Case report: Dravet syndrome, feeding difficulties and gastrostomy

Dravet syndrome (DS) is a developmental and epileptic encephalopathy associated with variants in the voltage-gated sodium channel alpha 1 subunit (SCN1A) gene in around 90% of individuals. The core phenotype is well-recognized, and is characterized by seizure onset in infancy, typically with prolonged febrile seizures, followed by the emergence of multiple seizure types that are frequently drug-resistant, developmental delay, and intellectual disability. Comorbidities are common and include autism spectrum disorder, gait impairment, scoliosis, and sleep disorder. Feeding difficulties and weight loss are frequently reported by DS caregivers, and negatively impact quality of life, yet have received little attention. Here we report an adult with DS who developed reduced food and fluid intake in adolescence, resulting in weight loss and malnutrition. No underlying cause for her feeding difficulties was identified, and she subsequently required insertion of a percutaneous endoscopic gastrostomy. We review the occurrence of feeding difficulties in people with DS and discuss potential mechanisms

Generation and characterisation of anti-C6 monoclonal antibodies in C6-deficient mice : the search for an anti-C6 therapy

For the second approach, monoclonal antibodies were raised against rabbit, rat, mouse and human C6. The two most interesting antibodies were raised against human C6 and inhibited complement-mediated haemolysis in a cell-based assay. Both of these antibodies were species specific, excluding the possibility of testing their therapeutic properties in animal models of complement-mediated disease. Instead, an ex vivo model of cardiopulmonary bypass was established and used to test the ability of these antibodies to block soluble C5b-9 formation. Neither antibody inhibited soluble C5b-9 formation, suggesting that they might be interfering with the insertion of C6 into the cell membrane during MAC assembly.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Detecting transient gravitational waves in non-Gaussian noise with partially redundant analysis methods

There is a broad class of astrophysical sources that produce detectable, transient, gravitational waves. Some searches for transient gravitational waves are tailored to known features of these sources. Other searches make few assumptions about the sources. Typically events are observable with multiple search techniques. This work describes how to combine the results of searches that are not independent, treating each search as a classifier for a given event. This will be shown to improve the overall sensitivity to gravitational-wave events while directly addressing the problem of consistent interpretation of multiple trials.Comment: 11 pages, 5 figure

Cognitive Processes Associated with Sequential Tool Use in New Caledonian Crows

Background: Using tools to act on non-food objects-for example, to make other tools-is considered to be a hallmark of human intelligence, and may have been a crucial step in our evolution. One form of this behaviour, 'sequential tool use', has been observed in a number of non-human primates and even in one bird, the New Caledonian crow (Corvus moneduloides). While sequential tool use has often been interpreted as evidence for advanced cognitive abilities, such as planning and analogical reasoning, the behaviour itself can be underpinned by a range of different cognitive mechanisms, which have never been explicitly examined. Here, we present experiments that not only demonstrate new tool-using capabilities in New Caledonian crows, but allow examination of the extent to which crows understand the physical interactions involved. Methodology/Principal Findings: In two experiments, we tested seven captive New Caledonian crows in six tasks requiring the use of up to three different tools in a sequence to retrieve food. Our study incorporated several novel features: (i) we tested crows on a three-tool problem (subjects were required to use a tool to retrieve a second tool, then use the second tool to retrieve a third one, and finally use the third one to reach for food); (ii) we presented tasks of different complexity in random rather than progressive order; (iii) we included a number of control conditions to test whether tool retrieval was goal-directed; and (iv) we manipulated the subjects' pre-testing experience. Five subjects successfully used tools in a sequence (four from their first trial), and four subjects repeatedly solved the three-tool condition. Sequential tool use did not require, but was enhanced by, pre-training on each element in the sequence ('chaining'), an explanation that could not be ruled out in earlier studies. By analyzing tool choice, tool swapping and improvement over time, we show that successful subjects did not use a random probing strategy. However, we find no firm evidence to support previous claims that sequential tool use demonstrates analogical reasoning or human-like planning. Conclusions/Significance: While the ability of subjects to use three tools in sequence reveals a competence beyond that observed in any other species, our study also emphasises the importance of parsimony in comparative cognitive science: seemingly intelligent behaviour can be achieved without the involvement of high-level mental faculties, and detailed analyses are necessary before accepting claims for complex cognitive abilities.Publisher PDFPeer reviewe

Generation and characterisation of anti-C6 monoclonal antibodies in C6-deficient mice: the search for an anti-C6 therapy.

For the second approach, monoclonal antibodies were raised against rabbit, rat, mouse and human C6. The two most interesting antibodies were raised against human C6 and inhibited complement-mediated haemolysis in a cell-based assay. Both of these antibodies were species specific, excluding the possibility of testing their therapeutic properties in animal models of complement-mediated disease. Instead, an ex vivo model of cardiopulmonary bypass was established and used to test the ability of these antibodies to block soluble C5b-9 formation. Neither antibody inhibited soluble C5b-9 formation, suggesting that they might be interfering with the insertion of C6 into the cell membrane during MAC assembly

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

Likelihood-ratio ranking of gravitational-wave candidates in a non-Gaussian background

We describe a general approach to detection of transient gravitational-wave signals in the presence of non-Gaussian background noise. We prove that under quite general conditions, the ratio of the likelihood of observed data to contain a signal to the likelihood of it being a noise fluctuation provides optimal ranking for the candidate events found in an experiment. The likelihood-ratio ranking allows us to combine different kinds of data into a single analysis. We apply the general framework to the problem of unifying the results of independent experiments and the problem of accounting for non-Gaussian artifacts in the searches for gravitational waves from compact binary coalescence in LIGO data. We show analytically and confirm through simulations that in both cases the likelihood ratio statistic results in an improved analysis.Comment: 10 pages, 6 figure