Pediatric malignancies in neurofibromatosis type 1 : A population-based cohort study

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome with an incidence of 1:2,000. Patients with NF1 have an increased cancer risk and mortality, but there are no population-based cohort studies specifically investigating the risk of childhood malignancies. We used the Finnish NF1 cohort to analyze the incidence, risk and prognosis of malignancies in NF1 patientsPeer reviewe

Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome A randomised trial using nuclear magnetic resonance spectroscopy

BACKGROUND Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml(-1); n = 40), propofol (1.7 mu g ml(-1); n = 40), sevoflurane (0.9% end-tidal; n = 39), S-ketamine (0.75 mu g ml(-1); n = 20) or placebo (n = 20). MAIN OUTCOME MEASURES Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min post-anaesthesia. RESULTS All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereasbranched chain amino acids and tyrosine decreased. CONCLUSION A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror a2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties.Peer reviewe

Permutation-based significance analysis reduces the type 1 error rate in bisulfite sequencing data analysis of human umbilical cord blood samples

DNA methylation patterns are largely established in-utero and might mediate the impacts of in-utero conditions on later health outcomes. Associations between perinatal DNA methylation marks and pregnancy-related variables, such as maternal age and gestational weight gain, have been earlier studied with methylation microarrays, which typically cover less than 2% of human CpG sites. To detect such associations outside these regions, we chose the bisulphite sequencing approach. We collected and curated clinical data on 200 newborn infants; whose umbilical cord blood samples were analysed with the reduced representation bisulphite sequencing (RRBS) method. A generalized linear mixed-effects model was fit for each high coverage CpG site, followed by spatial and multiple testing adjustment of P values to identify differentially methylated cytosines (DMCs) and regions (DMRs) associated with clinical variables, such as maternal age, mode of delivery, and birth weight. Type 1 error rate was then evaluated with a permutation analysis. We discovered a strong inflation of spatially adjusted P values through the permutation analysis, which we then applied for empirical type 1 error control. The inflation of P values was caused by a common method for spatial adjustment and DMR detection, implemented in tools comb-p and RADMeth. Based on empirically estimated significance thresholds, very little differential methylation was associated with any of the studied clinical variables, other than sex. With this analysis workflow, the sex-associated differentially methylated regions were highly reproducible across studies, technologies, and statistical models.Peer reviewe

Umbilical cord blood DNA methylation in children who later develop type 1 diabetes

Aims/hypothesis Distinct DNA methylation patterns have recently been observed to precede type 1 diabetes in whole blood collected from young children. Our aim was to determine whether perinatal DNA methylation is associated with later progression to type 1 diabetes. Methods Reduced representation bisulphite sequencing (RRBS) analysis was performed on umbilical cord blood samples collected within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study. Children later diagnosed with type 1 diabetes and/or who tested positive for multiple islet autoantibodies (n = 43) were compared with control individuals (n = 79) who remained autoantibody-negative throughout the DIPP follow-up until 15 years of age. Potential confounding factors related to the pregnancy and the mother were included in the analysis. Results No differences in the umbilical cord blood methylation patterns were observed between the cases and controls at a false discovery rate Conclusions/interpretation Based on our results, differences between children who progress to type 1 diabetes and those who remain healthy throughout childhood are not yet present in the perinatal DNA methylome. However, we cannot exclude the possibility that such differences would be found in a larger dataset.Peer reviewe

Neurofibromatosis Type 1 Gene Mutation Analysis Using Sequence Capture and High-throughput Sequencing

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Standard of hygiene and immune adaptation in newborn infants

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Composition Portfolio, Maria Kallionpää

Supporting composition portfolio to DPhil thesis: Beyond the piano: the super instrument. Widening the instrumental capacities in the context of the piano music of the 21st century. Individual scores give instruction to performing the work. Maria Kallionpää, Dphil in Music (Composition), Faculty of Music, University of Oxford. TT 2014 Table of Contents Composition Portfolio Orchestral and Choral Works El Canto de la Guerra/The Song of War Kuru Seamar Chamber Music Works Toccata Solo Works Fantasia Raindrops El Safari de la Muerte/Le Safari de la Mort Sonnenschände – Sonnenwende CD Celestifilia, acoustic version Celestifilia, principal version, digital realisation El Canto de la Guerra/The Song of War Kuru La Safari de la Muerte/Le Safari de la Mort DVD Sonnenschände – Sonnenwende, video file Toccata, video file</ul

Composition Portfolio, Maria Kallionpää

Supporting composition portfolio to DPhil thesis: Beyond the piano: the super instrument. Widening the instrumental capacities in the context of the piano music of the 21st century. Individual scores give instruction to performing the work

Beyond the piano: the super instrument. Widening the instrumental capacities in the context of the piano music of the 21st century

Thanks to the development of new technology, musical instruments are no more tied to their existing acoustic or technical limitations as almost all parameters can be augmented or modified in real time. An increasing number of composers, performers, and computer programmers have thus become interested in different ways of "supersizing" acoustic instruments in order to open up previously-unheard instrumental sounds. This leads us to the question of what constitutes a super instrument and what challenges does it pose aesthetically and technically? This work explores the effects that super instruments have on the identity of a given solo instrument, on the identity of a composition and on the experience of performing this kind of repertoire. The super instrument comes to be defined as a bundle of more than one instrumental lines that achieve a coherent overall identity when generated in real time. On the basis of my own personal experience of performing the works discussed in this dissertation, super instruments vary a great deal but each has a transformative effect on the identity and performance practice of the pianist. This discussion approaches the topic from the viewpoint of contemporary keyboard music, showcasing examples of super instrument compositions of the 21st century. Thus, the main purposes of this practise based research project is to explore the essence and role of piano or toy piano in a super instrument constellation, as well as the performer's role as a "super instrumentalist". I consider these issues in relation to case studies drawn from my own compositional work and a selection of works composed by Karlheinz Essl and Jeff Brown. Appendix: Contents of CD and DVD CD Track 1: Maria Kallionpää: Zusammenbindenbinden.Winden? –Hommage a Schumann. Tuuli Lempa, piano; Marko Myöhänen, electronics. Helsinki 2012. Track 2: Maria Kallionpää: Trinity Mania. Maria Kallionpää, piano; Florian Hartlieb, electronics. Vienna 2010. DVD Track 1: Karlheinz Essl: Sequitur V. Maria Kallionpää, toy piano; Karlheinz Essl, electronics</p