One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency

PURPOSE: To assess olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. METHODS: This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. RESULTS: Twenty patients were enrolled: four adolescents (12–17 years), nine children (6–11 years), and seven infants/early child (1–5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). CONCLUSION: In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints

Teaching linguistic politeness: a methodological proposal

The aim of this article is to explore theoretical and methodological aspects of the teaching of pragmatics in a second language. Taking as point of departure the pragmatic continuum, which includes pragmalinguistics and sociopragmatics, we focus on the promotion of sociopragmatic knowledge in classroom contexts. More specifically, it is argued that a revised contextual and interactional view of Brown and Levinson¿s (1987) model of linguistic politeness, related to such notions as genre and politeness systems, offers suitable tools of pragmatic description for use in teaching and learning second languages. We start with a brief overview of linguistic politeness from a socio-cognitive framework. Then, we revise the main methodological approaches to the teaching of pragmatic knowledge in general and the specific teaching of linguistic politeness in particular. Finally, we make a methodological proposal for use in foreign language instruction

AGB Variables and the Mira Period-Luminosity Relation

Published data for large amplitude asymptotic giant branch variables in the Large Magellanic Cloud are re-analysed to establish the constants for an infrared (K) period-luminosity relation of the form: Mk=rho[log P-2.38] + delta. A slope of rho=-3.51+/-0.20 and a zero point of delta=-7.15+/-0.06 are found for oxygen-rich Miras (if a distance modulus of 18.39+/-0.05 is used for the LMC). Assuming this slope is applicable to Galactic Miras we discuss the zero-point for these stars using the revised Hipparcos parallaxes together with published VLBI parallaxes for OH Masers and Miras in Globular Clusters. These result in a mean zero-point of delta=-7.25+/-0.07 for O-rich Galactic Miras. The zero-point for Miras in the Galactic Bulge is not significantly different from this value. Carbon-rich stars are also discussed and provide results that are consistent with the above numbers, but with higher uncertainties. Within the uncertainties there is no evidence for a significant difference between the period-luminosity relation zero-points for systems with different metallicity.Comment: 15 pages, 3 figures, accepted for MNRA

Common Polymorphisms at the <i>CYP17A1 </i>Locus Associate With Steroid Phenotype:Support for Blood Pressure Genome-Wide Association Study Signals at This Locus

Genome-wide association studies implicate the CYP17A1 gene in human blood pressure regulation although the causative polymorphisms are as yet unknown. We sought to identify common polymorphisms likely to explain this association. We sequenced the CYP17A1 locus in 60 normotensive individuals and observed 24 previously identified single-nucleotide polymorphisms with minor allele frequency &gt;0.05. From these, we selected, for further studies, 7 polymorphisms located ≤2 kb upstream of the CYP17A1 transcription start site. In vitro reporter gene assays identified 3 of these (rs138009835, rs2150927, and rs2486758) as having significant functional effects. We then analyzed the association between the 7 polymorphisms and the urinary steroid metabolites in a hypertensive cohort (n=232). Significant associations included that of rs138009835 with aldosterone metabolite excretion; rs2150927 associated with the ratio of tetrahydrodeoxycorticosterone to tetrahydrodeoxycortisol, which we used as an index of 17α-hydroxylation. Linkage analysis showed rs138009835 to be the only 1 of the 7 polymorphisms in strong linkage disequilibrium with the blood pressure–associated polymorphisms identified in the previous studies. In conclusion, we have identified, characterized, and investigated common polymorphisms at the CYP17A1 locus that have functional effects on gene transcription in vitro and associate with corticosteroid phenotype in vivo. Of these, rs138009835—which we associate with changes in aldosterone level—is in strong linkage disequilibrium with polymorphisms linked by genome-wide association studies to blood pressure regulation. This finding clearly has implications for the development of high blood pressure in a large proportion of the population and justifies further investigation of rs138009835 and its effects

Newly detected ozone-depleting substances in the atmosphere

Ozone-depleting substances emitted through human activitiescause large-scale damage to the stratospheric ozone layer, and influence global climate. Consequently, the production of many of these substances has been phased out; prominent examples are the chlorofluorocarbons (CFCs), and their intermediate replacements, the hydrochlorofluorocarbons (HCFCs). So far, seven types of CFC and six types of HCFC have been shown to contribute to stratospheric ozone destruction 1,2. Here, we report the detection and quantification of a further three CFCs and one HCFC. We analysed the composition of unpolluted air samples collected in Tasmania between 1978 and 2012, and extracted from deep firn snow in Greenland in 2008, using gas chromatography with mass spectrometric detection. Using the firn data, we show that all four compounds started to emerge in the atmosphere in the 1960s. Two of the compounds continue to accumulate in the atmosphere. We estimate that, before 2012, emissions of all four compounds combined amounted to more than 74,000 tonnes. This is small compared with peak emissions of other CFCs in the 1980s of more than one million tonnes each year 2. However, the reported emissions are clearly contrary to the intentions behind the Montreal Protocol, and raise questions about the sources of these gases

The Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis, a multicentre observational study (ARISE FLUIDS observational study): Rationale, methods and analysis plan

There is uncertainty about the optimal i.v. fluid volume and timing of vasopressor commencement in the resuscitation of patients with sepsis and hypotension. We aim to study current resuscitation practices in EDs in Australia and New Zealand (the Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis [ARISE FLUIDS] observational study).ARISE FLUIDS is a prospective, multicentre observational study in 71 hospitals in Australia and New Zealand. It will include adult patients presenting to the ED during a 30 day period with suspected sepsis and hypotension (systolic blood pressur

A novel role for Teneurin C-terminal Associated Peptide (TCAP) in the regulation of cardiac activity in the Sydney rock oyster, Saccostrea glomerata

Teneurin C-terminal associated peptide (TCAP) is an ancient bioactive peptide that is highly conserved in metazoans. TCAP administration reduces cellular and behavioural stress in vertebrate and urochordate models, yet despite numerous studies in higher animals, there is limited knowledge of its role in invertebrates. In particular, there are no studies on TCAP’s effects on the heart of any metazoan, which is a critical organ in the stress response. We used the Sydney rock oyster (SRO) as an invertebrate model to investigate a potential role for sroTCAP in regulating cardiac activity, including during stress. sroTCAP is localized to the neural innervation network of the SRO heart, and suggested binding with various heart proteins related to metabolism and stress, including SOD, GAPDH and metabotropic glutamate receptor. Intramuscular injection of sroTCAP (10 pmol) significantly altered the expression of heart genes that are known to regulate remodelling processes under different conditions, and modulated several gene families responsible for stress mitigation. sroTCAP (1 and 10 pmol) was shown to cause transient bradycardia (heart rate was reduced by up to 63% and for up to 40 min post-administration), indicative of an unstressed state. In summary, this study has established a role for a TCAP in the regulation of cardiac activity through modulation of physiological and molecular components associated with energy conservation, stress and adaptation. This represents a novel function for TCAP and may have implications for higher-order metazoans