Publications by authors named "Adam Jackson"

47 Publications

Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.

PLoS One 2021 13;16(8):e0256181. Epub 2021 Aug 13.

MRC Human Genetics Unit, IGMM, University of Edinburgh (UoE), Edinburgh, United Kingdom.

Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256181PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362966PMC
August 2021

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.

Genet Med 2021 Aug 3. Epub 2021 Aug 3.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Purpose: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort.

Methods: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays.

Results: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.

Conclusion: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.
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http://dx.doi.org/10.1038/s41436-021-01246-2DOI Listing
August 2021

Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies.

Genet Med 2021 Jul 9. Epub 2021 Jul 9.

Department of Bioinformatics & Biotechnology, Faculty of Basic and Applied Sciences, International Islamic University, Islamabad, Pakistan.

Purpose: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition.

Methods: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable.

Results: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4.

Conclusion: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.
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http://dx.doi.org/10.1038/s41436-021-01260-4DOI Listing
July 2021

Patients with symptomatic permanent atrial fibrillation show quantitative signs of pain sensitisation.

Open Heart 2021 Jun;8(1)

Department of Cardiology, Faculty of Medicine and Health, Örebro University, Sweden, Örebro, Sweden

Objective: Most patients with atrial fibrillation (AF) report symptoms, while one-third are asymptomatic. We hypothesised that sensory processing, in particular pain, differs in patients with symptomatic and asymptomatic AF.

Methods: Thirty individuals with permanent AF (15 symptomatic and 15 asymptomatic) completed the Atrial Fibrillation 6 (AF6) and short form 36 Health Survey questionnaires and underwent quantitative pain sensitisation testing using pressure algometry at the sternum (referred pain area) and the tibialis anterior muscle (generalised pain area). The primary objective was to assess differences in pressure pain thresholds (PPT), temporal summation of pain (TSP) and conditioned pain modulation (CPM) in the two groups. The secondary objective was to determine association of demographic and clinical parameters to measures of pain sensitisation.

Results: The symptomatic group had lower PPTs at both tibialis (p=0.004) and sternum (p=0.01), and impaired CPM (p=0.025) and facilitated TSP (p=0.008) at the tibialis but not sternum, compared with the asymptomatic group. The AF6 sum score was negatively correlated to PPT on both tibialis (r=-0.50, p=0.005) and sternum (r=-0.42, p=0.02) and positively correlated to TSP on both tibialis (r=0.57, p=0.001) and sternum (r=0.45, p=0.01), but not to CPM. The physical component summary score was positively correlated to the PPT on both tibialis (r=0.52, p=0.003) and sternum (r=0.40, p=0.03) and negatively to TSP on the tibialis (r=-0.53, p=0.003) but not sternum.

Conclusions: Patients with symptomatic AF exhibit lower pain tolerance than patients with asymptomatic AF, as well as impaired pain inhibitory control and facilitated summation of pain, indicating that pain sensitisation may be of importance in symptomatic AF.Trial registration numberNCT04649437.
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http://dx.doi.org/10.1136/openhrt-2021-001699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212408PMC
June 2021

Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Inserm UMR1231 team GAD, University of Burgundy and Franche-Comté, Dijon, France.

Purpose: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.

Methods: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.

Results: We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity.

Conclusion: We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.
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http://dx.doi.org/10.1038/s41436-021-01218-6DOI Listing
June 2021

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype.

Am J Med Genet A 2021 10 1;185(10):3083-3091. Epub 2021 Jun 1.

Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.
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http://dx.doi.org/10.1002/ajmg.a.62370DOI Listing
October 2021

Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.

Am J Hum Genet 2021 06 21;108(6):1069-1082. Epub 2021 May 21.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206390PMC
June 2021

Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders.

Genome Med 2021 May 21;13(1):90. Epub 2021 May 21.

Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder.

Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.

Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.

Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.
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http://dx.doi.org/10.1186/s13073-021-00900-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140440PMC
May 2021

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Am J Hum Genet 2021 03 16;108(3):502-516. Epub 2021 Feb 16.

Division of Medical Genetics, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008487PMC
March 2021

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

Input-Output Relationship of CA1 Pyramidal Neurons Reveals Intact Homeostatic Mechanisms in a Mouse Model of Fragile X Syndrome.

Cell Rep 2020 08;32(6):107988

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK; Centre for Brain Development and Repair, InStem, GKVK Campus, Bangalore 560065, India. Electronic address:

Cellular hyperexcitability is a salient feature of fragile X syndrome animal models. The cellular basis of hyperexcitability and how it responds to changing activity states is not fully understood. Here, we show increased axon initial segment length in CA1 of the Fmr1 mouse hippocampus, with increased cellular excitability. This change in length does not result from reduced AIS plasticity, as prolonged depolarization induces changes in AIS length independent of genotype. However, depolarization does reduce cellular excitability, the magnitude of which is greater in Fmr1 neurons. Finally, we observe reduced functional inputs from the entorhinal cortex, with no genotypic difference in the firing rates of CA1 pyramidal neurons. This suggests that AIS-dependent hyperexcitability in Fmr1 mice may result from adaptive or homeostatic regulation induced by reduced functional synaptic connectivity. Thus, while AIS length and intrinsic excitability contribute to cellular hyperexcitability, they may reflect a homeostatic mechanism for reduced synaptic input onto CA1 neurons.
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http://dx.doi.org/10.1016/j.celrep.2020.107988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435362PMC
August 2020

Central skull base osteomyelitis manifesting with a preclival mass and internal carotid artery mycotic aneurysm.

Radiol Case Rep 2020 Sep 4;15(9):1512-1517. Epub 2020 Jul 4.

Madigan Army Medical Center, 9040A Jackson Avenue, Tacoma WA 98431, USA.

Central skull base osteomyelitis is a rare entity that can demonstrate confounding radiologic, clinical, and laboratory data leading to a delay in diagnosis. The morbidity and mortality for skull base osteomyelitis are both high, thus a rapid diagnosis is required for appropriate treatment. In this case report, we discuss a 68-year-old male who presented with acute left facial nerve paralysis in the setting of chronic headache and left mucoid middle ear effusion. Radiologic evaluation revealed abnormal hypointense marrow of the central skull base on T1 weighted magnetic resonance imaging, preclival mass-like tissue, and short segment luminal narrowing of the left cervical ICA with mycotic aneurysm formation. Extensive workup via a multidisciplinary approach, including neurology, otolaryngology, neurosurgery and radiology led to a diagnosis of central skull base osteomyelitis. A familiarity of this disease process is important for the radiologist in order to facilitate appropriate patient referral and treatment. This case emphasizes the importance of considering this diagnosis in the setting of headache, cranial neuropathy, and abnormal skull base imaging with adjacent preclival soft tissue mass.
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http://dx.doi.org/10.1016/j.radcr.2020.05.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338986PMC
September 2020

Altered dendritic spine function and integration in a mouse model of fragile X syndrome.

Nat Commun 2019 10 23;10(1):4813. Epub 2019 Oct 23.

Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.

Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.
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http://dx.doi.org/10.1038/s41467-019-11891-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811549PMC
October 2019

Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes.

Arch Dis Child 2020 04 3;105(4):384-389. Epub 2019 Sep 3.

Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK.

Introduction: Fetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.

Methods: We reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.

Results: Seven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).

Conclusions: This study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.
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http://dx.doi.org/10.1136/archdischild-2018-316547DOI Listing
April 2020

Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability.

Orphanet J Rare Dis 2019 07 19;14(1):180. Epub 2019 Jul 19.

Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Gladstone Rd, Exeter, UK.

Background: A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature.

Methods: An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation.

Results: Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero.

Conclusion: The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.
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http://dx.doi.org/10.1186/s13023-019-1064-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642533PMC
July 2019

Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.

Sci Transl Med 2019 05;11(494)

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.

Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown. Similarly, whether a brief, early intervention can have long-lasting beneficial effects, even after treatment cessation, is also unknown. To address these questions, we first examined the developmental profile for the acquisition of associative learning in a rat model of FXS. Associative memory was tested using a range of behavioral paradigms that rely on an animal's innate tendency to explore novelty. knockout (KO) rats showed a developmental delay in their acquisition of object-place recognition and did not demonstrate object-place-context recognition paradigm at any age tested (up to 23 weeks of age). Treatment of KO rats with lovastatin between 5 and 9 weeks of age, during the normal developmental period that this associative memory capability is established, prevents the emergence of deficits but has no effect in wild-type animals. Moreover, we observe no regression of cognitive performance in the FXS rats over several months after treatment. This restoration of the normal developmental trajectory of cognitive function is associated with the sustained rescue of both synaptic plasticity and altered protein synthesis. The findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention.
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http://dx.doi.org/10.1126/scitranslmed.aao0498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162683PMC
May 2019

Lattice dynamics of the tin sulphides SnS, SnS and SnS: vibrational spectra and thermal transport.

Phys Chem Chem Phys 2017 May;19(19):12452-12465

Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.

We present an in-depth first-principles study of the lattice dynamics of the tin sulphides SnS, Pnma and π-cubic SnS and SnS. An analysis of the harmonic phonon dispersion and vibrational density of states reveals phonon bandgaps between low- and high-frequency modes consisting of Sn and S motion, respectively, and evidences a bond-strength hierarchy in the low-dimensional SnS, Pnma SnS and SnS crystals. We model and perform a complete characterisation of the infrared and Raman spectra, including temperature-dependent anharmonic linewidths calculated using many-body perturbation theory. We illustrate how vibrational spectroscopy could be used to identify and characterise phase impurities in tin sulphide samples. The spectral linewidths are used to model the thermal transport, and the calculations indicate that the low-dimensional SnS has a very low lattice thermal conductivity, potentially giving it superior performance to SnS as a candidate thermoelectric material.
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http://dx.doi.org/10.1039/c7cp01680hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450010PMC
May 2017

Correction: A universal chemical potential for sulfur vapours.

Chem Sci 2016 Oct 26;7(10):6574. Epub 2016 Aug 26.

Centre for Sustainable Chemical Technologies , Dept. of Chemistry , University of Bath , Claverton Down , Bath BA2 7AY , UK . Email: Global E3 Institute , Department of Materials Science and Engineering , Yonsei University , Seoul 120-749 , Korea.

Correction for 'A universal chemical potential for sulfur vapours' by Adam J. Jackson , , 2016, , 1082-1092.
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http://dx.doi.org/10.1039/c6sc90058eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134365PMC
October 2016

Evolutionary Connectionism: Algorithmic Principles Underlying the Evolution of Biological Organisation in Evo-Devo, Evo-Eco and Evolutionary Transitions.

Evol Biol 2016 8;43(4):553-581. Epub 2015 Dec 8.

Agents, Interactions and Complexity, ECS, University of Southampton, Southampton, UK.

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term "evolutionary connectionism" to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions.
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http://dx.doi.org/10.1007/s11692-015-9358-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119841PMC
December 2015

Computational Screening of All Stoichiometric Inorganic Materials.

Chem 2016 Oct 13;1(4):617-627. Epub 2016 Oct 13.

Department of Chemistry, Centre for Sustainable Chemical Technologies, University of Bath, Claverton Down, Bath BA2 7AY, UK; Department of Materials Science and Engineering, Global E Institute, Yonsei University, Seoul 120-749, Korea; Department of Materials, Imperial College London, Exhibition Road, London SW7 2AZ, UK.

Forming a four-component compound from the first 103 elements of the periodic table results in more than 10 combinations. Such a materials space is intractable to high-throughput experiment or first-principle computation. We introduce a framework to address this problem and quantify how many materials can exist. We apply principles of valency and electronegativity to filter chemically implausible compositions, which reduces the inorganic quaternary space to 10 combinations. We demonstrate that estimates of band gaps and absolute electron energies can be made simply on the basis of the chemical composition and apply this to the search for new semiconducting materials to support the photoelectrochemical splitting of water. We show the applicability to predicting crystal structure by analogy with known compounds, including exploration of the phase space for ternary combinations that form a perovskite lattice. Computer screening reproduces known perovskite materials and predicts the feasibility of thousands more. Given the simplicity of the approach, large-scale searches can be performed on a single workstation.
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http://dx.doi.org/10.1016/j.chempr.2016.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074417PMC
October 2016

The Mechanism by Which Arabinoxylanases Can Recognize Highly Decorated Xylans.

J Biol Chem 2016 Oct 16;291(42):22149-22159. Epub 2016 Aug 16.

From the Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom,

The enzymatic degradation of plant cell walls is an important biological process of increasing environmental and industrial significance. Xylan, a major component of the plant cell wall, consists of a backbone of β-1,4-xylose (Xylp) units that are often decorated with arabinofuranose (Araf) side chains. A large penta-modular enzyme, CtXyl5A, was shown previously to specifically target arabinoxylans. The mechanism of substrate recognition displayed by the enzyme, however, remains unclear. Here we report the crystal structure of the arabinoxylanase and the enzyme in complex with ligands. The data showed that four of the protein modules adopt a rigid structure, which stabilizes the catalytic domain. The C-terminal non-catalytic carbohydrate binding module could not be observed in the crystal structure, suggesting positional flexibility. The structure of the enzyme in complex with Xylp-β-1,4-Xylp-β-1,4-Xylp-[α-1,3-Araf]-β-1,4-Xylp showed that the Araf decoration linked O to the xylose in the active site is located in the pocket (-2* subsite) that abuts onto the catalytic center. The -2* subsite can also bind to Xylp and Arap, explaining why the enzyme can utilize xylose and arabinose as specificity determinants. Alanine substitution of Glu, Tyr, or Asn, which interact with arabinose and xylose side chains at the -2* subsite, abrogates catalytic activity. Distal to the active site, the xylan backbone makes limited apolar contacts with the enzyme, and the hydroxyls are solvent-exposed. This explains why CtXyl5A is capable of hydrolyzing xylans that are extensively decorated and that are recalcitrant to classic endo-xylanase attack.
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http://dx.doi.org/10.1074/jbc.M116.743948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063996PMC
October 2016

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

Am J Hum Genet 2016 Feb 28;98(2):363-72. Epub 2016 Jan 28.

Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK. Electronic address:

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.
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http://dx.doi.org/10.1016/j.ajhg.2015.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746363PMC
February 2016

A universal chemical potential for sulfur vapours.

Chem Sci 2016 Feb 16;7(2):1082-1092. Epub 2015 Oct 16.

Centre for Sustainable Chemical Technologies , Dept. of Chemistry , University of Bath , Claverton Down , Bath BA2 7AY , UK . Email:

The unusual chemistry of sulfur is illustrated by the tendency for catenation. Sulfur forms a range of open and closed S species in the gas phase, which has led to speculation on the composition of sulfur vapours as a function of temperature and pressure for over a century. Unlike elemental gases such as O and N, there is no widely accepted thermodynamic potential for sulfur. Here we combine a first-principles global structure search for the low energy clusters from S to S with a thermodynamic model for the mixed-allotrope system, including the Gibbs free energy for all gas-phase sulfur on an atomic basis. A strongly pressure-dependent transition from a mixture dominant in S to S is identified. A universal chemical potential function, (,), is proposed with wide utility in modelling sulfurisation processes including the formation and annealing of metal chalcogenide semiconductors.
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http://dx.doi.org/10.1039/c5sc03088aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954976PMC
February 2016

Crystal structure optimisation using an auxiliary equation of state.

J Chem Phys 2015 Nov;143(18):184101

Centre for Sustainable Chemical Technologies and Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.

Standard procedures for local crystal-structure optimisation involve numerous energy and force calculations. It is common to calculate an energy-volume curve, fitting an equation of state around the equilibrium cell volume. This is a computationally intensive process, in particular, for low-symmetry crystal structures where each isochoric optimisation involves energy minimisation over many degrees of freedom. Such procedures can be prohibitive for non-local exchange-correlation functionals or other "beyond" density functional theory electronic structure techniques, particularly where analytical gradients are not available. We present a simple approach for efficient optimisation of crystal structures based on a known equation of state. The equilibrium volume can be predicted from one single-point calculation and refined with successive calculations if required. The approach is validated for PbS, PbTe, ZnS, and ZnTe using nine density functionals and applied to the quaternary semiconductor Cu2ZnSnS4 and the magnetic metal-organic framework HKUST-1.
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http://dx.doi.org/10.1063/1.4934716DOI Listing
November 2015

Convergence of Hippocampal Pathophysiology in Syngap+/- and Fmr1-/y Mice.

J Neurosci 2015 Nov;35(45):15073-81

Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, Centre for Brain Development and Repair, inStem, Bangalore 560065, India,

Unlabelled: Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap(+/-) and Fmr1(-/y) mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap(+/-) hippocampal slices. Super-resolution microscopy reveals that Syngap(+/-) and Fmr1(-/y) mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras-ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.

Significance Statement: As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap(+/-) mice phenocopy Fmr1(-/y) mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu5 receptor-ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1(-/y) mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.
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http://dx.doi.org/10.1523/JNEUROSCI.1087-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642239PMC
November 2015

In utero exposure to valproate increases the risk of isolated cleft palate.

Arch Dis Child Fetal Neonatal Ed 2016 May 25;101(3):F207-11. Epub 2015 Sep 25.

Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, Manchester, UK.

Introduction: Orofacial clefting (OFC) has been described in infants exposed to valproic acid (VPA) prenatally, but often no distinction is made between cleft lip and palate (CLP) and isolated cleft palate (ICP). This distinction is important as these conditions have different management implications and the distinction has implications too for understanding the teratogenic mechanisms.

Methods: We searched EMBASE, Medline and Web of Science for observational studies describing OFC in association with VPA exposure. Searches for similarly exposed patients referred to a regional genetic centre and those recorded in the UK Epilepsy and Pregnancy Register (UKEPR) were undertaken. Cleft type and, where available, VPA doses prescribed were recorded.

Results: A total of 4459 cases of VPA exposure were reported in the literature in nine separate studies with 50 cases of OFC, the majority of which did not differentiate the cleft type. Eight patients ascertained through the regional genetic centre had ICP. Thirteen cases of OFC occurred in 1282 VPA monotherapy-exposed pregnancies in the UKEPR; nine had ICP and four had CLP, representing an 11.3-fold and 3.5-fold increase risk in ICP and CLP, respectively, over general population risk. Doses ranged from 200 to 2500 mg VPA daily with 73% of monotherapy ICP cases from the local cohort and UKEPR occurring at doses over 1000 mg.

Conclusion: ICP is the predominant cleft type seen in prenatal VPA exposure. Parents should be counselled appropriately and infants should undergo review after delivery for ICP. Pregnancy registers collecting information on congenital anomalies should make the distinction between CLP and ICP as the risk differs across the two conditions.
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http://dx.doi.org/10.1136/archdischild-2015-308278DOI Listing
May 2016

Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS.

Hum Mol Genet 2015 Nov 4;24(21):5977-84. Epub 2015 Aug 4.

Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India,

Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal-dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory.
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http://dx.doi.org/10.1093/hmg/ddv299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599667PMC
November 2015

Lateralized effect of pallidal stimulation on self-mutilation in Lesch-Nyhan disease.

J Neurosurg Pediatr 2014 Dec 10;14(6):594-7. Epub 2014 Oct 10.

Departments of Neurosurgery and.

Lesch-Nyhan disease (LND) is an X-linked hereditary disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase. This syndrome is characterized by hyperuricemia, self-mutilation, cognitive impairment, and movement disorders such as spasticity and dystonia. The authors describe the case of a 15-year-old boy who underwent bilateral placement of globus pallidus internus (GPi) deep brain stimulation (DBS) electrodes for the treatment of generalized dystonia. His self-mutilating behavior gradually disappeared several weeks after the start of GPi stimulation. The dystonia and self-mutilating behavior returned on the left side only after a right lead fracture. This case is the first reported instance of LND treated with DBS in which the stimulation was interrupted and the self-mutilation returned in a lateralized fashion. The findings indicate that the neurobehavioral aspect of LND is lateralized and that contralateral GPi stimulation is responsible for lateralized improvement in self-injurious behavior.
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http://dx.doi.org/10.3171/2014.8.PEDS1451DOI Listing
December 2014

Developing a grapefruit model for assessment and training of diabetic foot ulcer debridement.

Simul Healthc 2014 Oct;9(5):331-6

From the Manchester Medical School (A.J.), The University of Manchester, Manchester; Lancashire Teaching Hospitals NHS Trust (S.R.), Chorley; and University of Central Lancashire (S.R.), Preston, Lancashire, United Kingdom.

Introduction: Sharp debridement is the criterion standard treatment for diabetic foot ulcers (DFUs) and is performed by podiatrists in the United Kingdom. This study aimed to create a DFU model that could be used as a learning tool for trainees.

Methods: In a pilot study, a penny-sized circle was drawn onto an orange to simulate a DFU. This was then critiqued by podiatrists, and the feedback received was used to create a grapefruit model with irregular shape. All podiatrists supported the switch to a grapefruit model due to improved contrast between skin and fruit. This grapefruit model was then reassessed by 50 podiatrists from the North West of England. Two freely available computer programs were assessed to measure the area debrided, and a depth scale was used to determine the depth debrided. A questionnaire was completed by the podiatrists as to the utility of the model.

Results: A DFU was successfully simulated using a grapefruit and plastic template. After debridement, debrided area and depth were calculated using Image J and a depth score. Podiatrists rated this model for its utility as a training tool on a continuous rating scale with an average score of 61.9%.

Conclusions: This model has potential for development as it is inexpensive and easily accessible. This model's fidelity could be bolstered by using more accurate techniques for area and depth measurement. More research is needed to determine the superiority or inferiority of this model to previous simulated DFU models.
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http://dx.doi.org/10.1097/SIH.0000000000000046DOI Listing
October 2014

Expansion of CAG repeats in Escherichia coli is controlled by single-strand DNA exonucleases of both polarities.

Genetics 2014 Oct 31;198(2):509-17. Epub 2014 Jul 31.

Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3JR, United Kingdom

The expansion of CAG·CTG repeat tracts is responsible for several neurodegenerative diseases, including Huntington disease and myotonic dystrophy. Understanding the molecular mechanism of CAG·CTG repeat tract expansion is therefore important if we are to develop medical interventions limiting expansion rates. Escherichia coli provides a simple and tractable model system to understand the fundamental properties of these DNA sequences, with the potential to suggest pathways that might be conserved in humans or to highlight differences in behavior that could signal the existence of human-specific factors affecting repeat array processing. We have addressed the genetics of CAG·CTG repeat expansion in E. coli and shown that these repeat arrays expand via an orientation-independent mechanism that contrasts with the orientation dependence of CAG·CTG repeat tract contraction. The helicase Rep contributes to the orientation dependence of repeat tract contraction and limits repeat tract expansion in both orientations. However, RuvAB-dependent fork reversal, which occurs in a rep mutant, is not responsible for the observed increase in expansions. The frequency of repeat tract expansion is controlled by both the 5'-3' exonuclease RecJ and the 3'-5' exonuclease ExoI, observations that suggest the importance of both 3'and 5' single-strand ends in the pathway of CAG·CTG repeat tract expansion. We discuss the relevance of our results to two competing models of repeat tract expansion.
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http://dx.doi.org/10.1534/genetics.114.168245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196609PMC
October 2014
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