Einfluss von Cyclodextrinen auf das Hörvermögen - Erste Ergebnisse der Phase 2b/3 von VTS-270 (2-Hydroxypropyl-beta-cyclodextrin) bei Probanden mit Niemann-Pick Typ C

Hintergrund: Cyclodextrine haben die Fähigkeit, zelluläre Lipide zu mobilisieren und werden daher als neuer Therapieansatz der autosomal rezessiven Niemann-Pick TypC Erkrankung (NPC) im Rahmen von Studien überprüft. NPC ist eine seltene Erkrankung (Inzidenz 1:120.000-1:150.000) des Lipidstoffwechsels, die durch endolysosomale Akkumulation von Cholesterin gekennzeichnet ist. Im Verlauf der Erkrankung kommt es zur progressiven Neurodegeneration. Bei NPC1 Mäusen und Katzen verlangsamte die Therapie mit Kleptose HPB das Fortschreiten der Erkrankung und verlängerte die Lebensdauer, führte aber zu einem signifikanten Hörverlust.Material und Methoden: Im Rahmen der von Vtesse geförderten Phase 2b/3 von VTS-270 (2-Hydroxypropyl-beta-cyclodextrin) wird unter der zweiwöchentlichen intrathekalen Verabreichung von VTS-270 an drei NPC-erkrankten Probanden das Hörvermögen durch eine umfassende Audiometrie einschließlich Reintonaudiometrie, DPOAE-Messung, überschwelliger BERA sowie Sprachaudiometrie verlaufskontrolliert.Ergebnisse: Unter der Therapie mit VTS-270 zeigt sich ein progredienter sensorineuraler Hörverlust ab 2 kHz. Die erhöhten Schwellenwerte gingen mit einer Eliminierung der DPOAE einher. Bei einem Probanden zeigte sich nach der Verabreichung ein akuter pantonaler, hochtonbetonter Hörverlust, der sich nach Therapiepause und Dosisreduzierung im Tieftonbereich wieder regenerierte.Diskussion: Sowohl die Manifestation der NPC-Krankheit als auch die Therapie mit VTS-270 führen zu einem hochfrequenten Hörverlust. Bei NPC-Patienten ist eine retrocochleäre Schwerhörigkeit häufig, die Hörverluste unter der Therapie gehen hingegen mit einer Eliminierung der DPOAE einher. Dies deutet auf einen Funktionsverlust der äußeren Haarzellen, der sich jedoch teilweise regenerierbar zeigt. Die Ergebnisse weisen zudem auf eine individuelle dosisabhängige Schädigung der äußeren Haarzellen.Fazit: VTS-270 wird derzeit in Studien für die Behandlung von NPC-Typ C getestet. Unter der Therapie zeigt sich ein signifikanter Hörverlust. Weitere Ergebnisse des neurologischen Outcomes unter der Therapie sowie des Hörverlustes nach jahrelanger Erhaltungstherapie müssen abgewartet werden, um Therapieempfehlungen aussprechen zu können

General Intelligence (G), Act Scores, And Theory Of Mind: (Act)G Predicts Limited Variance Among Theory Of Mind Tests

This study is the first to examine relations between general intelligence (g), non-g factors, and theory of mind (ToM) using structural equation modeling with multiple indicators of g and ToM. g was based on the subtests of the ACT, a college admissions test that is strongly g loaded, and ToM was based on the Reading the Mind in the Eyes Test and the Short Story Test (SST). g correlated strongly with a latent ToM factor (β =.65) and moderately with the two ToM tests (β ≈.34), which correlated modestly with each other (β =.27). The modest correlation between the ToM tests indicates that g predicted a small amount of variance among the ToM tests (7%) and suggests that the ToM tests had little in common. In addition, non-g residuals of the ACT subtests, obtained after removing g, correlated negligibly with the ToM factor and the ToM tests (|β| \u3c 0.06). Similar results were obtained for the ToM residuals, which correlated trivially with the ACT subtests. The trivial non-g effects suggest that g-ToM relations were attributable to “not much more than g.” The results replicated with different combinations of ACT subtests, controls for possible confounds (reading comprehension on the SST), and another college admissions test (the SAT). The use of a convenience sample (college students) and the limited measures of g and ToM are discussed as limitations. Future research should examine the robustness of effects using different measures of g and ToM and also examine possible mediators of g-ToM relations (e.g., executive functions)

Anchored phylogenomics of burrowing mayflies (Ephemeroptera) and the evolution of tusks : Phylogeny of burrowing mayflies

This study investigated the phylogenetic relationships among seven burrowing mayfly families. Genetic data from four ribosomal DNA genes (12S, 16S, 18S and 28S) generated with Sanger sequencing, 448 protein-coding loci generated using a novel hybrid enrichment probe set and available RNAseq and genome assembly for 19 ingroup taxa and four outgroup taxa. Maximum likelihood and Bayesian analyses were carried out to estimate phylogenetic relationships. The results indicated that Potamanthidae, Euthyplociidae, Behningiidae and Palingeniidae were recovered as monophyletic. Ephemeridae was not monophyletic. Mandibular tusks evolved in the common ancestor of burrowing mayflies and were lost in the lineage leading to Behningiidae

Antibiotic resistance in European wastewater treatment plants mirrors the pattern of clinical antibiotic resistance prevalence

Integrated antibiotic resistance (AR) surveillance is one of the objectives of the World Health Organization global action plan on antimicrobial resistance. Urban wastewater treatment plants (UWTPs) are among the most important receptors and sources of environmental AR. On the basis of the consistent observation of an increasing north-to-south clinical AR prevalence in Europe, this study compared the influent and final effluent of 12 UWTPs located in seven countries (Portugal, Spain, Ireland, Cyprus, Germany, Finland, and Norway). Using highly parallel quantitative polymerase chain reaction, we analyzed 229 resistance genes and 25 mobile genetic elements. This first trans-Europe surveillance showed that UWTP AR profiles mirror the AR gradient observed in clinics. Antibiotic use, environmental temperature, and UWTP size were important factors related with resistance persistence and spread in the environment. These results highlight the need to implement regular surveillance and control measures, which may need to be appropriate for the geographic regions.This work was financed by the Water JPI through the national funding agencies supporting the consortium WaterJPI/0001/2013 STARE—“Stopping Antibiotic Resistance Evolution” (Cyprus, RPF; Germany, BMBF; Spain, MINECO; Finland, AKA; Ireland, EPA; Norway, RCN; Portugal, FCT). I.V.-M. was supported by the FCT grant SFRH/BPD/87360/2012, C.N.-d.-R. by the FCT grant SFRH/BD/97131/2013, and I.H. by the FCT contract IF/00492/2013. Other funders: A grant from the Michigan State University Center for Health Impacts of Agriculture (CHIA) and the National Natural Science Foundation of China (21677149)

Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy—A Case Report

ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction