110 results on '"Dickinson AJ"'
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2. Realignment of the planets: Brexit and European Private International Law
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Dickinson, AJ
- Abstract
At 11pm (GMT) on 31 December 2020, the United Kingdom moved out of its orbit of the European Union's legal system, with the end of the transition period in its Withdrawal Agreement and the conclusion of the new Trade and Cooperation Agreement. This article examines the impact of this realignment on private international law, for civil and commercial matters, within the legal systems of the UK, the EU and third countries with whom the UK and the EU had established relationships before their separation. It approaches that subject from three perspectives. First, in describing the rules that will now be applied by UK courts to situations connected to the remaining EU Member States. Secondly, by examining more briefly the significance for the EU and its Member States of the change in the UK's status from Member State to third country. Thirdly, by considering the impact on the UK's and the EU's relationships with third countries, with particular reference to the 2007 Lugano Convention and Hague Choice of Court Convention. The principal focus will be on questions of jurisdiction, the recognition and enforcement of judgments and choice of law for contract and tort.
- Published
- 2021
3. The interference paradox (case comment)
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Dickinson, AJ
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Discusses the court's reasoning in SAS Institute Inc v World Programming Ltd (CA) when granting an anti-suit injunction to restrain a foreign creditor from seeking foreign court orders concerning the transfer of intangible property in the UK. Reviews the 10 steps in the court's approach, criticises its combination of national and international conflict of laws rules, and suggests why its reasoning questions traditional bases for such injunctions.
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- 2020
4. Different bone loading patterns due to fixation of three-unit and five-unit implant prostheses
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Karl, M, Winter, W, Dickinson, AJ, Wichmann, MG, and Heckmann, SM
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- 2007
5. Status check: Trustee liability to third parties in the conflict of laws
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Dickinson, AJ
- Abstract
The Privy Council’s decision in Investec Trust (Guernsey) Ltd v Glenalla Properties Ltd 1 is no advertisement for the common law. It serves to demonstrate how legal rules can apparate and take a foothold in the law without any satisfactory foundation. It also illustrates the crude nature of the tools with which judges are equipped to resolve questions of characterisation in cross-border cases. Finally, the decision highlights the curious position of the Privy Council in the United Kingdom’s constitutional structure, and leaves the law in an uncertain and unsatisfactory state.
- Published
- 2018
6. Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures
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European Group on Graves' Orbitopathy, Mourits, Mp, Bijl, H, Nardi, Marco, Altea, Ma, Pinchera, Aldo, Baldeschi, Lelio, SELLARI FRANCESCHINI, Stefano, Boboridis, K, Marcocci, Claudio, Currò, N, Dickinson, Aj, Eckstein, A, Freidel, M, Guastella, C, Kahaly, Gj, Kalmann, R, Krassas, Ge, Lane, Cm, Lareida, J, Marcocci, C, Marino', Michele, Nardi, M, Mohr, Ch, Neoh, C, Pinchera, A, Orgiazzi, J, Pitz, S, Saeed, P, Salvi, M, Sellari Franceschini, S, Stahl, M, von Arx, G, Wiersinga, W. M., Faculteit der Geneeskunde, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Guided Treatment in Optimal Selected Cancer Patients (GUTS), AII - Amsterdam institute for Infection and Immunity, Ophthalmology, Other Research, CCA -Cancer Center Amsterdam, and Endocrinology
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Adult ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Visual acuity ,Adolescent ,Decompression ,Eye disease ,Visual Acuity ,OF-LIFE QUESTIONNAIRE ,DISEASE ,Graves' ophthalmopathy ,Young Adult ,Cellular and Molecular Neuroscience ,REMOVAL ,medicine ,Humans ,Exophthalmus ,Aged ,Diplopia ,EUROPEAN GROUP ,LATERAL WALL ,biology ,business.industry ,Length of Stay ,Middle Aged ,Decompression, Surgical ,biology.organism_classification ,medicine.disease ,Sensory Systems ,Surgery ,Graves Ophthalmopathy ,Ophthalmology ,Treatment Outcome ,medicine.anatomical_structure ,Coronal plane ,Quality of Life ,Female ,OPHTHALMOPATHY ,Eyelid ,medicine.symptom ,business ,GO-QOL ,DIPLOPIA ,Orbit - Abstract
Aim: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves' orbitopathy (GO) receiving surgery for disfiguring proptosis.Method: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed.Results: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points.Conclusions: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.
- Published
- 2009
7. Management of Graves’ orbitopathy in Europe: a questionnaire survey conducted by the European Group on Graves Orbitopathy (EU.GO.GO)
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Perros, P, Baldeschi, Lelio, Boboridis, K, Dickinson, Aj, Hullo, A, Kahaly, Gj, Kendall Taylor, P, Krassas, Ge, Lane, Cm, Lazarus, Jh, Marcocci, Claudio, Mourits, Mp, Nardi, Marco, Orgiazzi, J, Pinchera, A, Pitz, S, Prummel, Mf, and Wiersinga, Wm
- Published
- 2006
8. Where do we stand with chronic prostatitis? An update.
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Khastgir J and Dickinson AJ
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- 2003
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9. Dyrk1a is required for craniofacial development in Xenopus laevis.
- Author
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Johnson HK, Wahl SE, Sesay F, Litovchick L, and Dickinson AJ
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- Animals, Branchial Region embryology, Branchial Region metabolism, Craniofacial Abnormalities genetics, Craniofacial Abnormalities embryology, Craniofacial Abnormalities metabolism, Embryo, Nonmammalian metabolism, Embryo, Nonmammalian embryology, Gene Expression Regulation, Developmental, Neural Crest embryology, Neural Crest metabolism, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases metabolism, Protein-Tyrosine Kinases genetics, Signal Transduction, Dyrk Kinases, Xenopus laevis embryology, Xenopus laevis metabolism, Xenopus Proteins metabolism, Xenopus Proteins genetics
- Abstract
Loss of function variations in the dual specificity tyrosine-phosphorylation-regulated kinase 1 A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis. Dyrk1a mRNA and protein were expressed throughout the developing head and both were enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators, sox9 and pax3 are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with variants of DYRK1A., (Published by Elsevier Inc.)
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- 2024
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10. A century of studying plant secondary metabolism-From "what?" to "where, how, and why?"
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Dixon RA and Dickinson AJ
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- History, 20th Century, History, 21st Century, Plants metabolism, Plants genetics, Secondary Metabolism genetics
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Over the past century, early advances in understanding the identity of the chemicals that collectively form a living plant have led scientists to deeper investigations exploring where these molecules localize, how they are made, and why they are synthesized in the first place. Many small molecules are specific to the plant kingdom and have been termed plant secondary metabolites, despite the fact that they can play primary and essential roles in plant structure, development, and response to the environment. The past 100 yr have witnessed elucidation of the structure, function, localization, and biosynthesis of selected plant secondary metabolites. Nevertheless, many mysteries remain about the vast diversity of chemicals produced by plants and their roles in plant biology. From early work characterizing unpurified plant extracts, to modern integration of 'omics technology to discover genes in metabolite biosynthesis and perception, research in plant (bio)chemistry has produced knowledge with substantial benefits for society, including human medicine and agricultural biotechnology. Here, we review the history of this work and offer suggestions for future areas of exploration. We also highlight some of the recently developed technologies that are leading to ongoing research advances., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)
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- 2024
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11. Pluripotency of a founding field: rebranding developmental biology.
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Rogers CD, Amemiya C, Arur S, Babonis L, Barresi M, Bartlett M, Behringer R, Benham-Pyle B, Bergmann D, Blackman B, Brown CT, Browne B, Camacho J, Chabu CY, Chow I, Cleaver O, Cool J, Dennis MY, Dickinson AJ, Di Talia S, Frank M, Gillmor S, Haag ES, Hariharan I, Harland R, Husbands A, Jerome-Majewska L, Koenig K, Labonne C, Layden M, Lowe C, Mani M, Martik M, McKown K, Moens C, Mosimann C, Onyenedum J, Reed R, Rivera A, Rokhsar D, Royer L, Rutaganira F, Shahan R, Sinha N, Swalla B, Van Norman JM, Wagner DE, Wikramanayake A, Zebell S, and Brady SM
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- Developmental Biology
- Abstract
The field of developmental biology has declined in prominence in recent decades, with off-shoots from the field becoming more fashionable and highly funded. This has created inequity in discovery and opportunity, partly due to the perception that the field is antiquated or not cutting edge. A 'think tank' of scientists from multiple developmental biology-related disciplines came together to define specific challenges in the field that may have inhibited innovation, and to provide tangible solutions to some of the issues facing developmental biology. The community suggestions include a call to the community to help 'rebrand' the field, alongside proposals for additional funding apparatuses, frameworks for interdisciplinary innovative collaborations, pedagogical access, improved science communication, increased diversity and inclusion, and equity of resources to provide maximal impact to the community., (© 2024. Published by The Company of Biologists Ltd.)
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- 2024
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12. Insights from the protein interaction Universe of the multifunctional "Goldilocks" kinase DYRK1A.
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Ananthapadmanabhan V, Shows KH, Dickinson AJ, and Litovchick L
- Abstract
Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is encoded by a dosage-dependent gene located in the Down syndrome critical region of human chromosome 21. The known substrates of DYRK1A include proteins involved in transcription, cell cycle control, DNA repair and other processes. However, the function and regulation of this kinase is not fully understood, and the current knowledge does not fully explain the dosage-dependent function of this kinase. Several recent proteomic studies identified DYRK1A interacting proteins in several human cell lines. Interestingly, several of known protein substrates of DYRK1A were undetectable in these studies, likely due to a transient nature of the kinase-substrate interaction. It is possible that the stronger-binding DYRK1A interacting proteins, many of which are poorly characterized, are involved in regulatory functions by recruiting DYRK1A to the specific subcellular compartments or distinct signaling pathways. Better understanding of these DYRK1A-interacting proteins could help to decode the cellular processes regulated by this important protein kinase during embryonic development and in the adult organism. Here, we review the current knowledge of the biochemical and functional characterization of the DYRK1A protein-protein interaction network and discuss its involvement in human disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ananthapadmanabhan, Shows, Dickinson and Litovchick.)
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- 2023
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13. Editorial overview: Tapping into the secret life of small molecules: Addressing the "dark matter" of metabolomes.
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Skirycz A and Dickinson AJ
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- Metabolome, Plants metabolism
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2023
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14. Inter-observer Variability of Clinical Activity Score: Assessments in Patients With Thyroid Eye Disease.
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Perros P, Žarković M, Pearce SH, Razvi S, Kolli H, and Dickinson AJ
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- Humans, Observer Variation, Prospective Studies, Reproducibility of Results, Graves Ophthalmopathy diagnosis
- Abstract
Purpose: Thyroid eye disease (TED) can be difficult to manage. The range of available treatments is expanding rapidly; however, cost is a concern and some patients do not respond. The Clinical Activity Score (CAS) was devised as a measure of disease activity and a potential predictor of response to anti-inflammatory treatment. Despite the widespread use of the CAS, inter-observer variability has not been investigated. The aim of the study was to determine the inter-observer variability of the CAS in patients with TED., Design: Prospective reliability analysis., Methods: Nine patients with a spectrum of clinical features of TED were assessed by 6 experienced observers on the same day. Agreement among the observers was analyzed using the Krippendorff alpha., Results: The Krippendorff alpha for the total CAS was 0.532 (95% CI = 0.199-0.665), whereas alpha values for the individual components of the CAS varied between 0.171 (CI = 0.000-0.334) for lid redness and 0.671 (CI = 0.294-1.000) for spontaneous pain. Assuming that a CAS value ≥3 implies suitability of the patient for anti-inflammatory treatment, the calculated Krippendorff alpha for agreement among assessors on whether treatment should be given or not given was 0.332 (95% CI = 0.0011-0.5862)., Conclusions: This study has shown unreliable inter-observer variability in total CAS and most individual CAS components, thus highlighting the need for improving the performance of the CAS or seeking other methods to assess activity., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)
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- 2023
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15. Non-canonical and developmental roles of the TCA cycle in plants.
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Zhang T, Peng JT, Klair A, and Dickinson AJ
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- Animals, Plants metabolism, Plant Growth Regulators metabolism, Plant Development, Citric Acid Cycle, Epigenesis, Genetic
- Abstract
Over recent years, our understanding of the tricarboxylic acid cycle (TCAC) in living organisms has expanded beyond its canonical role in cellular energy production. In plants, TCAC metabolites and related enzymes have important roles in physiology, including vacuolar function, chelation of metals and nutrients, photorespiration, and redox regulation. Research in other organisms, including animals, has demonstrated unexpected functions of the TCAC metabolites in a number of biological processes, including signaling, epigenetic regulation, and cell differentiation. Here, we review the recent progress in discovery of non-canonical roles of the TCAC. We then discuss research on these metabolites in the context of plant development, with a focus on research related to tissue-specific functions of the TCAC. Additionally, we review research describing connections between TCAC metabolites and phytohormone signaling pathways. Overall, we discuss the opportunities and challenges in discovering new functions of TCAC metabolites in plants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexandra J. Dickinson reports financial support was provided by National Institutes of Health. Alexandra J. Dickinson reports financial support was provided by National Science Foundation. Alexandra J. Dickinson reports financial support was provided by Hellman Foundation., (Copyright © 2023. Published by Elsevier Ltd.)
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- 2023
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16. Recognition of H2AK119ub plays an important role in RSF1-regulated early Xenopus development.
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Parast SM, Yu D, Chen C, Dickinson AJ, Chang C, and Wang H
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Polycomb group (PcG) proteins are key regulators of gene expression and developmental programs via covalent modification of histones, but the factors that interpret histone modification marks to regulate embryogenesis are less studied. We previously identified Remodeling and Spacing Factor 1 (RSF1) as a reader of histone H2A lysine 119 ubiquitination (H2AK119ub), the histone mark deposited by Polycomb Repressive Complex 1 (PRC1). In the current study, we used Xenopus laevis as a model to investigate how RSF1 affects early embryonic development and whether recognition of H2AK119ub is important for the function of RSF1. We showed that knockdown of Xenopus RSF1, rsf1 , not only induced gastrulation defects as reported previously, but specific targeted knockdown in prospective neural precursors induced neural and neural crest defects, with reductions of marker genes. In addition, similar to knockdown of PRC1 components in Xenopus , the anterior-posterior neural patterning was affected in rsf1 knockdown embryos. Binding of H2AK119ub appeared to be crucial for rsf1 function, as a construct with deletion of the UAB domain, which is required for RSF1 to recognize the H2AK119ub nucleosomes, failed to rescue rsf1 morphant embryos and was less effective in interfering with early Xenopus development when ectopically expressed. Furthermore, ectopic deposition of H2AK119ub on the Smad2 target gene gsc using a ring1a - smad2 fusion protein led to ectopic recruitment of RSF1. The fusion protein was inefficient in inducing mesodermal markers in the animal region or a secondary axis when expressed in the ventral tissues. Taken together, our results reveal that rsf1 modulates similar developmental processes in early Xenopus embryos as components of PRC1 do, and that RSF1 acts at least partially through binding to the H2AK119ub mark via the UAB domain during development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Parast, Yu, Chen, Dickinson, Chang and Wang.)
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- 2023
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17. Chemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development.
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Zhang T, Noll SE, Peng JT, Klair A, Tripka A, Stutzman N, Cheng C, Zare RN, and Dickinson AJ
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- Citric Acid Cycle, Diagnostic Imaging, Growth and Development, Tricarboxylic Acids, Spectrometry, Mass, Electrospray Ionization methods
- Abstract
Understanding how plants grow is critical for agriculture and fundamental for illuminating principles of multicellular development. Here, we apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to the chemical mapping of the developing maize root. This technique reveals a range of small molecule distribution patterns across the gradient of stem cell differentiation in the root. To understand the developmental logic of these patterns, we examine tricarboxylic acid (TCA) cycle metabolites. In both Arabidopsis and maize, we find evidence that elements of the TCA cycle are enriched in developmentally opposing regions. We find that these metabolites, particularly succinate, aconitate, citrate, and α-ketoglutarate, control root development in diverse and distinct ways. Critically, the developmental effects of certain TCA metabolites on stem cell behavior do not correlate with changes in ATP production. These results present insights into development and suggest practical means for controlling plant growth., (© 2023. The Author(s).)
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- 2023
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18. Immunophenotypic assessment of PNH clones in major and minor cell lineages in the peripheral blood of patients with paroxysmal nocturnal hemoglobinuria.
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Richards SJ, Dickinson AJ, Newton DJ, and Hillmen P
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- Humans, Immunophenotyping, Cell Lineage, Flow Cytometry, CD59 Antigens metabolism, Clone Cells, Hemoglobinuria, Paroxysmal
- Abstract
Background: Flow cytometric immunophenotyping is essential for the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). Most cases have easy to interpret flow cytometry profiles with red cells, neutrophils and monocytes showing complete deficiency of glycophosphatidylinositol (GPI) linked antigen expression. Some cases are more challenging to interpret due to the presence of multiple populations of PNH cells and variable levels of GPI antigen expression., Methods: We studied 46 known PNH patients, many with complex immunophenotypic profiles using a novel, single tube, multi-parameter 7-color immunophenotyping assay that allowed simultaneous detection and assessment of PNH clones within multiple lineages of peripheral blood leucocytes. Red cell PNH clones were also assessed in total and immature (CD71+) components by CD59 expression., Results: For individual patients, total PNH clones in each cell lineage were highly correlated. Monocytes, eosinophils and basophils showed the highest proportions of PNH cells. Red cell PNH clones were typically smaller than monocyte and neutrophil PNH clones. In most cases, PNH clones were detectable in minor leucocyte populations where multiple populations of PNH cells were present, variability in the proportions of type II and type III cells was seen across different cell lineages, even though total PNH clones remained similar., Conclusions: This study shows that PNH patients with multiple PNH clones do not always display the same abnormality across all cell lineages routinely tested. There is no simple explanation for this but is likely due to a combination of complex molecular, genetic and biochemical dysfunction in different blood cell types., (© 2022 International Clinical Cytometry Society.)
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- 2022
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19. UK national bladder outlet obstruction surgery snapshot audit.
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Aning JJ, Calvert RC, Harding C, Fowler S, Nitkunan T, Lee SM, McGrath JS, Cresswell J, Hagan P, Hermans L, and Dickinson AJ
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- Female, Humans, Male, Retrospective Studies, United Kingdom epidemiology, Urodynamics, Prostatic Hyperplasia complications, Transurethral Resection of Prostate methods, Urinary Bladder Neck Obstruction etiology, Urinary Bladder Neck Obstruction surgery
- Abstract
Objectives: To determine the preoperative assessment and perioperative outcomes of men undergoing bladder outlet obstruction (BOO) surgery in the UK., Patients and Methods: A retrospective cohort study was conducted of all men undergoing BOO surgery in 105 UK hospitals over a 1-month period. The study included 1456 men, of whom 42% were catheter dependent prior to undergoing surgery., Results: There was no evidence that a frequency-volume chart or urinary symptom questionnaire had been completed in 73% or 50% of men, respectively in the non-catheter-dependent group. Bipolar transurethral resection of the prostate (TURP) was the most common BOO surgical procedure performed (38%). Monopolar TURP was the next most prevalent modality (23%); however, minimally invasive BOO surgical procedures combined accounted for 17% of all procedures performed. Of the cohort 5% of men had complications within 30 days of surgery, only 1% had Clavien-Dindo Grade ≥III complications. Less than 1% of the cohort received a blood transfusion after BOO surgery and 2% were re-admitted to hospital after their BOO surgery. In total only 4% of the whole cohort were catheter dependent after BOO surgery. Pre- and postoperative paired International Prostate Symptom Score scores reviewed suggest that minimally invasive surgical procedures achieved comparable levels of improvement in both symptoms and bother at 3 months postoperatively in men who were not catheter dependent preoperatively., Conclusions: There has been a substantial shift in the available choice of procedure for BOO surgery around the UK in recent years. However, men can be reassured that overall BOO surgery treatments are safe and effective. Evidence of adherence to guidelines in the preoperative assessment of men with lower urinary tract symptoms undergoing surgery was poorly documented and must be improved., (© 2021 The Authors BJU International © 2021 BJU International.)
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- 2022
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20. A nationwide trend away from radical prostatectomy for Gleason Grade Group 1 prostate cancer.
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John JB, Pascoe J, Fowler S, Walton T, Johnson M, Challacombe B, Dickinson AJ, Aning J, and McGrath JS
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- Humans, Male, Neoplasm Grading, Prostate, Prostate-Specific Antigen, Prostatectomy, Prostatic Neoplasms surgery
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- 2022
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21. Screening for apocarotenoid plant growth regulators in Arabidopsis.
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Alagoz Y, Mi J, Al-Babili S, Dickinson AJ, and Jia KP
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- Carotenoids metabolism, Fungi metabolism, Plant Growth Regulators metabolism, Plant Growth Regulators pharmacology, Plants metabolism, Arabidopsis metabolism
- Abstract
Apocarotenoids are bioactive metabolites found in animals, fungi and plants. Several carotenoid-derived compounds, apocarotenoids, were recently identified as new growth regulators in different plant species. Here, we introduce basic chemical screening methods, using a model plant, Arabidopsis thaliana, to elucidate the function of bioactive apocarotenoids in determining plant phenotypic traits. These short guidelines include essential practices, such as selecting the plant growth conditions and the type of treatment, as well as phenotyping methodologies for the initial screening of novel apocarotenoid plant growth regulators., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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22. Imaging retinaldehyde-protein binding in plants using a merocyanine reporter.
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Luciano MP, Timilsina R, Schnermann MJ, and Dickinson AJ
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- Benzopyrans, Indoles, Plants genetics, Plants metabolism, Protein Binding, Retinaldehyde metabolism, Retinol-Binding Proteins metabolism
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Retinoid-binding proteins (RBPs) are a diverse category of proteins that have been most extensively characterized for their role in vertebrate development. Recent work has uncovered new functions of RBPs in invertebrates and plants. Here, we present a methodology for applying a fluorescent chemical probe to characterize RBP binding in plants. This reporter, called merocyanine aldehyde (MCA), fluoresces upon binding to RBPs and therefore enables in vivo investigations into their functions with high spatio-temporal resolution. MCA treatment is simple, fast, non-destructive, and does not require prior knowledge of the RBP encoding genes. Therefore, a major advantage of this methodology is that it can be performed in species that are not genetically tractable. Furthermore, many of the methods presented here apply to diverse species within and beyond the plant kingdom., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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23. A plant lipocalin promotes retinal-mediated oscillatory lateral root initiation.
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Dickinson AJ, Zhang J, Luciano M, Wachsman G, Sandoval E, Schnermann M, Dinneny JR, and Benfey PN
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- Arabidopsis genetics, Arabidopsis Proteins chemistry, Arabidopsis Proteins genetics, Fluorescence, Lipocalins chemistry, Lipocalins genetics, Meristem metabolism, Mutation, Organogenesis, Plant, Plant Roots metabolism, Protein Binding, Pyrimidinones metabolism, Retinaldehyde pharmacology, Signal Transduction, Arabidopsis growth & development, Arabidopsis metabolism, Arabidopsis Proteins metabolism, Lipocalins metabolism, Plant Roots growth & development, Retinaldehyde metabolism
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In Arabidopsis , de novo organogenesis of lateral roots is patterned by an oscillatory mechanism called the root clock, which is dependent on unidentified metabolites. To determine whether retinoids regulate the root clock, we used a chemical reporter for retinaldehyde (retinal)–binding proteins. We found that retinal binding precedes the root clock and predicts sites of lateral root organogenesis. Application of retinal increased root clock oscillations and promoted lateral root formation. Expression of an Arabidopsis protein with homology to vertebrate retinoid-binding proteins, TEMPERATURE INDUCED LIPOCALIN (TIL), oscillates in the region of retinal binding to the reporter, confers retinal-binding activity in a heterologous system, and, when mutated, decreases retinal sensitivity. These results demonstrate a role for retinal and its binding partner in lateral root organogenesis.
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- 2021
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24. The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK's population-based haematological malignancy research network 2004-2018.
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Richards SJ, Painter D, Dickinson AJ, Griffin M, Munir T, Arnold L, Payne D, Pike A, Muus P, Hill A, Newton DJ, McKinley C, Jones R, Kelly R, Smith A, Roman E, and Hillmen P
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- Adolescent, Adult, Aged, Aged, 80 and over, Anemia, Aplastic diagnosis, Anemia, Aplastic history, Biomarkers, Child, Child, Preschool, Female, Hemoglobinuria, Paroxysmal diagnosis, Hemoglobinuria, Paroxysmal history, History, 21st Century, Humans, Immunophenotyping, Incidence, Male, Middle Aged, Population Surveillance, Prevalence, Retrospective Studies, Syndrome, United Kingdom epidemiology, Young Adult, Anemia, Aplastic complications, Anemia, Aplastic epidemiology, Hemoglobinuria, Paroxysmal complications, Hemoglobinuria, Paroxysmal epidemiology
- Abstract
Objectives: A retrospective population-based study to determine the incidence and prevalence of patients with the rare blood disease paroxysmal nocturnal haemoglobinuria (PNH)., Methods: All patients were identified by flow cytometric detection of blood cells deficient in glycosylphosphatidylinositol (GPI) linked proteins at a single diagnostic reference laboratory that serves the Yorkshire based, Haematological Malignancy Research Network (HMRN) with a population of 3.8 million., Results: One hundred and ninety-seven patients with detectable PNH clones at a level of >0.01% in at least two lineages of cells (neutrophils, monocytes and/or red cells) were identified over a 15-year period (2004-2018). Of these, 88% had aplastic anaemia (AA), 8% classical PNH and 3% myelodysplastic syndrome. The overall incidence rate was estimated at 0.35 cases per 100 000 people per year. This equates to 220 cases newly diagnosed in the United Kingdom each year. The overall prevalence rate was 3.81 per 100 000, this equates to an estimated 2400 prevalent cases in the UK. The overall and relative 5-year survival rates were 72% and 82.7%, respectively., Conclusions: This study showed that classical haemolytic PNH is a rare disease and represents only a small proportion overall of patients with detectable PNH cells, the majority of which have aplastic anaemia., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2021
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25. Presentation clinical, haematological and immunophenotypic features of 1081 patients with GPI-deficient (paroxysmal nocturnal haemoglobinuria) cells detected by flow cytometry.
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Richards SJ, Dickinson AJ, Cullen MJ, Griffin M, Munir T, McKinley C, Mitchell LD, Newton DJ, Arnold L, Hill A, and Hillmen P
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- Adolescent, Adult, Aged, Aged, 80 and over, Anemia, Aplastic etiology, Anemia, Hemolytic etiology, CD55 Antigens deficiency, CD59 Antigens deficiency, Child, Child, Preschool, Clonal Evolution, Clone Cells pathology, Disease Progression, Female, Flow Cytometry, Hemoglobinuria, Paroxysmal complications, Hemoglobinuria, Paroxysmal genetics, Hemoglobinuria, Paroxysmal pathology, Humans, Immunophenotyping, Infant, Lymphocytes pathology, Male, Middle Aged, Myeloproliferative Disorders etiology, Neutrophils pathology, Receptors, Transferrin blood, Retrospective Studies, Thrombosis etiology, Young Adult, Glycosylphosphatidylinositols deficiency, Hemoglobinuria, Paroxysmal blood
- Abstract
A retrospective analysis of presentation clinical, laboratory and immunophenotypic features of 1 081 patients with paroxysmal nocturnal haemoglobinuria (PNH) clones [glycosylphosphatidylinositol (GPI)-deficient blood cells] identified at our hospital by flow cytometry over the past 25 years was undertaken. Three distinct clusters of patients were identified and significant correlations between presentation disease type and PNH clone sizes were evident. Smaller PNH clones predominate in cytopenic and myelodysplastic subtypes; large PNH clones were associated with haemolytic, thrombotic and haemolytic/thrombotic subtypes. Rare cases with an associated chronic myeloproliferative disorder had either large or small PNH clones. Cytopenia was a frequent finding, highlighting bone marrow failure as the major underlying feature associated with the detection of PNH clones in the peripheral blood. Red cell PNH clones showed significant correlations between the presence of type II (partial GPI deficiency) red cells and thrombotic disease. Haemolytic PNH was associated with type III (complete GPI deficiency) red cell populations of >20%. Those with both haemolytic and thrombotic features had major type II and type III red cell populations. Distinct patterns of presentation age decade were evident for clinical subtypes with a peak incidence of haemolytic PNH in the 30-49 year age group and a biphasic age distribution for the cytopenia group., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2020
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26. Anchorene is a carotenoid-derived regulatory metabolite required for anchor root formation in Arabidopsis .
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Jia KP, Dickinson AJ, Mi J, Cui G, Xiao TT, Kharbatia NM, Guo X, Sugiono E, Aranda M, Blilou I, Rueping M, Benfey PN, and Al-Babili S
- Subjects
- Arabidopsis genetics, Gene Expression Profiling, Indoleacetic Acids metabolism, Plant Roots genetics, Plant Shoots genetics, Arabidopsis metabolism, Carotenoids metabolism, Gene Expression Regulation, Plant physiology, Plant Roots metabolism, Plant Shoots metabolism, Signal Transduction physiology
- Abstract
Anchor roots (ANRs) arise at the root-shoot junction and are the least investigated type of Arabidopsis root. Here, we show that ANRs originate from pericycle cells in an auxin-dependent manner and a carotenogenic signal to emerge. By screening known and assumed carotenoid derivatives, we identified anchorene, a presumed carotenoid-derived dialdehyde (diapocarotenoid), as the specific signal needed for ANR formation. We demonstrate that anchorene is an Arabidopsis metabolite and that its exogenous application rescues the ANR phenotype in carotenoid-deficient plants and promotes the growth of normal seedlings. Nitrogen deficiency resulted in enhanced anchorene content and an increased number of ANRs, suggesting a role of this nutrient in determining anchorene content and ANR formation. Transcriptome analysis and treatment of auxin reporter lines indicate that anchorene triggers ANR formation by modulating auxin homeostasis. Together, our work reveals a growth regulator with potential application to agriculture and a new carotenoid-derived signaling molecule., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2019
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27. β-Cyclocitral is a conserved root growth regulator.
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Dickinson AJ, Lehner K, Mi J, Jia KP, Mijar M, Dinneny J, Al-Babili S, and Benfey PN
- Subjects
- Arabidopsis, Aldehydes pharmacology, Diterpenes pharmacology, Plant Growth Regulators pharmacology, Plant Roots drug effects, Plant Roots growth & development
- Abstract
Natural compounds capable of increasing root depth and branching are desirable tools for enhancing stress tolerance in crops. We devised a sensitized screen to identify natural metabolites capable of regulating root traits in Arabidopsis β-Cyclocitral, an endogenous root compound, was found to promote cell divisions in root meristems and stimulate lateral root branching. β-Cyclocitral rescued meristematic cell divisions in ccd1ccd4 biosynthesis mutants, and β-cyclocitral-driven root growth was found to be independent of auxin, brassinosteroid, and reactive oxygen species signaling pathways. β-Cyclocitral had a conserved effect on root growth in tomato and rice and generated significantly more compact crown root systems in rice. Moreover, β-cyclocitral treatment enhanced plant vigor in rice plants exposed to salt-contaminated soil. These results indicate that β-cyclocitral is a broadly effective root growth promoter in both monocots and eudicots and could be a valuable tool to enhance crop vigor under environmental stress., Competing Interests: Conflict of interest statement: A.J.D. and P.N.B. have filed a patent application on the use of β-cyclocitral in enhancing root growth.
- Published
- 2019
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28. Clinical and Patient-reported Outcome Measures in Men Referred for Consideration of Surgery to Treat Lower Urinary Tract Symptoms: Baseline Results and Diagnostic Findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM).
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Lewis AL, Young GJ, Abrams P, Blair PS, Chapple C, Glazener CMA, Horwood J, McGrath JS, Noble S, Taylor GT, Ito H, Belal M, Davies MC, Dickinson AJ, Foley CL, Foley S, Fulford S, Gammal MM, Garthwaite M, Harris MRE, Ilie PC, Jones R, Sabbagh S, Mason RG, McLarty E, Mishra V, Mom J, Morley R, Natale S, Nitkunan T, Page T, Payne D, Rashid TG, Saeb-Parsy K, Sandhu SS, Simoes A, Singh G, Sullivan M, Tempest HV, Viswanath S, Walker RMH, Lane JA, and Drake MJ
- Subjects
- Age Factors, Aged, Humans, Lower Urinary Tract Symptoms physiopathology, Lower Urinary Tract Symptoms surgery, Male, Middle Aged, Patient Satisfaction, Penile Erection, Prostate surgery, Surveys and Questionnaires, Lower Urinary Tract Symptoms diagnosis, Patient Reported Outcome Measures, Prostatectomy methods, Urodynamics physiology
- Abstract
Background: Clinical evaluation of male lower urinary tract symptoms (MLUTS) in secondary care uses a range of assessments. It is unknown how MLUTS evaluation influences outcome of therapy recommendations and choice, notably urodynamics (UDS; filling cystometry and pressure flow studies)., Objective: To report participants' sociodemographic and clinical characteristics, and initial diagnostic findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM). UPSTREAM is a randomised controlled trial evaluating whether symptoms are noninferior and surgery rates are lower if UDS is included., Design, Setting, and Participants: A total of 820 men (≥18 yr of age) seeking treatment for bothersome LUTS were recruited from 26 National Health Service hospital urology departments., Intervention: Care pathway based on routine, noninvasive tests (control) or routine care plus UDS (intervention arm)., Outcome Measurements and Statistical Analysis: The primary outcome is International Prostate Symptom Score (IPSS) and the key secondary outcome is surgery rates 18 mo after randomisation. International Consultation on Incontinence Questionnaires were captured for MLUTS, sexual function, and UDS satisfaction. Baseline clinical and patient-reported outcome measures (PROMs), and UDS findings were informally compared between arms. Trends across age groups for urinary and sexual PROMs were evaluated with a Cuzick's test, and questionnaire items were compared using Pearson's correlation coefficient., Results and Limitations: Storage LUTS, notably nocturia, and impaired sexual function are prominent in men being assessed for surgery. Sociodemographic and clinical evaluations were similar between arms. Overall mean IPSS and quality of life scores were 18.94 and 4.13, respectively. Trends were found across age groups, with older men suffering from higher rates of incontinence, nocturia, and erectile dysfunction, and younger men suffering from increased daytime frequency and voiding symptoms. Men undergoing UDS testing expressed high satisfaction with the procedure., Conclusions: Men being considered for surgery have additional clinical features that may affect treatment decision making and outcomes, notably storage LUTS and impaired sexual function., Patient Summary: We describe initial assessment findings from a large clinical study of the treatment pathway for men suffering with bothersome urinary symptoms who were referred to hospital for further treatment, potentially including surgery. We report the patient characteristics and diagnostic test results, including symptom questionnaires, bladder diaries, flow rate tests, and urodynamics., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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29. Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.
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Mellington FE, Dayan CM, Dickinson AJ, Hickey JL, MacEwen CJ, McLaren J, Perros P, Rose GE, Uddin J, Vaidya B, Foley P, Lazarus JH, Mitchell A, and Ezra DG
- Subjects
- Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Female, Glucocorticoids administration & dosage, Graves Ophthalmopathy epidemiology, Graves Ophthalmopathy psychology, Humans, Iodine Radioisotopes administration & dosage, Male, Middle Aged, Prospective Studies, Surveys and Questionnaires, United Kingdom, Young Adult, Graves Ophthalmopathy therapy, Health Services Accessibility statistics & numerical data, Management Audit, Patient Satisfaction statistics & numerical data
- Abstract
This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.
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- 2017
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30. Role of JNK during buccopharyngeal membrane perforation, the last step of embryonic mouth formation.
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Houssin NS, Bharathan NK, Turner SD, and Dickinson AJ
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- Adherens Junctions, Animals, Cadherins metabolism, Cheek, Endocytosis, Mouth growth & development, Pharynx, Intracellular Membranes metabolism, JNK Mitogen-Activated Protein Kinases physiology, Mouth embryology, Xenopus laevis embryology
- Abstract
Background: The buccopharyngeal membrane is a thin layer of cells covering the embryonic mouth. The perforation of this structure creates an opening connecting the external and the digestive tube which is essential for oral cavity formation. In humans, persistence of the buccopharyngeal membrane can lead to orofacial defects such as choanal atresia, oral synechiaes, and cleft palate. Little is known about the causes of a persistent buccopharyngeal membrane and, importantly, how this structure ruptures., Results: We have determined, using antisense and pharmacological approaches, that Xenopus embryos deficient c-Jun N-terminal kinase (JNK) signaling have a persistent buccopharyngeal membrane. JNK deficient embryos have decreased cell division and increased cellular stress and apoptosis. However, altering these processes independently of JNK did not affect buccopharyngeal membrane perforation. JNK deficient embryos also have increased intercellular adhesion and defects in e-cadherin localization. Conversely, embryos with overactive JNK have epidermal fragility, increased E-cadherin internalization, and increased membrane localized clathrin. In the buccopharyngeal membrane, clathrin is colocalized with active JNK. Furthermore, inhibition of endocytosis results in a persistent buccopharyngeal membrane, mimicking the JNK deficient phenotype., Conclusions: The results of this study suggest that JNK has a role in the disassembly adherens junctions by means of endocytosis that is required during buccopharyngeal membrane perforation. Developmental Dynamics 246:100-115, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2017
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31. Using frogs faces to dissect the mechanisms underlying human orofacial defects.
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Dickinson AJ
- Subjects
- Animals, Gene-Environment Interaction, Humans, Maxillofacial Development genetics, Xenopus laevis growth & development, Disease Models, Animal, Xenopus laevis genetics
- Abstract
In this review I discuss how Xenopus laevis is an effective model to dissect the mechanisms underlying orofacial defects. This species has been particularly useful in studying the understudied structures of the developing face including the embryonic mouth and primary palate. The embryonic mouth is the first opening between the foregut and the environment and is critical for adult mouth development. The final step in embryonic mouth formation is the perforation of a thin layer of tissue covering the digestive tube called the buccopharyngeal membrane. When this tissue does not perforate in humans it can pose serious health risks for the fetus and child. The primary palate forms just dorsal to the embryonic mouth and in non-amniotes it functions as the roof of the adult mouth. Defects in the primary palate result in a median oral cleft that appears similar across the vertebrates. In humans, these median clefts are often severe and surgically difficult to repair. Xenopus has several qualities that make it advantageous for craniofacial research. The free living embryo has an easily accessible face and we have also developed several new tools to analyze the development of the region. Further, Xenopus is readily amenable to chemical screens allowing us to uncover novel gene-environment interactions during orofacial development, as well as to define underlying mechanisms governing such interactions. In conclusion, we are utilizing Xenopus in new and innovative ways to contribute to craniofacial research., (Published by Elsevier Ltd.)
- Published
- 2016
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32. Xenopus as a model for developmental biology.
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Dickinson AJ and Lowery LA
- Subjects
- Animals, Developmental Biology, Humans, Models, Animal, Xenopus growth & development
- Published
- 2016
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33. Future Research in Graves' Orbitopathy: From Priority Setting to Trial Design Through Patient and Public Involvement.
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Perros P, Dayan CM, Dickinson AJ, Ezra DG, Hickey JL, Hintschisch C, Kahaly G, Lazarus JH, Ludgate M, Bartès B, MacEwen CJ, Mitchell AL, Morris D, O'Connor N, Pearce SH, Rose GE, Salvi M, Wiersinga WM, and Williamson A
- Subjects
- Clinical Trials as Topic, Humans, Graves Ophthalmopathy, Patient Participation, Research, Research Design
- Published
- 2015
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34. The role of folate metabolism in orofacial development and clefting.
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Wahl SE, Kennedy AE, Wyatt BH, Moore AD, Pridgen DE, Cherry AM, Mavila CB, and Dickinson AJ
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- Animals, Apoptosis drug effects, Biomarkers metabolism, Cartilage drug effects, Cartilage embryology, Cartilage pathology, Cell Cycle drug effects, Cell Proliferation drug effects, Cell Survival drug effects, DNA Damage, DNA Methylation drug effects, Embryo, Nonmammalian abnormalities, Embryo, Nonmammalian drug effects, Embryo, Nonmammalian pathology, Gene Expression Regulation, Developmental drug effects, Leucovorin pharmacology, Methotrexate pharmacology, Models, Biological, Morpholinos pharmacology, Mouth metabolism, Muscles drug effects, Muscles embryology, Muscles pathology, Neural Crest drug effects, Neural Crest metabolism, Oligonucleotides, Antisense pharmacology, Receptors, Retinoic Acid antagonists & inhibitors, Receptors, Retinoic Acid metabolism, Signal Transduction drug effects, Tetrahydrofolate Dehydrogenase metabolism, Tretinoin metabolism, Xenopus laevis, Cleft Palate embryology, Cleft Palate metabolism, Face embryology, Folic Acid metabolism, Mouth embryology
- Abstract
Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation. We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage. In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts. In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition. This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects., (Published by Elsevier Inc.)
- Published
- 2015
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35. A 10-year review of orbital biopsy: the Newcastle Eye Centre Study.
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Ting DS, Perez-Lopez M, Chew NJ, Clarke L, Dickinson AJ, and Neoh C
- Subjects
- Adult, Aged, Biopsy methods, Diplopia etiology, England, Female, Humans, Male, Middle Aged, Orbital Diseases physiopathology, Postoperative Complications etiology, Retrospective Studies, Visual Acuity physiology, Young Adult, Orbital Diseases pathology
- Abstract
Purpose: To review the histopathological diagnoses, visual outcome, and complication rate of orbital biopsy in a UK tertiary referral centre., Methods: This was a retrospective, clinical-pathological, interventional, consecutive case series. All orbital biopsies performed between July 2004 and June 2014 in Newcastle Eye Centre (Newcastle upon Tyne, UK) were included in this study. All relevant data collected from the local electronic database and medical records were analysed., Results: A total of 166 orbital biopsies were identified during the study period: 86 patients (53.1%) were female and the mean age was 53.7 ± 19.7 years. Of all the cases, orbital biopsies were performed unilaterally in 158 (97.5%) patients and bilaterally in 4 (2.5%) patients. The mean follow-up period was 2.2 ± 2.3 years. The two most common histopathological diagnoses were non-specific inflammatory disease (62, 38.3%) and lymphoproliferative disease (40, 24.7%). None of the patients experienced ≥ 2-Snellen line visual loss. There were 7 (4.2%) postoperative complications noted: 1 (0.6%) orbital haemorrhage with no loss of vision, 4 (2.4%) diplopia, 1 (0.6%) short-term symblepharon, and 1 (0.6%) conjunctival granuloma. Postoperative diplopia was associated with lateral orbitotomy (P = 0.044) and excisional biopsy (P = 0.015)., Conclusions: Orbital biopsy serves as a safe diagnostic tool in managing orbital diseases. Patient should be made aware of the risk of postoperative diplopia. Our data provides useful guidance to clinicians when counselling patients for orbital biopsy.
- Published
- 2015
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36. Analysis of sphingosine kinase activity in single natural killer cells from peripheral blood.
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Dickinson AJ, Meyer M, Pawlak EA, Gomez S, Jaspers I, and Allbritton NL
- Subjects
- Cells, Cultured, Enzyme Activation, Humans, Killer Cells, Natural enzymology, Phosphotransferases (Alcohol Group Acceptor) blood, Phosphotransferases (Alcohol Group Acceptor) chemistry
- Abstract
Sphingosine-1-phosphate (S1P), a lipid second messenger formed upon phosphorylation of sphingosine by sphingosine kinase (SK), plays a crucial role in natural killer (NK) cell proliferation, migration, and cytotoxicity. Dysregulation of the S1P pathway has been linked to a number of immune system disorders and therapeutic manipulation of the pathway has been proposed as a method of disease intervention. However, peripheral blood NK cells, as identified by surface markers (CD56(+)CD45(+)CD3(-)CD16) consist of a highly diverse population with distinct phenotypes and functions and it is unknown whether the S1P pathway is similarly diverse across peripheral blood NK cells. In this work, we measured the phosphorylation of sphingosine-fluorescein (SF) and subsequent metabolism of S1P fluorescein (S1PF) to form hexadecanoic acid fluorescein (HAF) in 111 single NK cells obtained from the peripheral blood of four healthy human subjects. The percentage of SF converted to S1PF or HAF was highly variable amongst the cells ranging from 0% to 100% (S1PF) and 0% to 97% (HAF). Subpopulations of cells with varying levels of S1PF formation and metabolism were readily identified. Across all subjects, the average percentage of SF converted to S1PF or HAF was 37 ± 36% and 12 ± 19%, respectively. NK cell metabolism of SF by the different subjects was also distinct with hierarchical clustering suggesting two possible phenotypes: low (<20%) or high (>50%) producers of S1PF. The heterogeneity of SK and downstream enzyme activity in NK cells may enable NK cells to respond effectively to a diverse array of pathogens as well as incipient tumor cells. NK cells from two subjects were also loaded with S1PF to assess the activity of S1P phosphatase (S1PP), which converts S1P to sphingosine. No NK cells (n = 41) formed sphingosine, suggesting that S1PP was minimally active in peripheral blood NK cells. In contrast to the SK activity, S1PP activity was homogeneous across the peripheral blood NK cells, suggesting a bias in the SK pathway towards proliferation and migration, activities supported by S1P.
- Published
- 2015
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37. Management of patients with Graves' orbitopathy: initial assessment, management outside specialised centres and referral pathways.
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Perros P, Dayan CM, Dickinson AJ, Ezra D, Estcourt S, Foley P, Hickey J, Lazarus JH, MacEwen CJ, McLaren J, Rose GE, Uddin J, and Vaidya B
- Subjects
- Graves Ophthalmopathy physiopathology, Humans, Ophthalmology methods, Practice Guidelines as Topic, Referral and Consultation, Graves Ophthalmopathy diagnosis, Graves Ophthalmopathy therapy
- Abstract
Graves' orbitopathy (GO) is uncommon, but responsible for considerable morbidity. A coordinated approach between healthcare professionals is required in order to meet the needs of patients. Early diagnosis can be achieved by a simple clinical assessment. Low-cost effective interventions can be initiated by generalists, which may improve outcomes. Moderate-to-severe GO should be referred to specialised centres. Recommendations for clinical diagnosis, initial management and referral pathways are highlighted., (© 2015 Royal College of Physicians.)
- Published
- 2015
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38. Diagnosis of Graves' orbitopathy (DiaGO): results of a pilot study to assess the utility of an office tool for practicing endocrinologists.
- Author
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Mitchell AL, Goss L, Mathiopoulou L, Morris M, Vaidya B, Dickinson AJ, Quinn A, Dayan C, McLaren J, Hickey JL, Lazarus JH, Rose GE, Foley P, MacEwen CJ, and Perros P
- Subjects
- Adolescent, Adult, Aged, Checklist, Female, Humans, Male, Middle Aged, Office Visits, Pilot Projects, Professional Practice, Young Adult, Diagnostic Techniques, Endocrine, Graves Ophthalmopathy diagnosis, Surveys and Questionnaires
- Abstract
Context: In active Graves' orbitopathy (GO), treatment can improve the final cosmetic and visual outcome. Diagnostic delay results in significant morbidity and increases patient dissatisfaction. However, it can be challenging for endocrinologists to recognize GO and decide who should be referred for ophthalmic care., Objective: DiaGO, a clinical assessment tool, was developed for use in patients with Graves' disease (GD). The tool is designed to alert clinicians to the possibility of GO and prompt early ophthalmic assessment., Design and Setting: A 20-point assessment tool was devised and tested on 104 GD patients: 27 "positive controls" with GO and 77 people with GD attending endocrine clinics over 17 months. Those scoring positively in endocrine clinics were referred for ophthalmic assessment. Both the appropriateness of the referral and subsequent treatment were assessed., Results: Eighty-eight of the 104 patients (85%) were female (mean age, 48.5 y; range, 18-76 y). All 27 "controls" scored positively. Of the 77 people evaluated with GD, 27 (35%) scored above the threshold for referral and GO was confirmed in 24/26 (92%) who attended for specialist ophthalmic assessment. Twelve of these 24 (50%) were offered specific treatment following ophthalmology review., Conclusions: The timely diagnosis of GO is important because early intervention in active disease can improve prognosis. DiaGO alerts clinicians to the possibility of GO and prompts referral to specialist ophthalmic care. It is quick and easy to use and does not require specialist ophthalmic skills. Overall, half of those referred after use of DiaGO were offered specific treatment, suggesting its use might significantly improve the management of patients.
- Published
- 2015
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39. Quantification of orofacial phenotypes in Xenopus.
- Author
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Kennedy AE and Dickinson AJ
- Subjects
- Animals, Female, Male, Phenotype, Xenopus laevis anatomy & histology, Maxillofacial Development physiology, Xenopus laevis embryology
- Abstract
Xenopus has become an important tool for dissecting the mechanisms governing craniofacial development and defects. A method to quantify orofacial development will allow for more rigorous analysis of orofacial phenotypes upon abrogation with substances that can genetically or molecularly manipulate gene expression or protein function. Using two dimensional images of the embryonic heads, traditional size dimensions-such as orofacial width, height and area- are measured. In addition, a roundness measure of the embryonic mouth opening is used to describe the shape of the mouth. Geometric morphometrics of these two dimensional images is also performed to provide a more sophisticated view of changes in the shape of the orofacial region. Landmarks are assigned to specific points in the orofacial region and coordinates are created. A principle component analysis is used to reduce landmark coordinates to principle components that then discriminate the treatment groups. These results are displayed as a scatter plot in which individuals with similar orofacial shapes cluster together. It is also useful to perform a discriminant function analysis, which statistically compares the positions of the landmarks between two treatment groups. This analysis is displayed on a transformation grid where changes in landmark position are viewed as vectors. A grid is superimposed on these vectors so that a warping pattern is displayed to show where significant landmark positions have changed. Shape changes in the discriminant function analysis are based on a statistical measure, and therefore can be evaluated by a p-value. This analysis is simple and accessible, requiring only a stereoscope and freeware software, and thus will be a valuable research and teaching resource.
- Published
- 2014
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40. Single-cell sphingosine kinase activity measurements in primary leukemia.
- Author
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Dickinson AJ, Hunsucker SA, Armistead PM, and Allbritton NL
- Subjects
- Electrophoresis, Capillary, Humans, K562 Cells, Leukemia enzymology, Phosphotransferases (Alcohol Group Acceptor) metabolism
- Abstract
Sphingosine kinase (SK) is a promising therapeutic target in a number of cancers, including leukemia. Traditionally, SK has been measured in bulk cell lysates, but this technique obscures the cellular heterogeneity present in this pathway. For this reason, SK activity was measured in single cells loaded with a fluorescent sphingosine reporter. An automated capillary electrophoresis (CE) system enabled rapid separation and quantification of the phosphorylated and nonphosphorylated sphingosine reporter in single cells. SK activity was measured in tissue-cultured cells derived from chronic myelogenous leukemia (K562), primary peripheral blood mononuclear cells (PBMCs) from three patients with different forms of leukemia, and enriched leukemic blasts from a patient with acute myeloid leukemia (AML). Significant intercellular heterogeneity existed in terms of the degree of reporter phosphorylation (as much as an order of magnitude difference), the amount of reporter uptake, and the metabolites formed. In K562 cells, the average amount of reporter converted to the phosphorylated form was 39 ± 26% per cell. Of the primary PBMCs analyzed, the average amount of phosphorylated reporter was 16 ± 25%, 11 ± 26%, and 13 ± 23% in a chronic myelogenous leukemia (CML) patient, an AML patient, and a B-cell acute lymphocytic leukemia (B-ALL) patient, respectively. These experiments demonstrated the challenge of studying samples comprised of multiple cell types, with tumor blasts present at 5 to 87% of the cell population. When the leukemic blasts from a fourth patient with AML were enriched to 99% of the cell population, 19 ± 36% of the loaded sphingosine was phosphorylated. Thus, the diversity in SK activity remained even in a nearly pure tumor sample. These enriched AML blasts loaded significantly less reporter (0.12 ± 0.2 amol) relative to that loaded into the PBMCs in the other samples (≥1 amol). The variability in SK signaling may have important implications for SK inhibitors as therapeutics for leukemia and demonstrates the value of single-cell analysis in characterizing the nature of oncogenic signaling in cancer.
- Published
- 2014
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41. Retinoic acid induced-1 (Rai1) regulates craniofacial and brain development in Xenopus.
- Author
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Tahir R, Kennedy A, Elsea SH, and Dickinson AJ
- Subjects
- Animals, Brain embryology, Brain metabolism, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, Cell Movement, Chondrogenesis, Conserved Sequence, Facial Bones embryology, Facial Bones metabolism, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Humans, Mice, Neural Crest cytology, Neural Crest metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Skull embryology, Skull metabolism, Transcription Factors chemistry, Transcription Factors genetics, Tretinoin metabolism, Xenopus genetics, Xenopus Proteins chemistry, Xenopus Proteins genetics, Xenopus laevis genetics, Transcription Factors metabolism, Xenopus embryology, Xenopus metabolism, Xenopus Proteins metabolism, Xenopus laevis embryology, Xenopus laevis metabolism
- Abstract
Retinoic acid induced-1 (RAI1) is an important yet understudied histone code reader that when mutated in humans results in Smith-Magenis syndrome (SMS), a neurobehavioral disorder accompanied by signature craniofacial abnormalities. Despite previous studies in mouse and human cell models, very little is known about the function of RAI1 during embryonic development. In the present study, we have turned to the model vertebrates Xenopus laevis and Xenopus tropicalis to better understand the developmental roles of Rai1. First we demonstrate that the Rai1 protein sequence is conserved in frogs, especially in known functional domains. By in situ hybridization we revealed expression of rai1 in the developing craniofacial tissues and the nervous system. Knockdown of Rai1 using antisense morpholinos resulted in defects in the developing brain and face. In particular, Rai1 morphants display midface hypoplasia and malformed mouth shape analogous to defects in humans with SMS. These craniofacial defects were accompanied with aberrant neural crest migration and reduction in the size of facial cartilage elements. Rai1 morphants also had defects in axon patterns and decreased forebrain ventricle size. Such brain defects correlated with a decrease in the neurotrophic factor, bdnf, and increased forebrain apoptosis. Our results emphasize a critical role of Rai1 for normal neural and craniofacial development, and further the current understanding of potential mechanisms that cause SMS., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
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42. Quantitative analysis of orofacial development and median clefts in Xenopus laevis.
- Author
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Kennedy AE and Dickinson AJ
- Subjects
- Animals, Female, Male, Cleft Palate, Maxillofacial Development physiology, Morphogenesis, Palate growth & development, Xenopus laevis growth & development
- Abstract
Xenopus has become a useful tool to study the molecular mechanisms underlying orofacial development. However, few quantitative analyses exist to describe the anatomy of this region. In this study we combine traditional facial measurements with geometric morphometrics to describe anatomical changes in the orofacial region during normal and abnormal development. Facial measurements and principal component (PC) analysis indicate that during early tadpole development the face expands primarily in the midface region accounting for the development of the upper jaw and primary palate. The mouth opening correspondingly becomes flatter and wider as it incorporates the jaw elements. A canonical variate analysis of orofacial and mouth opening shape emphasized that changes in the orofacial shape occur gradually. Orofacial anatomy was quantified after altered levels of retinoic acid using all-trans retinoic acid or an inhibitor of retinoic acid receptors or by injecting antisense oligos targeting RALDH2. Such perturbations resulted in major decreases in the width of the midface and the mouth opening illustrated in facial measurements and a PC analysis. The mouth opening shape also had a gap in the primary palate resulting in a median cleft in the mouth opening that was only illustrated quantitatively in the morphometric analysis. Finally, canonical and discriminant function analysis statistically distinguished the orofacial and mouth opening shape changes among the different modes used to alter retinoic acid signaling levels. By combining quantitative analyses with molecular studies of orofacial development we will be better equipped to understand the complex morphogenetic processes involved in palate development and clefting., (Copyright © 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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43. Facial transplants in Xenopus laevis embryos.
- Author
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Jacox LA, Dickinson AJ, and Sive H
- Subjects
- Animals, Facial Bones embryology, Facial Bones growth & development, Female, Maxillofacial Development physiology, Models, Animal, Neural Crest embryology, Neural Crest growth & development, Skull embryology, Skull growth & development, Xenopus laevis, Facial Transplantation methods
- Abstract
Craniofacial birth defects occur in 1 out of every 700 live births, but etiology is rarely known due to limited understanding of craniofacial development. To identify where signaling pathways and tissues act during patterning of the developing face, a 'face transplant' technique has been developed in embryos of the frog Xenopus laevis. A region of presumptive facial tissue (the "Extreme Anterior Domain" (EAD)) is removed from a donor embryo at tailbud stage, and transplanted to a host embryo of the same stage, from which the equivalent region has been removed. This can be used to generate a chimeric face where the host or donor tissue has a loss or gain of function in a gene, and/or includes a lineage label. After healing, the outcome of development is monitored, and indicates roles of the signaling pathway within the donor or surrounding host tissues. Xenopus is a valuable model for face development, as the facial region is large and readily accessible for micromanipulation. Many embryos can be assayed, over a short time period since development occurs rapidly. Findings in the frog are relevant to human development, since craniofacial processes appear conserved between Xenopus and mammals.
- Published
- 2014
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- View/download PDF
44. Response of single leukemic cells to peptidase inhibitor therapy across time and dose using a microfluidic device.
- Author
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Kovarik ML, Dickinson AJ, Roy P, Poonnen RA, Fine JP, and Allbritton NL
- Subjects
- Cell Survival drug effects, Dose-Response Relationship, Drug, Glycine administration & dosage, Glycine pharmacology, Humans, Hydroxamic Acids administration & dosage, Leukemia, Myeloid, Acute enzymology, Longitudinal Studies, Microscopy, Fluorescence, Protease Inhibitors administration & dosage, Regression Analysis, U937 Cells, Glycine analogs & derivatives, Hydroxamic Acids pharmacology, Leukemia, Myeloid, Acute drug therapy, Peptide Hydrolases metabolism, Protease Inhibitors pharmacology
- Abstract
Single-cell methodologies are revealing cellular heterogeneity in numerous biological processes and pathologies. For example, cancer cells are characterized by substantial heterogeneity in basal signaling and in response to perturbations, such as drug treatment. In this work, we examined the response of 678 individual U937 (human acute myeloid leukemia) cells to an aminopeptidase-inhibiting chemotherapeutic drug (Tosedostat) over the course of 95 days. Using a fluorescent reporter peptide and a microfluidic device, we quantified the rate of reporter degradation as a function of dose. While the single-cell measurements reflected ensemble results, they added a layer of detail by revealing unique degradation patterns and outliers within the larger population. Regression modeling of the data allowed us to quantitatively explore the relationships between reporter loading, incubation time, and drug dose on peptidase activity in individual cells. Incubation time was negatively correlated with the number of peptide fragment peaks observed, while peak area (which was proportional to reporter loading) was positively correlated with both the number of fragment peaks observed and the degradation rate. Notably, a statistically significant change in the number of peaks observed was identified as dose increased from 2 to 4 μM. Similarly, a significant difference in degradation rate as a function of reporter loading was observed for doses ≥2 μM compared to the 1 μM dose. These results suggest that additional enzymes may become inhibited at doses >1 μM and >2 μM, demonstrating the utility of single-cell data to yield novel biological hypotheses.
- Published
- 2014
- Full Text
- View/download PDF
45. The effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid-refractory Graves' orbitopathy.
- Author
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Mitchell AL, Gan EH, Morris M, Johnson K, Neoh C, Dickinson AJ, Perros P, and Pearce SH
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived therapeutic use, Female, Graves Ophthalmopathy therapy, Humans, Male, Methylprednisolone administration & dosage, Middle Aged, Receptors, Thyrotropin immunology, Rituximab, Treatment Outcome, Antibodies immunology, Antibodies, Monoclonal, Murine-Derived administration & dosage, B-Lymphocytes cytology, Glucocorticoids therapeutic use, Graves Ophthalmopathy immunology, Thyrotropin immunology
- Abstract
Objective: This case series documents the response of nine individuals with glucocorticoid-refractory Graves' orbitopathy (GO) to B cell depletion therapy with rituximab (RTX)., Context: Graves' disease (GD) is one of the commonest autoimmune conditions and is frequently associated with inflammatory changes around the eyes (GO). GO frequently results in significant functional visual impairment, and in the most severe cases, it can result in permanent loss of sight. RTX is a therapeutic monoclonal antibody, which targets cell-surface CD-20, resulting in depletion of circulating B lymphocytes. It has been found to be useful for the treatment of a number of autoimmune conditions including, in preliminary studies, GO., Design and Patients: We have treated nine individuals (1 male, 8 female, age range 37-87 years) with glucocorticoid-resistant GO with RTX since 2008. RTX was administered in divided doses at fortnightly intervals, following 500 mg IV methylprednisolone pretreatment., Measurements: Each patient underwent thorough assessment before and after RTX therapy, including thyroid function tests, B cell counts, thyroid autoantibody levels and detailed clinical assessment according to EUGOGO standard protocols. All patients have now been followed up for 16 months or more., Results: There was a significant reduction in thyrotropin receptor binding inhibitory immunoglobulin (TBII) levels in all patients following RTX treatment and a reduction in the clinical activity score (CAS) was seen in all cases. We also report striking improvement in pretibial thyroid dermopathy in one patient following RTX., Conclusions: This case series adds to the growing literature demonstrating that RTX, administered in our patients with concomitant methylprednisolone, is safe and clinically effective in the treatment of active, moderate to severe and sight-threatening GO. Randomized controlled trials are now needed to confirm the efficacy of RTX for GO., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
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- View/download PDF
46. Automated capillary electrophoresis system for fast single-cell analysis.
- Author
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Dickinson AJ, Armistead PM, and Allbritton NL
- Subjects
- Animals, Electrophoresis, Capillary, PC12 Cells, Rats, Tumor Cells, Cultured, Automation, Single-Cell Analysis
- Abstract
Capillary electrophoresis (CE) is a promising technique for single-cell analysis, but its use in biological studies has been limited by low throughput. This paper presents an automated platform employing microfabricated cell traps and a three-channel system for rapid buffer exchange for fast single-cell CE. Cells loaded with fluorescein and Oregon green were analyzed at a throughput of 3.5 cells/min with a resolution of 2.3 ± 0.6 for the fluorescein and Oregon green. Cellular protein kinase B (PKB) activity, as measured by immunofluorescence staining of phospho-PKB, was not altered, suggesting that this stress-activated kinase was not upregulated during the CE experiments and that basal cell physiology was not perturbed prior to cell lysis. The activity of sphingosine kinase (SK), which is often upregulated in cancer, was measured in leukemic cells by loading a sphingosine-fluorescein substrate into cells. Sphingosine fluorescein (SF), sphingosine-1-phosphate fluorescein (S1PF), and a third fluorescent species were identified in single cells. A single-cell throughput of 2.1 cells/min was achieved for 219 total cells. Eighty-eight percent of cells possessed upregulated SK activity, although subpopulations of cells with markedly different SK activity relative to that of the population average were readily identified. This system was capable of stable and reproducible separations of biological compounds in hundreds of adherent and nonadherent cells, enabling measurements of previously uncharacterized biological phenomena.
- Published
- 2013
- Full Text
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47. Micro total analysis systems: fundamental advances and applications in the laboratory, clinic, and field.
- Author
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Kovarik ML, Ornoff DM, Melvin AT, Dobes NC, Wang Y, Dickinson AJ, Gach PC, Shah PK, and Allbritton NL
- Subjects
- Equipment Design, Clinical Laboratory Techniques instrumentation, Laboratories, Microtechnology instrumentation
- Published
- 2013
- Full Text
- View/download PDF
48. Median facial clefts in Xenopus laevis: roles of retinoic acid signaling and homeobox genes.
- Author
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Kennedy AE and Dickinson AJ
- Subjects
- Aldehyde Dehydrogenase 1 Family, Aldehyde Oxidase metabolism, Animals, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Larva metabolism, Morphogenesis, Palate abnormalities, Palate embryology, Receptors, Retinoic Acid metabolism, Retinal Dehydrogenase, Signal Transduction, Xenopus Proteins metabolism, Xenopus laevis abnormalities, Xenopus laevis metabolism, Retinoic Acid Receptor gamma, Genes, Homeobox, Tretinoin metabolism, Xenopus laevis embryology
- Abstract
The upper lip and primary palate form an essential separation between the brain, nasal structures and the oral cavity. Surprisingly little is known about the development of these structures, despite the fact that abnormalities can result in various forms of orofacial clefts. We have uncovered that retinoic acid is a critical regulator of upper lip and primary palate development in Xenopus laevis. Retinoic acid synthesis enzyme, RALDH2, and retinoic acid receptor gamma (RARγ) are expressed in complementary and partially overlapping regions of the orofacial prominences that fate mapping revealed contribute to the upper lip and primary palate. Decreased RALDH2 and RARγ result in a median cleft in the upper lip and primary palate. To further understand how retinoic acid regulates upper lip and palate morphogenesis we searched for genes downregulated in response to RARγ inhibition in orofacial tissue, and uncovered homeobox genes lhx8 and msx2. These genes are both expressed in overlapping domains with RARγ, and together their loss of function also results in a median cleft in the upper lip and primary palate. Inhibition of RARγ and decreased Lhx8/Msx2 function result in decreased cell proliferation and failure of dorsal anterior cartilages to form. These results suggest a model whereby retinoic acid signaling regulates Lhx8 and Msx2, which together direct the tissue growth and differentiation necessary for the upper lip and primary palate morphogenesis. This work has the potential to better understand the complex nature of the upper lip and primary palate development which will lead to important insights into the etiology of human orofacial clefts., (Copyright © 2012. Published by Elsevier Inc.)
- Published
- 2012
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- View/download PDF
49. Orbital decompression for Graves' orbitopathy in England.
- Author
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Perros P, Chandler T, Dayan CM, Dickinson AJ, Foley P, Hickey J, Macewen CJ, Lazarus JH, McLaren J, Rose GE, Uddin JM, and Vaidya B
- Subjects
- Analysis of Variance, England, Health Services Accessibility, Hospitals, Public statistics & numerical data, Humans, Primary Health Care statistics & numerical data, Referral and Consultation statistics & numerical data, Decompression, Surgical statistics & numerical data, Graves Ophthalmopathy surgery
- Abstract
Aims: The purpose of this study was to obtain data on orbital decompression procedures performed in England, classed by hospital and locality, to evaluate regional variation in care., Methods: Data on orbital decompression taking place in England over a 2-year period between 2007 and 2009 were derived from CHKS Ltd and analysed by the hospital and primary care trust., Results and Conclusions: In all, 44% of these operations took place in hospitals with an annual workload of 10 or fewer procedures. Analysis of the same data by primary care trust suggests an almost 30-fold variance in the rates of decompression performed per unit population. Expertise available to patients with Graves' orbitopathy and rates of referral for specialist care in England appears to vary significantly by geographic location. These data, along with other outcome measures, will provide a baseline by which progress can be judged.
- Published
- 2012
- Full Text
- View/download PDF
50. Patient-specific risk of undetected malignant disease after investigation for haematuria, based on a 4-year follow-up.
- Author
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Edwards TJ, Dickinson AJ, Gosling J, McInerney PD, Natale S, and McGrath JS
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Clinical Protocols, Cystoscopy, Delayed Diagnosis, Epidemiologic Methods, Female, Humans, Male, Middle Aged, Urologic Neoplasms complications, Young Adult, Early Detection of Cancer methods, Hematuria etiology, Urologic Neoplasms diagnosis
- Abstract
Objectives: • To estimate the diagnostic accuracy of a guidelines-based haematuria clinic protocol by measuring the incidence of undetected malignancy during a follow-up period. • To estimate an individual's post-test risk of having undetected malignancy using the protocol likelihood ratio and the population prevalence of disease., Methods: • Data were collected prospectively on a cohort of 4020 consecutive patients who were referred to a 'one-stop' haematuria clinic between 1998 and 2003. • All patients had a plain radiograph taken and underwent ultrasonography and flexible cystoscopy as a part of 'first-line' investigation. • Intravenous urography was performed where indicated after abnormal first-line tests or in patients with persistent haematuria where no abnormality had been detected. • Records of the initial 687 participants from the first year of the study were reviewed 4 years after the original consultation. Missed diagnoses of urinary tract malignancy were recorded and sensitivities, likelihood ratios and the post-test probability of missing all disease and upper tract malignancy were calculated., Results: • As previously reported, the overall prevalence of malignant disease was 12.1% (18.9% for macroscopic haematuria compared with 4.8% for microscopic haematuria). • The records of the first year's cohort of patients (N = 687) were analysed 4 years after their original consultation and 10 potentially 'missed' tumours were identified. • The sensitivity of the protocol was 90.9% for the detection of all urinary tract malignancy (95% CI, 82.4 to 95.5) and 71% for upper tract tumours alone (95% CI, 45.4-88.3). The latter improves to 78.6% (95% CI, 52.4-92.4) with the addition of further upper tract testing. • The probability of missing malignant disease overall was 1.7% (95% CI, 0.95-3.04) but this rose sharply to >4% for males over 60 with macroscopic haematuria. • For those with non-visible haematuria, the percentage probability of missed malignant disease was less than 1%., Conclusions: • The haematuria clinic protocol described is robust but it is not infallible. • The risk of missing malignant disease in the higher risk groups identified in the study is much greater than previous studies would suggest. • If additional upper tract testing or interval follow-up were to be recommended, it could be rationally targeted at these groups, given the measurable risk shown here., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)
- Published
- 2011
- Full Text
- View/download PDF
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