16 research outputs found

    A Novel Tandem Mass Spectrometry Method for Rapid Confirmation of Medium- and Very Long-Chain acyl-CoA Dehydrogenase Deficiency in Newborns

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    BACKGROUND:Newborn screening for medium- and very long-chain acyl-CoA dehydrogenase (MCAD and VLCAD, respectively) deficiency, using acylcarnitine profiling with tandem mass spectrometry, has increased the number of patients with fatty acid oxidation disorders due to the identification of additional milder, and so far silent, phenotypes. However, especially for VLCADD, the acylcarnitine profile can not constitute the sole parameter in order to reliably confirm disease. Therefore, we developed a new liquid chromatography tandem mass spectrometry (LC-MS/MS) method to rapidly determine both MCAD- and/or VLCAD-activity in human lymphocytes in order to confirm diagnosis. METHODOLOGY:LC-MS/MS was used to measure MCAD- or VLCAD-catalyzed production of enoyl-CoA and hydroxyacyl-CoA, in human lymphocytes. PRINCIPAL FINDINGS:VLCAD activity in controls was 6.95+/-0.42 mU/mg (range 1.95 to 11.91 mU/mg). Residual VLCAD activity of 4 patients with confirmed VLCAD-deficiency was between 0.3 and 1.1%. Heterozygous ACADVL mutation carriers showed residual VLCAD activities of 23.7 to 54.2%. MCAD activity in controls was 2.38+/-0.18 mU/mg. In total, 28 patients with suspected MCAD-deficiency were assayed. Nearly all patients with residual MCAD activities below 2.5% were homozygous 985A>G carriers. MCAD-deficient patients with one other than the 985A>G mutation had higher MCAD residual activities, ranging from 5.7 to 13.9%. All patients with the 199T>C mutation had residual activities above 10%. CONCLUSIONS:Our newly developed LC-MS/MS method is able to provide ample sensitivity to correctly and rapidly determine MCAD and VLCAD residual activity in human lymphocytes. Importantly, based on measured MCAD residual activities in correlation with genotype, new insights were obtained on the expected clinical phenotype

    Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia

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    Although movement disorders (MDs) are known complications, the exact frequency and severity remains uncertain in patients with classical galactosemia, especially in children. We determined the frequency, classification and severity of MDs in a cohort of pediatric and adult galactosemia patients, and assessed the association with nonmotor neuropsychological symptoms and daily functioning. Patients from seven centers in the United Kingdom and the Netherlands with a confirmed galactosemia diagnosis were invited to participate. A videotaped neurological examination was performed and an expert panel scored the presence, classification and severity of MDs. Disease characteristics, nonmotor neuropsychological symptoms, and daily functioning were evaluated with structured interviews and validated questionnaires (Achenbach, Vineland, Health Assessment Questionnaire, SIP68). We recruited 37 patients; 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years). Subjective self-reports revealed motor symptoms in 19/37 (51.4%), similar to the objective (video) assessment, with MDs in 18/37 patients (48.6%). The objective severity scores were moderate to severe in one third (6/37). Dystonia was the overall major feature, with additional tremor in adults, and myoclonus in children. Behavioral or psychiatric problems were present in 47.2%, mostly internalizing problems, and associated with MDs. Daily functioning was significantly impaired in the majority of patients. Only one patient received symptomatic treatment for MDs. We show that MDs and nonmotor neuropsychological symptoms are frequent in both children and adults with classical galactosemia

    Abstracts from the Food Allergy and Anaphylaxis Meeting 2016

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    Insights Into ABC Transport in Archaea

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    In archaea, ATP-binding cassette (ABC) transporters play a crucial role in substrate uptake, export, and osmoregulation. Archaeal substrate-binding-protein-dependent ABC transporters are equipped with a very high affinity for their cognate substrates which provide these organisms with the ability to efficiently scavenge substrates from their environment even when present only at low concentration. Further adaptations to the archaeal way of life are especially found in the domain organization and anchoring of the substrate-binding proteins to the membrane. Examination of the signal peptides of binding proteins of 14 archaeal genomes showed clear differences between euryarchaeotes and crenarchaeotes. Furthermore, a profiling and comparison of ABC transporters in the three sequenced pyrococcal strains was performed.

    Sugar transport in (hyper)thermophilic archaea

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    Hyperthermophilic archaea show important metabolic adaptations for growth on carbohydrates under hostile conditions. For carbohydrate uptake so far only ABC-type transporters have been described that are equipped with a uniquely high affinity as compared to mesophilic bacterial systems. This allows these organisms to efficiently scavenge all available carbohydrates from the extreme environment.

    Insights into ABC Transport in Archaea

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    Biochemical evidence for the presence of two őĪ-glucoside ABC-transport systems in the hyperthermophilic archaeon Pyrococcus furiosus

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    The hyperthermophilic archaeon Pyrococcus furiosus can utilize different carbohydrates, such as starch, maltose and trehalose. Uptake of őĪ-glucosides is mediated by two different, binding protein-dependent, ATP-binding cassette (ABC)-type transport systems. The maltose transporter also transports trehalose, whereas the maltodextrin transport system mediates the uptake of maltotriose and higher malto-oligosaccharides, but not maltose. Both transport systems are induced during growth on their respective substrates

    Prolonged electrical stimulation-induced gluteal and hamstring muscle activation and sitting pressure in spinal cord injury: Effect of duty cycle

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    Pressure ulcers (PUs) are highly prevalent in people with spinal cord injury (SCI). Electrical stimulation (ES) activates muscles and might reduce risk factors. Our objectives were to study and compare the effects of two duty cycles during 3 h of ES-induced gluteal and hamstring activation on interface pressure distribution in sitting individuals with SCI and study the usability of a newly developed electrode garment (ES shorts). Ten individuals with SCI participated in this study, in which two ES protocols with different duty cycles (1:1 s vs 1:4 s on-off) were applied in counterbalanced order using a custom-made garment with built-in electrodes. Outcome variables included interface pressure of the ischial tuberosities (ITs) and pressure gradient. A questionnaire was used to determine usability of the ES shorts. In both protocols, ES caused a significant decrease in average IT pressure compared with rest (no ES); on average, 35% for protocol 1:4 and 13% for protocol 1:1. The ES on-off duty cycle of protocol 1:4 showed less muscle fatigue. In general, participants scored the usability of the ES shorts as satisfactory. In this study, the application of ES resulted in a significant decrease in IT pressure. The ES on-off duty cycle of 1:4 s is recommended because of the less fatiguing effect. ES of the hamstrings and gluteal muscles might be a promising method in preventing PUs, but further study is needed
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