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    ABSTRACT: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. European Union's Seventh Framework Programme; European Research Council.
    The Lancet Neurology 10/2013; 12(12). DOI:10.1016/S1474-4422(13)70258-8
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    ABSTRACT: Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.
    PLoS ONE 10/2013; 8(10):e77632. DOI:10.1371/journal.pone.0077632
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    ABSTRACT: Genetic testing is of increasing clinical utility for diagnosing inherited eye disease. Clarifying a clinical diagnosis is important for accurate estimation of prognosis, facilitating genetic counselling and management of families, and in the future will direct gene-specific therapeutic strategies. Often, precise diagnosis of genetic ophthalmic conditions is complicated by genetic heterogeneity, a difficulty that the so-called 'next generation sequencing' (NGS) technologies promise to overcome. Despite considerable counselling and ethical complexities, NGS offers to revolutionize clinical practice. This will necessitate considerable adjustment to standard practice but has the power to deliver a personalized approach to genomic medicine for many more patients and enhance the potential for preventing vision loss.
    Clinical and Experimental Ophthalmology 07/2013; DOI:10.1111/ceo.12159
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    ABSTRACT: The urofacial, or Ochoa, syndrome is characterised by congenital urinary bladder dysfunction together with an abnormal grimace upon smiling, laughing and crying. It can present as fetal megacystis. Postnatal features include urinary incontinence and incomplete bladder emptying due to simultaneous detrusor muscle and bladder outlet contractions. Vesicoureteric reflux is often present, and the condition can be complicated by urosepsis and end-stage renal disease. The syndrome has long been postulated to have neural basis, and it can be familial when it is inherited in an autosomal recessive manner. Most individuals with urofacial syndrome genetically studied to date carry biallelic, postulated functionally null mutations of HPSE2 or, less commonly, of LRIG2. Little is known about the biology of the respective encoded proteins, heparanase 2 and leucine-rich repeats and immunoglobulin-like domains 2. Nevertheless, the observations that heparanase 2 can bind heparan sulphate proteolgycans and inhibit heparanase 1 enzymatic activity and that LRIG2 can modulate receptor tyrosine kinase growth factor signalling each point to biological roles relevant to tissue differentiation. Moreover, both heparanase 2 and LRIG2 proteins are detected in autonomic nerves growing into fetal bladders. The collective evidence is consistent with the hypothesis that urofacial syndrome genes code for proteins which work in a common pathway to facilitate neural growth into, and/or function within, the bladder. This molecular pathway may also have relevance to our understanding of the pathogenesis of other lower tract diseases, including Hinman-Allen syndrome, or non-neurogenic neurogenic bladder, and of the subset of individuals who have primary vesicoureteric reflux accompanied by bladder dysfunction.
    Pediatric Nephrology 07/2013; 29(4). DOI:10.1007/s00467-013-2552-2
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    ABSTRACT: Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families. Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1. Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed. Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1.
    Journal of Medical Genetics 06/2013; 50(9). DOI:10.1136/jmedgenet-2013-101648
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    ABSTRACT: Mucopolysaccharidosistype IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosaminesulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments.We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LV) overexpressing SGSH in wild type (WT) hematopoietic stem cell transplants (LV-HSCT), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LV in autologous MPSIIIA HSC transplants.To improve brain expression via monocyte/microglial specificity, LV expressing eGFP under ubiquitous PGK, or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice.Eight months after HSCT, LV-PGK-coSGSH vectors produced similar bone marrow SGSH (576% normal activity) to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11% vs 7%), demonstrating improved brain specificity. LV-CD11b-coSGSHnormalized MPSIIIA behavior, brain heparan sulfate, GM2ganglioside and neuroinflammation to WT levels, whilst LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.Molecular Therapy (2013); doi:10.1038/mt.2013.141.
    Molecular Therapy 06/2013; 21(10). DOI:10.1038/mt.2013.141
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    ABSTRACT: BACKGROUND: UK genetic ophthalmology services for patients with retinal dystrophy (RD) are variable. Little research exists to define service requirements, or expectations, of patients and their families. This study aimed to explore the views and perceived benefits of genetic ophthalmology services among members of families with RD. METHODS: Twenty participants with known RD mutations were recruited through UK genetic ophthalmic clinics. Semistructured qualitative interviews explored interviewees' perceptions of the role of these services. Interviews were transcribed verbatim and analysed using inductive thematic analysis. RESULTS: Interviewees' expectations and requirements of genetic ophthalmology services were wide-ranging and often perceived to be unmet. Participant expectations were classified in three groups: (1) Medical expectations included obtaining a diagnosis and information about disease/prognosis, genetic risks and research (2) Psychosocial expectations related to participants' need for support in adjusting to RD (3) Practical expectations included the desire for information about welfare and support. CONCLUSIONS: Expectations of RD families for clinical services are complex, encompassing a range of healthcare specialties. Services that align to these expectations will need to reach beyond the diagnostic arena and provide practical and psychosocial support. The identification of measurable outcomes will facilitate future development and evaluation of service delivery models. Many of the expectations identified here map to an existing, previously validated, outcomes framework for clinical genetic services. However, an additional outcome domain, labelled 'Independence' was also identified; this could either be specific to vision loss or relate generally to disability caused by genetic conditions.
    The British journal of ophthalmology 06/2013; 97(8). DOI:10.1136/bjophthalmol-2012-302911
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    ABSTRACT: Aicardi-Goutières syndrome (AGS) is a genetically determined disorder, most particularly affecting the brain and the skin, characterized by the inappropriate induction of a type I interferon-mediated immune response. In most, but not all, cases the condition is severe, with a high associated morbidity and mortality. A number of important recent advances have helped to elucidate the biology of the AGS-related proteins, thus providing considerable insight into disease pathology. Here, we outline the clinical phenotype of AGS, paying particular attention to factors relevant to therapeutic intervention. We then discuss the pathogenesis of AGS from a molecular and cell biology perspective. Finally, we suggest possible treatment strategies in light of these emerging insights.
    Clinical & Experimental Immunology 04/2013; DOI:10.1111/cei.12115
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    ABSTRACT: BACKGROUND: The purpose of this study was to compare the incidence of iatrogenic anterior retinal breaks in 20-G vitrectomy (PPV) with transconjunctival 23-G PPV. METHODS: Retrospective, observational review study involving consecutive patients undergoing PPV in a single center in the UK during a 2-year period. RESULTS: Sclerotomy-related entry-site breaks (ESB) were found in 50/628 (7.9 %) 20-G PPV cases and 5/296 (1.7 %) 23-G PPV eyes (p < 0.0001*). Anterior non-sclerotomy iatrogenic breaks (ANSB) were present in 55/628 (8.7 %) 20-G PPV cases and 18/296 (6.1 %) 23-G PPV eyes (p = 0.19). The incidence of total anterior iatrogenic breaks (ANSB + ESB) was 105/628 (16.7 %) for 20-G PPV and 23/296 (7.8 %) for 23-G PPV (p = 0.002*). Univariate analysis showed that posterior vitreous detachment induction was the only risk factor significantly associated with the development of anterior retinal breaks for both 20-G and 23-G PPV. Multivariate logistic model of risk factors for development of iatrogenic retinal breaks demonstrated that 23-G PPV was the most important factor reducing the risk of anterior breaks (p < 0.0001*). CONCLUSIONS: We report the largest series of patients undergoing 20-G and 23-G vitrectomy, where 23-G vitrectomy was associated with a significantly lower incidence of anterior iatrogenic retinal breaks.
    Albrecht von Graæes Archiv für Ophthalmologie 03/2013; 251(6). DOI:10.1007/s00417-013-2299-2
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    ABSTRACT: INTRODUCTION: Syncytial nuclear aggregates (SNAs) are increased in pregnancy complications; however, little is known about their origin or function. This study aimed to characterise SNAs in more detail than has been reported previously. METHODS: Immunohistochemistry and morphological examination at the light and ultrastructural level were used to determine the nature and structure of SNAs. RESULTS: SNAs comprising bridges and syncytial knots had similar frequency with 974 per mm(3) of villous tissue (IQR 717-1193) and 833 per mm(3) (IQR 766-1190), respectively while there were approximately four times as many sectioning artefacts than knots and bridges combined. SNAs had increased proportions of condensed nuclei compared to the remaining syncytiotrophoblast (33.3% vs. 8.9%) and decreased proportions of euchromatic nuclei (0.0% vs. 16.2%), as assessed by examination of an electron micrograph archive. SNAs showed little evidence of apoptosis, with weak positivity for the apoptosis markers M30-neoepitope at 16.6% and TUNEL at 10.0%; strong staining was rarely seen for either marker. Immunofluorescence demonstrated rare association of actin (α, β or γ) with SNAs, whereas tubulin was in close proximity to SNAs and cytokeratin was seen within and surrounding SNAs. DISCUSSION: M30-positive SNAs traced through serial sections were significantly more likely to be syncytial knots or sectioning artefacts than bridges. Nuclei within SNAs showed signs consistent with degeneration; however, this is unlikely to be an apoptotic process. There are few changes in configuration of cytoskeletal proteins around SNAs. CONCLUSIONS: These data suggest that the biogenesis and functional significance of SNAs still require resolution.
    Placenta 03/2013; 34(5). DOI:10.1016/j.placenta.2013.02.007
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