine days between baseline and weeks 5–8 was −5·6 (SD 3·0) for the ALD403 group compared with −4·6 (3·6) for the placebo group (difference −1·0, 95% CI −2·0 to 0·1; one-sided p=0·0306). Interpretation No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days. Funding Alder Biopharmaceuticals.
Sudden cardiac death remains the leading cause of death in the U.S. A left ventricular ejection fraction (LVEF) <30% to 35% identifies a population of patients at increased risk for sudden cardiac ...death. Once identified, an implantable cardioverter-defibrillator (ICD) is effective in reducing the occurrence of sudden cardiac death. Yet in a substantial proportion of patients who receive an ICD based on reduced LVEF, the device never delivers therapy. Furthermore, the majority of patients who die suddenly do not qualify for ICD placement under current LVEF-based criteria in the guidelines. This review considers the potential role of cardiac imaging in improving the selection of patients most likely to benefit from an ICD. The presence of myocardial scar and/or unrevascularized myocardial ischemia provides an important substrate for the occurrence of potentially fatal ventricular arrhythmias. The presence of clinical heart failure further increases the risk of ventricular arrhythmia. The sympathetic nervous system provides an important trigger for major arrhythmic events, both through global overactivity and through regional heterogeneity of sympathetic activity. A mismatch of myocardial perfusion and innervation may pose a particularly great risk. Imaging modalities provide unique opportunities to investigate the anatomic and pathophysiologic substrates, as well as the triggering effects of cardiac sympathetic innervation. Combining imaging and electrophysiologic modalities offers promise for improved accuracy in future selection of patients with heart failure for ICD placement.
Objectives To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) and short stature (SS) with that of children with CKD and normal height (NH), to ...evaluate the impact of catch-up growth and growth hormone (GH) use on HRQoL, and to describe the concordance of perceptions of HRQoL between children with SS and NH and their parents. Study design Four hundred eighty-three children and/or parents enrolled in the multicenter Chronic Kidney Disease in Children study who had completed the Pediatric Quality of Life Inventory (Version 4.0) on at least 2 Chronic Kidney Disease in Children study visits composed this substudy population. Participants were dichotomized into NH or SS groups. The demographic characteristics that varied at baseline (sex, glomerular filtration rate, and parent education) were controlled for in the main analysis evaluating the impact of catch-up growth and use of GH on HRQoL. Results Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and GH use on parent–proxy reports of child physical functioning ( P < .05) and social functioning ( P < .05). Older children with CKD (15-17 years old) had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old). Conclusion The finding that height gains and GH use are associated with increases in physical and social functioning by parent report provides additional support for interventions to improve height in children with CKD. The importance of evaluating both the parent and child perceptions of HRQoL is supported by our results.
The rivers of Appalachia (United States) are among the most biologically diverse freshwater ecosystems in the temperate zone and are home to numerous endemic aquatic organisms. Throughout the Central ...Appalachian ecoregion, extensive surface coal mines generate alkaline mine drainage that raises the pH, salinity, and trace element concentrations in downstream waters. Previous regional assessments have found significant declines in stream macroinvertebrate and fish communities after draining these mined areas. Here, we expand these assessments with a more comprehensive evaluation across a broad range of organisms (bacteria, algae, macroinvertebrates, all eukaryotes, and fish) using high-throughput amplicon sequencing of environmental DNA (eDNA). We collected water samples from 93 streams in Central Appalachia (West Virginia, United States) spanning a gradient of mountaintop coal mining intensity and legacy to assess how this land use alters downstream water chemistry and affects aquatic biodiversity. For each group of organisms, we identified the sensitive and tolerant taxa along the gradient and calculated stream specific conductivity thresholds in which large synchronous declines in diversity were observed. Streams below mining operations had steep declines in diversity (−18 to −41%) and substantial shifts in community composition that were consistent across multiple taxonomic groups. Overall, large synchronous declines in bacterial, algal, and macroinvertebrate communities occurred even at low levels of mining impact at stream specific conductivity thresholds of 150–200 μS/cm that are substantially below the current U.S. Environmental Protection Agency aquatic life benchmark of 300 μS/cm for Central Appalachian streams. We show that extensive coal surface mining activities led to the extirpation of 40% of biodiversity from impacted rivers throughout the region and that current water quality criteria are likely not protective for many groups of aquatic organisms.
Multi‐scale transgressive–regressive cycles from the mid‐Jurassic were recognised in the Central Lusitanian Basin, Portugal. These cycles allow the depositional evolution of the basin to be better ...understood and aid in the construction of stratigraphic sequences composed of three hierarchies. The stacking pattern of high‐frequency transgressive–regressive sequences forms larger clusters that define medium‐frequency transgressive–regressive sequences. Likewise, the stacking pattern of medium‐frequency transgressive–regressive sequences generates two Bathonian–early Callovian low‐frequency transgressive–regressive sequences. Integration of several methods supported the interpretation of facies associations representing clastic deposition in offshore to shoreface environments and carbonate sediments in outer to inner ramp settings. New data from calcareous nannofossils and dinoflagellate assemblages constrained the interval's Bathonian–early Callovian age, thus unveiling the Middle–Upper Jurassic disconformity and filling the Middle Jurassic stratigraphic record gap in the Central Lusitanian Basin. This study may be helpful for similar successions in Tethyan domains and comparable depositional settings elsewhere.
Middle Jurassic multi‐scale transgressive–regressive cycles were recognised in the Central Lusitanian Basin, Portugal. New data from calcareous nannofossils and dinoflagellate assemblages constrained the Bathonian–early Callovian age for the studied interval, thus filling the gap of the Middle Jurassic in the Central Lusitanian Basin. Using descriptive criteria to identify sequences based on the T–R cycle anatomy, recurrence, and trends, cyclic stratigraphy has enabled the definition of a conceptual model for the deposition of the studied section that is more robust than conventional interpretations.
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