Cerebral Venous Thrombosis in the Mediterranean Area in Children

Cerebral Venous Sinus (sinovenous) Thrombosis (CSVT) is a serious and rare disorder, increasingly recognized and diagnosed in pediatric patients. The etiology and pathophisiology has not yet been completely clarified, and unlike adults with CSVT, management in children and neonates remains controversial. However, morbidity and mortality are significant, highlighting the continued need for high-quality studies within this field. The following review will highlight aspects of CSVT in the mediteranian area in children

Anxiety Detection Leveraging Mobile Passive Sensing

Anxiety disorders are the most common class of psychiatric problems affecting both children and adults. However, tools to effectively monitor and manage anxiety are lacking, and comparatively limited research has been applied to addressing the unique challenges around anxiety. Leveraging passive and unobtrusive data collection from smartphones could be a viable alternative to classical methods, allowing for real-time mental health surveillance and disease management. This paper presents eWellness, an experimental mobile application designed to track a full-suite of sensor and user-log data off an individual's device in a continuous and passive manner. We report on an initial pilot study tracking ten people over the course of a month that showed a nearly 76% success rate at predicting daily anxiety and depression levels based solely on the passively monitored features

The multi‐scale architecture of mammalian sperm flagella and implications for ciliary motility

Motile cilia are molecular machines used by a myriad of eukaryotic cells to swim through fluid environments. However, available molecular structures represent only a handful of cell types, limiting our understanding of how cilia are modified to support motility in diverse media. Here, we use cryo-focused ion beam milling-enabled cryo-electron tomography to image sperm flagella from three mammalian species. We resolve in-cell structures of centrioles, axonemal doublets, central pair apparatus, and endpiece singlets, revealing novel protofilament-bridging microtubule inner proteins throughout the flagellum. We present native structures of the flagellar base, which is crucial for shaping the flagellar beat. We show that outer dense fibers are directly coupled to microtubule doublets in the principal piece but not in the midpiece. Thus, mammalian sperm flagella are ornamented across scales, from protofilament-bracing structures reinforcing microtubules at the nano-scale to accessory structures that impose micron-scale asymmetries on the entire assembly. Our structures provide vital foundations for linking molecular structure to ciliary motility and evolution

Understanding and addressing mathematics anxiety using perspectives from education, psychology and neuroscience

Mathematics anxiety is a significant barrier to mathematical learning. In this article, we propose that state or on-task mathematics anxiety impacts on performance, while trait mathematics anxiety leads to the avoidance of courses and careers involving mathematics. We also demonstrate that integrating perspectives from education, psychology and neuroscience contributes to a greater understanding of mathematics anxiety in its state and trait forms. Research from cognitive psychology and neuroscience illustrates the effect of state mathematics anxiety on performance and research from cognitive, social and clinical psychology, and education can be used to conceptualise the origins of trait mathematics anxiety and its impact on avoidant behaviour. We also show that using this transdisciplinary framework to consider state and trait mathematics anxiety separately makes it possible to identify strategies to reduce the negative effects of mathematics anxiety. Implementation of these strategies among particularly vulnerable groups, such as pre-service teachers, could be beneficial

Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations. Methods: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. Results: We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes. Conclusion: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications

4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy

Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment

Understanding, treating, and renaming grandiose delusions : a qualitative study

Background Grandiose delusions are arguably the most neglected psychotic experience in research. Objectives We aimed to discover from patients: whether grandiose delusions have harmful consequences; the psychological mechanisms that maintain them; and what help patients may want from clinical services. Design A qualitative interview design was used to explore patients’ experiences of grandiose delusions. Method Fifteen patients with past or present experiences of grandiose delusions who were attending psychiatric services were interviewed. Thematic analysis and grounded theory were used to analyse the data. Results Participants reported physical, sexual, social, occupational, and emotional harms from grandiose delusions. All patients described the grandiose belief as highly meaningful: it provided a sense of purpose, belonging, or self‐identity, or it made sense of unusual or difficult events. The meaning from the belief was not synonymous with extreme superiority or arrogance. The meaning obtained appeared to be a key driver of the persistence of the beliefs. Other maintenance factors were subjectively anomalous experiences (e.g., voices), symptoms of mania, fantasy elaboration, reasoning biases, and immersive behaviours. Participants described insufficient opportunities to talk about their grandiose beliefs and related experiences and were generally positive about the possibility of a psychological therapy. Conclusions We conclude that grandiosity is a psychologically rich experience, with a number of maintenance factors that may be amenable to a targeted psychological intervention. Importantly, the term ‘grandiose delusion’ is an imprecise description of the experience; we suggest ‘delusions of exceptionality’ may be a credible alternative. Practitioner points -Harm from grandiose delusions can occur across multiple domains (including physical, sexual, social, occupational, and emotional) and practitioners should assess accordingly. -However, grandiose delusions are experienced by patients as highly meaningful: they provide a sense of purpose, belonging, or self‐identity, or make sense of unusual or difficult events. -Possible psychological maintenance mechanisms that could be a target for intervention include the meaning of the belief, anomalous experiences, mania, fantasy elaboration, reasoning biases, and immersive behaviours. -Patients are keen to have the opportunity to access talking therapies for this experience. Taking extra time to talk at times of distress, ‘going the extra mile’, and listening carefully can help to facilitate trust

Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.The corrigendum to this article is in ORE: http://hdl.handle.net/10871/33588Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.D.M.E. and J.K. are supported by the Office of Naval Research (ONR) Grant N000141410538. M.S. is supported by the BBSRC (BB/K006231/1), a Wellcome Trust Institutional Strategic Support Award (WT097835MF, WT105618MA), and a Marie Curie Initial Training Network (ITN) action PerFuMe (316723). M.C.V.M., J.S., H.P., C.F., T.V. and W.A.G. are supported by the NGHRI Intramural Research Program. G.R. is supported by the Kahn Family Foundation and the Israeli Centers of Excellence (I-CORE) Program (ISF grant no. 41/11)

1Identification of genes differentially expressed in the embryonic pig cerebral cortex before and after appearance of gyration

<p>Abstract</p> <p>Background</p> <p>Mammalian evolution is characterized by a progressive expansion of the surface area of the cerebral cortex, an increase that is accompanied by gyration of the cortical surface. The mechanisms controlling this gyration process are not well characterized but mutational analyses indicate that genes involved in neuronal migration play an important function. Due to the lack of gyration of the rodent brain it is important to establish alternative models to examine brain development during the gyration process. The pig brain is gyrated and accordingly is a candidate alternative model.</p> <p>Findings</p> <p>In this study we have identified genes differentially expressed in the pig cerebral cortex before and after appearance of gyration. Pig cortical tissue from two time points in development representing a non-folded, lissencephalic, brain (embryonic day 60) and primary-folded, gyrencephalic, brain (embryonic day 80) were examined by whole genome expression microarray studies. 91 differentially expressed transcripts (fold change >3) were identified. 84 transcripts were annotated and encoding proteins involved in for example neuronal migration, calcium binding, and cytoskeletal structuring. Quantitative real-time PCR was used to confirm the regulation of a subset of the identified genes.</p> <p>Conclusion</p> <p>This study provides identification of genes which are differentially expressed in the pig cerebral cortex before and after appearance of brain gyration. The identified genes include novel candidate genes which could have functional importance for brain development.</p