Erwachsen werden mit Duchenne-Muskeldystrophie : Herausforderungen in der Transition vom Jugend- ins Erwachsenenalter

Thema: Aufgrund medizinischer und therapeutischer Fortschritte ist die Lebenserwartung von jungen Männern mit Duchenne-Muskeldystrophie (DMD) stark angestiegen. Die Betroffenen erreichen nun das Erwachsenenalter. Deshalb ist es relevant, sie in der Transition vom Jugend- ins Erwachsenenalter zu begleiten. In dieser Bachelorarbeit wird der Frage nachgegangen, welche Herausforderungen das Gelingen der Transition ins Erwachsenenalter bei Jugendlichen mit Duchenne-Muskeldystrophie beeinflussen. Daraus soll abgeleitet werden, wie die Ergotherapie diesen Transitionsprozess in der Praxis begleiten kann. Methode: Durch eine strukturierte Literaturrecherche in sechs Datenbanken wurden fünf Hauptstudien zur Bearbeitung der Fragestellung ausgewählt. Um eine Übersicht zu schaffen, wurden die Ergebnisse der Hauptstudien in das Occupational Therapy Practice Framework (OTPF) eingeteilt. Ergebnisse: Herausforderungen während der Transition vom Jugend- ins Erwachsenenalter konnten in 15 von 24 Bereichen des OTPF zugeordnet werden. Die Ergebnisse zeigen auf, dass DMD-Betroffene in den Bereichen Arbeit, soziale Partizipation, Werte, Glauben und Spiritualität, Körperfunktionen und sozialer Kontext am meisten Herausforderungen erleben. Schlussfolgerungen: Es ist notwendig, die Situation von Jugendlichen mit DMD aus verschiedenen Perspektiven zu betrachten, um eine optimale Begleitung während der Transition zu gewährleisten. Da eine ganzheitliche Sichtweise zu den Kernkompetenzen der Ergotherapie gehört, könnte sie eine tragende Rolle im Transitionsprozess einnehmen

Emerg Infect Dis

The present work is devoted to the study of stone beads and pendants from Bronze Age sites in Sicily and the Aeolian Islands. Macroscopic geological examination made it possible to identify the rock types and in some cases their probable provenance. A chronological and typological analysis of the objects as well as graphic and photographic documentation completes the study of the stone artifacts. Comparative research throughout the Mediterranean allows the distinction between local groups of beads and pendants (i.e. of local production and distribution) and groups of Near Eastern objects (mainly in carnelian) that arrived in Italy through Aegean contacts. This work enables a chronological classification of these objects, some of which arrived in Sicily via Mediterranean sea routes. As a result, it is possible to discuss in depth some issues regarding Aegean imports in Italy and the changing socio-economic role that ornaments played in the indigenous communities during the Bronze Age

Iron Source Preference and Regulation of Iron Uptake in Cryptococcus neoformans

The level of available iron in the mammalian host is extremely low, and pathogenic microbes must compete with host proteins such as transferrin for iron. Iron regulation of gene expression, including genes encoding iron uptake functions and virulence factors, is critical for the pathogenesis of the fungus Cryptococcus neoformans. In this study, we characterized the roles of the CFT1 and CFT2 genes that encode C. neoformans orthologs of the Saccharomyces cerevisiae high-affinity iron permease FTR1. Deletion of CFT1 reduced growth and iron uptake with ferric chloride and holo-transferrin as the in vitro iron sources, and the cft1 mutant was attenuated for virulence in a mouse model of infection. A reduction in the fungal burden in the brains of mice infected with the cft1 mutant was observed, thus suggesting a requirement for reductive iron acquisition during cryptococcal meningitis. CFT2 played no apparent role in iron acquisition but did influence virulence. The expression of both CFT1 and CFT2 was influenced by cAMP-dependent protein kinase, and the iron-regulatory transcription factor Cir1 positively regulated CFT1 and negatively regulated CFT2. Overall, these results indicate that C. neoformans utilizes iron sources within the host (e.g., holo-transferrin) that require Cft1 and a reductive iron uptake system

Polychlorinated Biphenyls Disrupt Blood–Brain Barrier Integrity and Promote Brain Metastasis Formation

Bac k g r o u n d: Polychlorinated biphenyls (PCBs) comprise a ubiquitous class of toxic substances associated with carcinogenic and tumor-promoting effects as well as neurotoxic properties in the brain. However, the effects of PCBs on the development of tumor metastases are not fully understood. Objective: We evaluated the hypothesis that exposure to individual PCB congeners can facilitate the development of brain metastases in immunocompetent mice via the disruption of the integrity of the blood–brain barrier (BBB). Met h o d s: C57/Bl6 mice were exposed to individual PCBs by oral gavage, and 48 hr later they were injected with luciferase-labeled K1735 M2 melanoma cells into the internal carotid artery. The development of metastatic nodules was monitored by bioluminescent imaging. In addition, we evaluated the functional permeability of the BBB by measuring permeability of sodium fluorescein across the brain microvessels. Expression and colocalization of tight junction (TJ) proteins were studied by Western blotting and immunofluorescence microscopy. Res u l t s: Oral administration of coplanar PCB126, mono-ortho-substituted PCB118, and noncoplanar PCB153 (each at 150 µmol/kg body weight) differentially altered expression of the TJ proteins claudin-5, occludin, and zonula occludens-1 in brain capillaries. These alterations wer

Organ-dependent in vivo priming of naive CD4+,but not CD8+,T cells by plasmacytoid dendritic cells

Plasmacytoid dendritic cells (PDCs) play a pivotal role as cytokine-secreting accessory cells in the antimicrobial immune defense. In contrast, the capacity of PDCs to act as antigen-presenting cells in naive T cell priming remains unclear. By studying T cell responses in mice that lack conventional DCs (cDCs), and by the use of a PDC-specific antigen-targeting strategy, we show that PDCs can initiate productive naive CD4+ T cell responses in lymph nodes, but not in the spleen. PDC-triggered CD4+ T cell responses differed from cDC-driven responses in that they were not associated with concomitant CD8+ T cell priming. Our results establish PDCs as a bona fide DC subset that initiates unique CD4+ Th cell–dominated primary immune responses

A Mutational Analysis of the Endophilin-A N-BAR Domain Performed in Living Flies

BACKGROUND: Endophilin is a cytoplasmic protein with an important function in clathrin-dependent endocytosis at synapses and elsewhere. Endophilin has a BAR (Bin/Amphiphysin/Rvs-homology) domain, which is implicated in the sensing and induction of membrane curvature. Previous structure-function studies of the endophilin-A BAR domain have almost exclusively been made in reduced systems, either in vitro or ex vivo in cultured cells. To extend and complement this work, we have analyzed the role played by the structural features of the endophilin-A BAR domain in Drosophila in vivo. METHODOLOGY/PRINCIPAL FINDINGS: The study is based on genetic rescue of endophilin-A (endoA) null mutants with wild type or mutated endoA transgenes. We evaluated the viability of the rescuants, the locomotor behavior in adult flies and the neurotransmission at the larval neuromuscular junction. Whereas mutating the endophilin BAR domain clearly affected adult flies, larval endophilin function was surprisingly resistant to mutagenesis. Previous reports have stressed the importance of a central appendage on the convex BAR surface, which forms a hydrophobic ridge able to directly insert into the lipid bilayer. We found that the charge-negative substitution A66D, which targets the hydrophobic ridge and was reported to completely disrupt the ability of endophilin-BAR to tubulate liposomes in vitro, rescued viability and neurotransmission with the same efficiency as wild type endoA transgenes, even in adults. A similar discrepancy was found for the hydrophilic substitutions A63S/A66S and A63S/A66S/M70Q. The A66W mutation, which introduces a bulky hydrophobic side chain and induces massive vesiculation of liposomes in vitro, strongly impeded eye development, even in presence of the endogenous endoA gene. Substantial residual function was observed in larvae rescued with the EndoA(Arf) transgene, which encodes a form of endophilin-A that completely lacks the central appendage. Whereas a mutation (D151P) designed to increase the BAR curvature was functional, another mutation (P143A, DeltaLEN) designed to decrease the curvature was not. CONCLUSIONS/SIGNIFICANCE: Our results provide novel insight into the structure/function relationship of the endophilin-A BAR domain in vivo, especially with relation to synaptic function

System to Measure Thermal Conductivity and Seebeck Coefficient for Thermoelectrics

The Seebeck coefficient, when combined with thermal and electrical conductivity, is an essential property measurement for evaluating the potential performance of novel thermoelectric materials. However, there is some question as to which measurement technique(s) provides the most accurate determination of the Seebeck coefficient at elevated temperatures. This has led to the implementation of nonstandardized practices that have further complicated the confirmation of reported high ZT materials. The major objective of the procedure described is for the simultaneous measurement of the Seebeck coefficient and thermal diffusivity within a given temperature range. These thermoelectric measurements must be precise, accurate, and reproducible to ensure meaningful interlaboratory comparison of data. The custom-built thermal characterization system described in this NASA-TM is specifically designed to measure the inplane thermal diffusivity, and the Seebeck coefficient for materials in the ranging from 73 K through 373 K

Development of a practical dietitian road map for the nutritional management of phenylketonuria (PKU) patients on pegvaliase

Funding Information: Outside the submitted work, the authors disclose the following. Bausell H received personal fees from BioMarin, Ultragenyx, Horizon and Vitaflo. Bélanger-Quintana A reports personal fees from BioMarin, Nutricia, Vitaflo, Orphan Europe, Takeda and Genzyme. Rocha JC received research grants from BioMarin, Glutamine and Cambrooke, as well as personal fees from BioMarin, Applied Pharma Research, Nutricia, Merck Serono, Vitaflo, Cambrooke, PIAM and Lifediet. MacDonald A reports research funding from BioMarin, Nutricia, Applied Pharma Research, Vitaflo, Galen, Metax, Mevalia and Arla, as well as lecture fees from BioMarin, Applied Pharma Research, Nutricia and Vitaflo, and consultancy fees from BioMarin, Applied Pharma Research, Arla, Nutricia and Vitaflo. Met Ed reports grant funding from BioMarin, Nutricia, Vitaflo and Horizon Pharmaceuticals. Bernstein L and Rohr F report lecture fees from Vitaflo. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.Background: The metabolic dietitian/nutritionist (hereafter ‘dietitian’) plays an essential role in the nutritional management of patients with phenylketonuria (PKU), including those on pegvaliase. Currently, more educational support and clinical experience is needed to ensure that dietitians are prepared to provide optimal nutritional management and counselling of pegvaliase-treated patients. Methods: Via a face-to-face data-review meeting, followed by a virtual consolidation meeting, a group of expert dietitians and one paediatrician discussed and developed a series of recommendations on the nutritional evaluation and management of patients receiving pegvaliase. The consensus group consisted of 10 PKU experts: six dietitians and one paediatrician from Europe and three dietitians from the US. One European and three US dietitians had experience with pegvaliase-treated patients. Results: The consensus group recommended that a physician, dietitian and nurse are part of the pegvaliase treatment team. Additionally, a psychologist/counsellor should be included if available. Practical proposals for the nutritional evaluation of pegvaliase-treated patients at baseline, during the induction and titration phases and for long-term maintenance were developed. The consensus group suggested assessment of blood Phe at least monthly or every 2 weeks in the event of low blood Phe (i.e., blood Phe <30 μmol/L). It may be appropriate to increase blood Phe monitoring when adjusting protein intake and/or pegvaliase dose. It was recommended that natural protein intake is increased by 10–20 g increments if blood Phe concentrations decrease to <240 μmol/L in patients who are not meeting the dietary reference intake for natural protein of 0.8 g/kg. It was proposed that with pegvaliase treatment blood Phe levels could be maintained <240 μmol/L but more evidence on the safety of achieving physiological blood Phe levels is necessary before any recommendation on the lower blood Phe target can be given. Finally, both patients and dietitians should have access to educational resources to optimally support patients receiving pegvaliase. Conclusion: This practical road map aims to provide initial recommendations for dietitians monitoring patients with PKU prescribed pegvaliase. Given that practical experience with pegvaliase is still limited, nutritional recommendations will require regular updating once more evidence is available and clinical experience evolves.publishersversionpublishe

Macrocerebellum: Significance and Pathogenic Considerations

Macrocerebellum is a rare finding characterized by an abnormally large cerebellum. Only few patients with a syndromal or isolated macrocerebellum have been reported so far. This article aims to categorize the magnetic resonance imaging (MRI) findings, quantitate the macrocerebellum by volumetric analysis, characterize the neurological and dysmorphic features and cognitive outcome, and report the results of genetic analyses in children with macrocerebellum. All MR images were qualitatively evaluated for infratentorial and supratentorial abnormalities. Volumetric analysis was performed. Data about neurological and dysmorphic features, outcome, and genetic analysis were collected from clinical histories and follow-up examinations. Five patients were included. Volumetric analysis in three patients confirmed large cerebellar size compared to age-matched controls. MR evaluation showed that thickening of the cortical gray matter of the cerebellar hemispheres is responsible for the macrocerebellum. Additional infratentorial and supratentorial abnormalities were present in all patients. Muscular hypotonia, as well as impaired motor and cognitive development, was found in all patients, with ocular movement disorders in three of five patients. The five patients differed significantly in terms of dysmorphic features and involvement of extracerebral organs. Submicroscopic chromosomal aberrations were found in two patients. Macrocerebellum is caused by thickening of the cortical gray matter of the cerebellar hemispheres, suggesting that cerebellar granule cells may be involved in its development. Patients with macrocerebellum show highly heterogeneous neuroimaging, clinical, and genetic findings, suggesting that macrocerebellum is not a nosological entity, but instead represents the structural manifestation of a deeper, more basic biological disturbance common to heterogeneous disorder

Evolution and Functional Diversification of Fructose Bisphosphate Aldolase Genes in Photosynthetic Marine Diatoms

Diatoms and other chlorophyll-c containing, or chromalveolate, algae are among the most productive and diverse phytoplankton in the ocean. Evolutionarily, chlorophyll-c algae are linked through common, although not necessarily monophyletic, acquisition of plastid endosymbionts of red as well as most likely green algal origin. There is also strong evidence for a relatively high level of lineage-specific bacterial gene acquisition within chromalveolates. Therefore, analyses of gene content and derivation in chromalveolate taxa have indicated particularly diverse origins of their overall gene repertoire. As a single group of functionally related enzymes spanning two distinct gene families, fructose 1,6-bisphosphate aldolases (FBAs) illustrate the influence on core biochemical pathways of specific evolutionary associations among diatoms and other chromalveolates with various plastid-bearing and bacterial endosymbionts. Protein localization and activity, gene expression, and phylogenetic analyses indicate that the pennate diatom Phaeodactylum tricornutum contains five FBA genes with very little overall functional overlap. Three P. tricornutum FBAs, one class I and two class II, are plastid localized, and each appears to have a distinct evolutionary origin as well as function. Class I plastid FBA appears to have been acquired by chromalveolates from a red algal endosymbiont, whereas one copy of class II plastid FBA is likely to have originated from an ancient green algal endosymbiont. The other copy appears to be the result of a chromalveolate-specific gene duplication. Plastid FBA I and chromalveolate-specific class II plastid FBA are localized in the pyrenoid region of the chloroplast where they are associated with β-carbonic anhydrase, which is known to play a significant role in regulation of the diatom carbon concentrating mechanism. The two pyrenoid-associated FBAs are distinguished by contrasting gene expression profiles under nutrient limiting compared with optimal CO2 fixation conditions, suggestive of a distinct specialized function for each. Cytosolically localized FBAs in P. tricornutum likely play a role in glycolysis and cytoskeleton function and seem to have originated from the stramenopile host cell and from diatom-specific bacterial gene transfer, respectively