551 results on '"Freeman, JL"'
Search Results
52. Altruistic activity: does it make a difference in the senior center?
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Williams AL, Haber D, Weaver GD, and Freeman JL
- Abstract
This study examined the effect of altruistic activity on the self-esteem and life satisfaction of participants (n = 12) at a senior center. The study was a repeated measure, crossover design, with the experimental group serving as its own control. Additional qualitative data were obtained through open-ended interview questions. Statistically significant results were found for life satisfaction change as a consequence of altruistic activity, but not from participation in recreational activity. Qualitative data suggested the altruistic activity impacted more on participant well-being than the recreational activity. [ABSTRACT FROM AUTHOR]
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- 1997
- Full Text
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53. The physiologic reservoir of Epstein-Barr virus does not map to upper aerodigestive tissues.
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Liavaag PG, Cheung RK, Kerrebijn JDF, Freeman JL, Irish JC, and Dosch H
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- 1998
54. Prognostic features in tall cell papillary carcinoma and insular thyroid carcinoma.
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van den Brekel MWM, Hekkenberg RJ, Asa SL, Tomlinson G, Rosen IB, Freeman JL, van den Brekel, M W, Hekkenberg, R J, Asa, S L, Tomlinson, G, Rosen, I B, and Freeman, J L
- Abstract
Tall cell papillary carcinoma (TCPC) and insular carcinoma (IC) are variants of thyroid carcinoma that are considered to be more aggressive than well differentiated papillary or follicular carcinoma. To determine the clinical significance of these diagnoses, we evaluated 65 patients with these tumors. There were 30 TCPCs, 27 ICs, and 8 ICs or TCPCs with focal anaplastic carcinoma (FAC). Forty-two patients (27 TCPCs, 14 ICs, and 1 FAC) are alive and free of disease. Nine patients with IC are alive with distant metastases. Ten patients (2 TCPCs, 2 ICs, and 7 FACs) died of disease. Univariate analysis of disease-free interval determined that, as for all thyroid carcinomas, patient age, tumor size, extrathyroidal extension, and lymph node metastases were significant for prognosis. ICs did significantly worse than TCPCs. Focal anaplastic dedifferentiation predicted a worse prognosis. Multivariate analysis for disease-free interval showed age, number of lymph node metastases, and tumor type to be significant. Analysis of the same factors for prediction of mortality showed that TCPC and IC were not significantly different. These data suggest that TCPC is less aggressive than IC, which often results in disseminated disease. Focal AC predicts poor survival. [ABSTRACT FROM AUTHOR]
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- 1997
55. Cause of death in patients with well-differentiated thyroid carcinoma.
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Beasley NJP, Walfish PG, Witterick I, and Freeman JL
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- 2001
56. Public health briefs. Geographic variations in breast cancer mortality: do higher rates imply elevated incidence or poorer survival?
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Goodwin JS, Freeman JL, Freeman D, and Nattinger AB
- Abstract
OBJECTIVES: Mortality rates from breast cancer are approximately 25% higher for women in the northeastern United States than for women in the South or West. This study examined the hypothesis that the elevation is due to decreased survival rather than increased incidence. METHODS: Data on breast cancer incidence, treatment, and mortality were reviewed. RESULTS: The elevated mortality in the Northeast is apparent only in older women. For women aged 65 years and older, breast cancer mortality is 26% higher in New England than in the South, while incidence is only 3% higher. Breast cancer mortality for older women by state correlates poorly with incidence (r = 0.28). CONCLUSIONS: Those seeking to explain the excess breast cancer mortality in the Northeast should assess survival and should examine differences in cancer control practices that affect survival. [ABSTRACT FROM AUTHOR]
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- 1998
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57. MR Imaging and Spectroscopic Study of Epileptogenic Hypothalamic Hamartomas: Analysis of 72 Cases
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Freeman, Jl, Coleman, Lt, Wellard, Rm, Kean, Mj, Rosenfeld, Jv, Graeme Jackson, Berkovic, Sf, and Harvey, As
58. Temporal and regional variation in the use of breast-conserving surgery and radiotherapy for older women with early-stage breast cancer from 1983 to 1995.
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Du X, Freeman JL, Freeman DH, Syblik DA, Goodwin JS, Du, X, Freeman, J L, Freeman, D H, Syblik, D A, and Goodwin, J S
- Abstract
Background: Authorities recommend radiation therapy after breast-conserving surgery for breast cancer. Numerous studies have reported that older women diagnosed with breast cancer are less likely to receive radiation after breast-conserving surgery. It is unclear how care of older women with breast cancer has changed over time.Methods: Women with local or regional stage breast cancer diagnosed between 1983-1995 were identified from the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries. The treatment information in SEER includes type of surgical procedures and receipt of radiation therapy.Results: There were small increases in the percentage of women receiving breast-conserving surgery during the 1980s followed by substantial increases in the 1990s. Age was a major factor in determining receipt of radiation therapy after breast-conserving surgery. A large increase in use of radiotherapy after surgery was observed in women aged > or = 75, from below 30% in 1983 to over 50% in 1995. Women aged > or = 75 diagnosed in 1992-1995 were 1.76 and 2.34 times more likely to receive radiation for local and regional stage respectively, as compared to those in 1983-1987. There was no increase in use of radiation for women aged < 65.Conclusions: There has been a substantial increase in use of breast-conserving surgery and in receipt of radiation therapy after breast-conserving surgery in older women. However, there was a net increase in the percentage of all women with breast cancer who received this surgery without radiotherapy, due to the large increase in the overall percentage of women receiving this surgery. [ABSTRACT FROM AUTHOR]- Published
- 1999
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59. Risk of fracture after androgen deprivation for prostate cancer.
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Shahinian VB, Kuo Y, Freeman JL, Goodwin JS, Shahinian, Vahakn B, Kuo, Yong-Fang, Freeman, Jean L, and Goodwin, James S
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Background: The use of androgen-deprivation therapy for prostate cancer has increased substantially over the past 15 years. This treatment is associated with a loss of bone-mineral density, but the risk of fracture after androgen-deprivation therapy has not been well studied.Methods: We studied the records of 50,613 men who were listed in the linked database of the Surveillance, Epidemiology, and End Results program and Medicare as having received a diagnosis of prostate cancer in the period from 1992 through 1997. The primary outcomes were the occurrence of any fracture and the occurrence of a fracture resulting in hospitalization. Cox proportional-hazards analyses were adjusted for characteristics of the patients and the cancer, other cancer treatment received, and the occurrence of a fracture or the diagnosis of osteoporosis during the 12 months preceding the diagnosis of cancer.Results: Of men surviving at least five years after diagnosis, 19.4 percent of those who received androgen-deprivation therapy had a fracture, as compared with 12.6 percent of those not receiving androgen-deprivation therapy (P<0.001). In the Cox proportional-hazards analyses, adjusted for characteristics of the patient and the tumor, there was a statistically significant relation between the number of doses of gonadotropin-releasing hormone received during the 12 months after diagnosis and the subsequent risk of fracture.Conclusions: Androgen-deprivation therapy for prostate cancer increases the risk of fracture. [ABSTRACT FROM AUTHOR]- Published
- 2005
60. The challenge of repurposed technologies for youth: Understanding the unique affordances of digital self-tracking for adolescents
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Jaimie L. Freeman, Gina Neff, Freeman, JL [0000-0002-2984-5774], Neff, G [0000-0001-9090-924X], and Apollo - University of Cambridge Repository
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Social comparison theory ,digital technologies ,Sociology and Political Science ,Adolescent ,Communication ,school ,affordances ,Self tracking ,Human–computer interaction ,social comparison ,self-tracking in everyday life ,survey ,Affordance ,Psychology ,self-tracking - Abstract
Adults’ digital self-tracking practices are relatively well studied, but these pre-existing models of digital self-tracking do not fit for how adolescents use these technologies. We apply the mechanisms-and-conditions framework of affordance theory to examine adolescents’ imagined affordances of self-tracking apps and devices. Based on qualitative data from an online survey of 16- to 18-year-olds in the United Kingdom, we find the following three key themes in how adolescents imagine the affordances of digital self-tracking: (1) the variability of use across adolescents and with adults, (2) the role of the social control of data in school settings, and (3) the salience of social comparisons among their peers. Using these findings, we show how social and institutional configurations come to matter for technological affordances. By examining adolescents’ imagined affordances for self-tracking, we suggest self-tracking research move away from a “one size fits all approach” and begin to highlight the differences in practices from adults and across adolescents.
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- 2021
61. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature
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Delphine Breuillard, Isabelle Marey, Claire Bar, Tayeb Sekhara, Candace T. Myers, Diane Doummar, Alice Poisson, Hervé Isnard, Nathalie Dorison, Gwenaël Le Guyader, Arnold Munnich, Alexandra Afenjar, Anne de Saint Martin, Jamel Chelly, Gaetan Lesca, Gaetano Terrone, Rima Nabbout, Jeremy L. Freeman, David Geneviève, Sophie Dupont, Cyril Mignot, Katherine B. Howell, Giulia Barcia, Melanie Jennesson, Patrick Berquin, Sylvie Odent, Boris Keren, Ingrid E. Scheffer, Renzo Guerrini, Emmanuel Scalais, Thierry Billette de Villemeur, Martino Montomoli, Agnès Guët, Pierre Meyer, Anca Nica, Anne-Sophie Lebre, Edor Kabashi, Carla Marini, Amy L Schneider, Marion Gérard, Salima El Chehadeh, Heather C Mefford, Lynette G. Sadleir, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), American Memorial Hospital, Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Melbourne, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), A Meyer Children's Hospital, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Amiens-Picardie, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Hôpital de Hautepierre [Strasbourg], Hôpitaux Universitaires de Strasbourg, Hôpital Louis-Mourier, Colombes, France., Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Rothschild Foundation Hospital, Paris., University of Washington [Seattle], Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia., A.Meyer Children's Hospital, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Section of Pediatrics-Child Neurology Unit, Federico II University, 80131, Naples, Italy, Centre Hospitalier Interrégional Edith Cavell (CHIREC), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CLAD-Ouest, CHU Rennes, France., University of Otago [Dunedin, Nouvelle-Zélande], Pediatric Neurology & Neurogenetics Unit and Laboratories, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, Epilepsy Research Centre, The Florey Institute of Neurosciences and Mental Health, Heidelberg, Victoria, Australia., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], H2020 European Research Council, Health Research Council of New Zealand, Agence Nationale de la Recherche, Seventh Framework Programme, Fondation Bettencourt Schueller, European Research Council, Bar, C, Barcia, G, Jennesson, M, Le Guyader, G, Schneider, A, Mignot, C, Lesca, G, Breuillard, D, Montomoli, M, Keren, B, Doummar, D, de Villemeur, Tb, Afenjar, A, Marey, I, Gerard, M, Isnard, H, Poisson, A, Dupont, S, Berquin, P, Meyer, P, Genevieve, D, De Saint Martin, A, El Chehadeh, S, Chelly, J, Guët, A, Scalais, E, Dorison, N, Myers, Ct, Mefford, Hc, Howell, Kb, Marini, C, Freeman, Jl, Nica, A, Terrone, G, Sekhara, T, Lebre, A, Odent, S, Sadleir, Lg, Munnich, A, Guerrini, R, Scheffer, Ie, Kabashi, E, Nabbout, R, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [APHP], Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Armand Trousseau, Hôpital Armand Trousseau, Paris, France., Centre de Référence déficiences intellectuelles de causes rares, GH Pitie-Salpêtrière-Charles Foix, F-, 75013, Paris, France., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier de Luxembourg, C.H.I.R.E.C, Brussels, Belgium., Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Children's Hospital A. Meyer-University of Florence (UNIFI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Naples Federico II = Università degli studi di Napoli Federico II, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Children's Hospital A. Meyer-Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière]
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Genotype ,[SDV]Life Sciences [q-bio] ,Biology ,Structure-Activity Relationship ,03 medical and health sciences ,Epilepsy ,Shab Potassium Channels ,KCNB1 ,Intellectual disability ,Genetic variation ,Genetics ,medicine ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Allele ,developmental and epileptic encephalopathy ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,030305 genetics & heredity ,Genetic Variation ,medicine.disease ,Axon initial segment ,Phenotype ,Neurodevelopmental Disorders ,epilepsy ,potassium channel - Abstract
International audience; Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the alpha subunit of the delayed-rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.
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- 2020
62. De novo SCN1A mutations in migrating partial seizures of infancy
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Samuel F. Berkovic, David R. Thorburn, L. Hamiwka, Arvid Suls, Heather C Mefford, P. De Jonghe, Leanne M. Dibbens, B. Appleton, Todor Arsov, Mark T Mackay, Elaine C. Wirrell, Simone C. Yendle, Ingrid E. Scheffer, Tommy Stödberg, Thierry Bienvenu, Jeremy L. Freeman, Kent Kelley, Jacinta M McMahon, John C. Mulley, D. Carranza Rojo, Rojo, D Carranza, Hamiwka, L, McMahon, JM, Dibbens, LM, Arsov, T, Suls, A, Stodberg, T, Kelley, K, Wirrell, E, Appleton, B, Mackay, M, Freeman, JL, Yendle, SC, Berkovic, SF, Bienvenu, T, De Jonghe, P, Thorburn, DR, Mulley, JC, Mefford, HC, and Scheffer, IE
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Male ,Pathology ,medicine.medical_specialty ,DNA Copy Number Variations ,CDKL5 ,Nerve Tissue Proteins ,DNA-Directed DNA Polymerase ,Protein Serine-Threonine Kinases ,Biology ,Bioinformatics ,Sodium Channels ,Epilepsy ,Munc18 Proteins ,Dravet syndrome ,Convulsion ,medicine ,Humans ,STXBP1 ,Missense mutation ,Genetic Predisposition to Disease ,Genetic Testing ,Copy-number variation ,Child ,Genetic testing ,severe infantile multifocal epilepsy ,medicine.diagnostic_test ,copy number variation ,Infant ,Articles ,Cadherins ,medicine.disease ,Protocadherins ,DNA Polymerase gamma ,NAV1.1 Voltage-Gated Sodium Channel ,epileptic encephalopathy ,Child, Preschool ,Mutation ,Female ,Human medicine ,Epilepsies, Partial ,Neurology (clinical) ,medicine.symptom - Abstract
Objective: To determine the genetic etiology of the severe early infantile onset syndrome of malignant migrating partial seizures of infancy (MPSI). Methods: Fifteen unrelated children with MPSI were screened for mutations in genes associated with infantile epileptic encephalopathies: SCN1A, CDKL5, STXBP1, PCDH19, and POLG. Microarray studies were performed to identify copy number variations. Results: One patient had a de novo SCN1A missense mutation p.R862G that affects the voltage sensor segment of SCN1A. A second patient had a de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screening of CDKL5 (13/15 patients), STXBP1 (13/15), PCDH19 (9/11 females), and the 3 common European mutations of POLG (11/15) was negative. Pathogenic copy number variations were not detected in 11/12 cases. Conclusion: Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet syndrome and severe infantile multifocal epilepsy. MPSI is now the most severe SCN1A phenotype described to date. While not a common cause of MPSI, SCN1A screening should now be considered in patients with this devastating epileptic encephalopathy. GLOSSARY: CNV: copy number variation EE: epileptic encephalopathy MPSI: malignant migrating partial seizures of infancy SIMFE: severe infantile multifocal epilepsy.
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- 2011
63. Cerebral Vascular Toxicity after Developmental Exposure to Arsenic (As) and Lead (Pb) Mixtures.
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Kiper K, Mild B, Chen J, Yuan C, Wells EM, Zheng W, and Freeman JL
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Arsenic (As) and lead (Pb) are environmental pollutants found in common sites linked to similar adverse health effects. This study determined driving factors of neurotoxicity on the developing cerebral vasculature with As and Pb mixture exposures. Cerebral vascular toxicity was evaluated at mixture concentrations of As and Pb representing human exposures levels (10 or 100 parts per billion; ppb; µg/L) in developing zebrafish by assessing behavior, morphology, and gene expression. In the visual motor response assay, hyperactivity was observed in all three outcomes in dark phases in larvae with exposure (1-120 h post fertilization, hpf) to 10 ppb As, 10 ppb Pb, or 10 ppb mix treatment. Time spent moving exhibited hyperactivity in dark phases for 100 ppb As and 100 ppb mix treatment groups only. A decreased brain length and ratio of brain length to total length in the 10 ppb mix group was measured with no alterations in other treatment groups or other endpoints (i.e., total larval length, head length, or head width). Alternatively, measurements of cerebral vasculature in the midbrain and cerebellum uncovered decreased total vascularization at 72 hpf in all treatment groups in the mesencephalon and in all treatment groups, except the 100 ppb Pb and 10 ppb As groups, in the cerebellum. In addition, decreased sprouting and branching occurred in the mesencephalon, while only decreased branching was measured in the cerebellum. The 10 ppb Pb group showed several cerebral vasculature modifications that were aligned with a specific gene expression alteration pattern different from other treatment groups. Additionally, the 100 ppb As group drove gene alterations, along with several other endpoints, for changes observed in the 100 ppb mix treatment group. Perturbations assessed in this study displayed non-linear concentration-responses, which are important to consider in environmental health outcomes for As and Pb neurotoxicity.
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- 2024
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64. Developmental neurotoxicity of PFOA exposure on hiPSC-derived cortical neurons.
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Wu S, Xie J, Zhao H, Zhao X, Sánchez OF, Rochet JC, Freeman JL, and Yuan C
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- Humans, Cerebral Cortex drug effects, Cerebral Cortex pathology, Transcriptome drug effects, Neurons drug effects, Fluorocarbons toxicity, Caprylates toxicity, Induced Pluripotent Stem Cells drug effects, Cell Differentiation drug effects
- Abstract
PFOA is a legacy Per- and Polyfluorinated Substances (PFAS), a group of chemicals widely used in various industrial applications and consumer products. Although there has been a voluntary phase out of PFOA since 2005, it is still widely detected in various water supplies. A growing body of evidence suggests an association between PFOA exposure, particularly during developmental stages, with increased risks of neurodegenerative diseases (NDs). The neurotoxic mechanism of developmental PFOA exposure, however, remains poorly understood. Utilizing human induced-pluripotent stem cell (hiPSC)-derived cortical neurons, we investigated the effect of PFOA exposure prior to differentiation and assessed changes in neuronal characteristics, transcriptome, and neurodegeneration markers mimicking a Developmental Origin of Health and Disease (DoHAD) paradigm. Exposure to PFOA before neuron differentiation resulted in persistent alterations in nuclear morphology, neuronal network, and calcium activity. RNA sequencing analysis further revealed transcriptomic changes aligning with Alzheimer's Disease (AD) after PFOA exposure. These observations were further corroborated by alterations in tau phosphorylation markers, the presence of fibrillar tau, an increase in liquid droplets, and a decrease in RNA translational efficiency characterized using a battery of biochemical assays. Taken together, our results revealed persistent deficits of key neuronal characteristics induced by pre-differentiation PFOA exposure, suggesting impairments in several AD-related pathways that can together contribute to the elevation of AD risk after pre-differentiation PFOA exposure., 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., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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65. Corrigendum to "Elevated parkinsonism pathological markers in dopaminergic neurons with developmental exposure to atrazine" [Sci. Total Environ. 908 2024: Article 168307].
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Zhao H, Xie J, Wu S, Zhao X, Sánchez OF, Min S, Dutta S, Rochet JC, Freeman JL, and Yuan C
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- 2024
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66. The impact of libraries and informationists on patient and population care: a mixed-methods study.
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Shannon C, Freeman JL, MacEachern M, Rana GK, Smith C, Smith JE, and Song J
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- Humans, Library Services organization & administration, Library Services statistics & numerical data, Patient Care, Surveys and Questionnaires, Female, Libraries, Medical organization & administration, Librarians
- Abstract
Objective: While several studies have examined the effectiveness of librarian interactions with clinicians and impact of librarians on patient care, no studies have explored a library's effects on population care. The goal of this study was to investigate the library's impact on both patient and population care., Methods: Using a sequential exploratory mixed-methods design, we first interviewed a small set of clinicians and researchers active in patient and population care. Based on the themes that we discovered through coding the interviews, we created a survey that was sent to faculty in the health sciences and the health system., Results: We collected data from a representative sample of our population. We discovered that all respondents value the library and informationists, using our services most for teaching, publishing, presenting, and professional development., Conclusion: We now have data to support our value to our population and to show where we can do more work to improve the use of our services. Our study shows the value of doing a mixed-methods sequential exploration in which themes that are important to our user community were identified prior to launching a large-scale survey., (Copyright © 2024 Carol Shannon, Jacqueline L. Freeman, Mark MacEachern, Gurpreet K. Rana, Craig Smith, Judith E. Smith, Jean Song.)
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- 2024
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67. Elevated parkinsonism pathological markers in dopaminergic neurons with developmental exposure to atrazine.
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Zhao H, Xie J, Wu S, Zhao X, Sánchez OF, Min S, Rochet JC, Freeman JL, and Yuan C
- Subjects
- Humans, Dopaminergic Neurons, Atrazine toxicity, Induced Pluripotent Stem Cells, Herbicides toxicity, Parkinson Disease
- Abstract
Atrazine (ATZ) is one of the most used herbicides in the US and a known endocrine disruptor. ATZ is frequently detected in drinking water, especially in Midwestern regions of the United States, exceeding the EPA regulation of maximum contamination level (MCL) of 3 ppb. Epidemiology studies have suggested an association between ATZ exposure and neurodegeneration. Less, however, is known about the neurotoxic mechanism of ATZ, particularly for exposures at a developmental stage. Here, we exposed floor plate progenitors (FPPs) derived from human induced pluripotent stem cells (hiPSCs) to low concentrations of ATZ at 0.3 and 3 ppb for two days followed by differentiation into dopaminergic (DA) neurons in ATZ-free medium. We then examined the morphology, activity, pathological protein aggregation, and transcriptomic changes of differentiated DA neurons. We observed significant decrease in the complexity of neurite network, increase of neuronal activity, and elevated tau- and α-synuclein (aSyn) pathologies after ATZ exposure. The ATZ-induced neuronal changes observed here align with pathological characteristics in Parkinson's disease (PD). Transcriptomic analysis further corroborates our findings; and collectively provides a strong evidence base that low-concentration ATZ exposure during development can elicit increased risk of neurodegeneration., 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2024
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68. Differential Developmental Neurotoxicity and Tissue Uptake of the Per- and Polyfluoroalkyl Substance Alternatives, GenX and PFBS.
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Wasel O, King H, Choi YJ, Lee LS, and Freeman JL
- Subjects
- Animals, Zebrafish, Tandem Mass Spectrometry, Dopamine, Carbon, Fluorocarbons toxicity, Alkanesulfonic Acids metabolism, Alkanesulfonic Acids toxicity
- Abstract
Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals with several applications. Multiple adverse health effects are reported for longer carbon chain (≤C8) PFAS. Shorter carbon chain PFAS, [e.g., hexafluoropropylene oxide dimer acid (HFPO-DA; GenX) and perfluorobutanesulfonic acid (PFBS)] were introduced as alternatives. Past studies indicate that longer-chain PFAS are neurotoxic targeting the dopamine pathway, but it is not known if shorter-chain PFAS act similarly. This study aimed to evaluate developmental neurotoxicity and tissue uptake of GenX and PFBS using the zebrafish ( Danio rerio ). First, acute toxicity was assessed by measuring LC50 at 120 h postfertilization (hpf). Body burden was determined after embryonic exposure (1-72 hpf) to sublethal concentrations of GenX or PFBS by LC-ESI-MS/MS. Locomotor activity using a visual motor response assay at 120 hpf and dopamine levels at 72 hpf was assessed after embryonic exposure. PFBS was more acutely toxic and bioaccumulative than GenX. GenX and PFBS caused hyperactivity at 120 hpf, but stronger behavioral alterations were observed for PFBS. An increase in whole organism dopamine occurred at 40 ppb of GenX, while a decrease was observed at 400 ppb of PFBS. Differences detected in dopamine for these two PFAS indicate differential mechanisms of developmental neurotoxicity.
- Published
- 2023
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69. Multiple cranial neuropathies in an adolescent with myelin-oligodendrocyte glycoprotein antibody-associated disease.
- Author
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Leung R, Mignone C, Kornberg AJ, Freeman JL, and Yiu EM
- Subjects
- Humans, Myelin-Oligodendrocyte Glycoprotein, Autoantibodies, Cranial Nerve Diseases diagnosis
- Published
- 2023
- Full Text
- View/download PDF
70. Adverse developmental impacts in progeny of zebrafish exposed to the agricultural herbicide atrazine during embryogenesis.
- Author
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Ahkin Chin Tai JK, Horzmann KA, Jenkins TL, Akoro IN, Stradtman S, Aryal UK, and Freeman JL
- Subjects
- Animals, Zebrafish metabolism, Proteomics, Gene Expression Regulation, Developmental, Embryonic Development, Atrazine toxicity, Atrazine metabolism, Herbicides toxicity, Herbicides metabolism
- Abstract
Atrazine (ATZ) is an herbicide commonly used on crops in the Midwestern US and other select global regions. The US Environmental Protection Agency ATZ regulatory limit is 3 parts per billion (ppb; µg/L), but this limit is often exceeded. ATZ has a long half-life, is a common contaminant of drinking water sources, and is indicated as an endocrine disrupting chemical in multiple species. The zebrafish was used to test the hypothesis that an embryonic parental ATZ exposure alters protein levels leading to modifications in morphology and behavior in developing progeny. Zebrafish embryos (F1) were collected from adults (F0) exposed to 0, 0.3, 3, or 30 ppb ATZ during embryogenesis. Differential proteomics, morphology, and behavior assays were completed with offspring aged 120 or 144 h with no additional chemical treatment. Proteomic analysis identified differential expression of proteins associated with neurological development and disease; and organ and organismal morphology, development, and injury, specifically the skeletomuscular system. Head length and ratio of head length to total length was significantly increased in the F1 of 0.3 and 30 ppb ATZ groups (p < 0.05). Based on molecular pathway alterations, further craniofacial morphology assessment found decreased distance for cartilaginous structures, decreased surface area and distance between saccular otoliths, and a more posteriorly positioned notochord (p < 0.05), indicating delayed ossification and skeletal growth. The visual motor response assay showed hyperactivity in progeny of the 30 ppb treatment group for distance moved and of the 0.3 and 30 ppb treatment groups for time spent moving (p < 0.05). Due to the changes in saccular otoliths, an acoustic startle assay was completed and showed decreased response in the 0.3 and 30 ppb treatments (p < 0.05). These findings suggest that a single embryonic parental exposure alters cellular pathways in their progeny that lead to perturbations in craniofacial development and behavior., 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., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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71. Developmental Pb exposure increases AD risk via altered intracellular Ca 2+ homeostasis in hiPSC-derived cortical neurons.
- Author
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Xie J, Wu S, Szadowski H, Min S, Yang Y, Bowman AB, Rochet JC, Freeman JL, and Yuan C
- Subjects
- Animals, Humans, Homeostasis, Neurons pathology, Alzheimer Disease genetics, Alzheimer Disease pathology, Induced Pluripotent Stem Cells pathology, Lead toxicity
- Abstract
Exposure to environmental chemicals such as lead (Pb) during vulnerable developmental periods can result in adverse health outcomes later in life. Human cohort studies have demonstrated associations between developmental Pb exposure and Alzheimer's disease (AD) onset in later life which were further corroborated by findings from animal studies. The molecular pathway linking developmental Pb exposure and increased AD risk, however, remains elusive. In this work, we used human iPSC-derived cortical neurons as a model system to study the effects of Pb exposure on AD-like pathogenesis in human cortical neurons. We exposed neural progenitor cells derived from human iPSC to 0, 15, and 50 ppb Pb for 48 h, removed Pb-containing medium, and further differentiated them into cortical neurons. Immunofluorescence, Western blotting, RNA-sequencing, ELISA, and FRET reporter cell lines were used to determine changes in AD-like pathogenesis in differentiated cortical neurons. Exposing neural progenitor cells to low-dose Pb, mimicking a developmental exposure, can result in altered neurite morphology. Differentiated neurons exhibit altered calcium homeostasis, synaptic plasticity, and epigenetic landscape along with elevated AD-like pathogenesis markers, including phosphorylated tau, tau aggregates, and Aβ42/40. Collectively, our findings provide an evidence base for Ca dysregulation caused by developmental Pb exposure as a plausible molecular mechanism accounting for increased AD risk in populations with developmental Pb exposure., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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72. Pre-differentiation GenX exposure induced neurotoxicity in human dopaminergic-like neurons.
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Wu S, Xie J, Zhao H, Sanchez O, Zhao X, Freeman JL, and Yuan C
- Subjects
- Humans, Neurons, Cell Line, Cell Differentiation, Dopaminergic Neurons metabolism, Neuroblastoma, Fluorocarbons metabolism, Parkinson Disease
- Abstract
GenX, also known as hexafluoropropylene oxide dimer acid (HFPO-DA) was introduced as a safer alternative to perfluorooctanoic acid (PFOA) in 2009. After nearly two decades of applications there are increasing safety concerns about GenX due to its association with various organ damages. Few studies, however, have systematically assessed the molecular neurotoxicity of low-dose GenX exposure. Here, we evaluated the effects of pre-differentiation exposure of GenX on dopaminergic (DA) -like neurons using SH-SY5Y cell line; and assessed changes in epigenome, mitochondrion, and neuronal characteristics. Low dose GenX exposure at 0.4 and 4 μg/L prior to differentiation induced persistent changes in nuclear morphology and chromatin arrangements, manifested specifically in the facultative repressive marker H3K27me3. We also observed impaired neuronal network, increased calcium activity along with alterations in Tyrosine hydroxylase (TH) and α-Synuclein (αSyn) after prior exposure to GenX. Collectively, our results identified neurotoxicity of low-dose GenX exposure in human DA-like neurons following a developmental exposure scheme. The observed changes in neuronal characteristics suggest GenX as a potential neurotoxin and risk factor for Parkinson's disease., 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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73. HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion.
- Author
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Lin JQ, Khuperkar D, Pavlou S, Makarchuk S, Patikas N, Lee FC, Zbiegly JM, Kang J, Field SF, Bailey DM, Freeman JL, Ule J, Metzakopian E, Ruepp MD, and Mallucci GR
- Subjects
- Humans, Cold Shock Proteins and Peptides metabolism, Cold Temperature, RNA, Messenger genetics, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Poisons
- Abstract
Enhanced expression of the cold-shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and in vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 cold induction remains elusive. To identify temperature-dependent modulators of RBM3, we performed a genome-wide CRISPR-Cas9 knockout screen using RBM3-reporter human iPSC-derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense-mediated decay. Importantly, we show that HNRNPH1 mediates this cold-dependent exon skipping via its thermosensitive interaction with a G-rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2023
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74. Facilitation of Definitive Cancer Diagnosis With Quantitative Molecular Assays of BRAF V600E and TERT Promoter Variants in Patients With Thyroid Nodules.
- Author
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Fu G, Chazen RS, Monteiro E, Vescan A, Freeman JL, Witterick IJ, and MacMillan C
- Subjects
- Female, Humans, Male, Mutation, Ontario, Adult, Middle Aged, Aged, Proto-Oncogene Proteins B-raf genetics, Telomerase genetics, Thyroid Neoplasms diagnosis, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Thyroid Nodule diagnosis, Thyroid Nodule genetics, Thyroid Nodule pathology
- Abstract
Importance: Molecular testing of the presence of pathogenic genomic variants in a tumor without quantifying the variant allele fraction (VAF) does not differentiate the variation extent among tumors, often resulting in an inconclusive diagnosis because of interpatient variability., Objective: To examine the association between the quantification of VAFs of BRAF V600E and TERT promoter variants and a definitive cancer diagnosis of thyroid tumors., Design, Setting, and Participants: This diagnostic study analyzed a cohort of 378 surgically resected thyroid tumors with a maximum dimension of 1 cm or larger between March 15, 2016, and March 16, 2020, and a separate cohort of 217 residual thyroid fine-needle aspiration (FNA) biopsy specimens obtained from January 22, 2020, to March 2, 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data analysis was conducted between February 1, 2021, and February 1, 2023., Exposures: Quantitative VAF assays of BRAF V600E and TERT promoter variants (C228T and C250T) were performed by digital polymerase chain reaction molecular assays., Main Outcomes and Measures: The VAFs of BRAF V600E and TERT promoter variants were correlated with tumor histologic diagnoses and histopathologic features to delineate the association of VAF assays with tumor malignancy. The receiver operating characteristic curve analysis, sensitivity, specificity, positive predictive value, negative predictive value, and logistic regression analysis based on follow-up histopathologic types were used to determine the diagnostic utility of the quantitative molecular assays., Results: A total of 595 specimens, including 378 surgically resected thyroid tumors and 217 thyroid nodule FNA biopsy specimens, were collected from 580 patients (436 [75.2%] female with a mean [SD] age of 50 [16] years and 144 [24.8%] male with a mean [SD] age of 55 [14] years). Sensitive VAF assays of 378 thyroid tumors revealed the presence of the BRAF V600E variant in 162 tumors (42.9%), with 26 (16.0%) at a low VAF of 1% or less and 136 (84.0%) at a high VAF of greater than 1%, and the presence of TERT promoter variants in 49 tumors (13.0%), including 45 C228T variants (91.8%), 15 (33.3%) of which were quantified as having a low VAF (≤1%) and 30 (66.7%) as having a high VAF (>1%), and 4 C250T variants (8.2%) with VAFs between 40.0% and 47.0%. All tumors detected with BRAF V600E and/or TERT promoter variants, whether at low or high VAFs, received a definitive cancer diagnosis. Further analysis delineated a significant association between high VAFs of either variant individually or different VAF levels for both variants in coexistence and aggressive histopathologic features of tumors. Excluding low VAFs assisted in identifying patients at an intermediate-to-high risk of recurrence (odds ratio, 5.3; 95% CI, 1.9-14.6; P = .001). The VAF assays on the residual FNA biopsy specimens showed a high agreement to those on surgical tissues (κ = 0.793, P < .001) and stratified malignancy in 40 of 183 indeterminate FNA cases (21.9%), with a sensitivity of 93.8% (95% CI, 67.7%-99.7%), specificity of 90.0% (95% CI, 75.4%-96.7%), positive predictive value of 78.9% (95% CI, 53.9%-93.0%), and negative predictive value of 97.3% (95% CI, 84.2%-99.9%)., Conclusions and Relevance: This diagnostic study suggests that sensitive quantitative VAF assays of BRAF V600E and TERT promoter variants can elucidate the interpatient variability in tumors and facilitate a definitive cancer diagnosis of thyroid nodules by differentiating the variation extent of genomic variants, even at low VAFs.
- Published
- 2023
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75. A cryptic pathogenic NDUFV1 variant identified by RNA-seq in a patient with normal complex I activity in muscle and transient magnetic resonance imaging changes.
- Author
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Kiss S, Christodoulou J, Thorburn DR, Freeman JL, Kornberg AJ, Mandelstam S, Compton AG, Cummings B, Pais L, Yaplito-Lee J, and White SM
- Subjects
- Humans, RNA-Seq, Whole Genome Sequencing, Brain, Electron Transport Complex I genetics, Muscles, Magnetic Resonance Imaging
- Abstract
Mitochondrial respiratory chain disorders (MRC) are amongst the most common group of inborn errors of metabolism. MRC, of which complex I deficiency accounts for approximately a quarter, are very diverse, causing a wide range of clinical problems and can be difficult to diagnose. We report an illustrative MRC case whose diagnosis was elusive. Clinical signs included failure to thrive caused by recurrent vomiting, hypotonia and progressive loss of motor milestones. Initial brain imaging suggested Leigh syndrome but without expected diffusion restriction. Muscle respiratory chain enzymology was unremarkable. Whole-genome sequencing identified a maternally inherited NDUFV1 missense variant [NM_007103.4 (NDUFV1):c.1157G > A; p.(Arg386His)] and a paternally inherited synonymous variant [NM_007103.4 (NDUFV1):c.1080G > A; (p.Ser360=)]. RNA sequencing demonstrated aberrant splicing. This case emphasizes the diagnostic odyssey of a patient in whom a confirmed diagnosis was elusive because of atypical features and normal muscle respiratory chain enzyme (RCE) activities, along with a synonymous variant, which are often filtered out from genomic analyses. It also illustrates the following points: (1) complete resolution of magnetic resonance imaging changes may be part of the picture in mitochondrial disease; (2) analysis for synonymous variants is important for undiagnosed patients; and (3) RNA-seq is a powerful tool to demonstrate pathogenicity of putative splicing variants., (© 2023 Wiley Periodicals LLC.)
- Published
- 2023
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76. How Adolescents Trust Health Information on Social Media: A Systematic Review.
- Author
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Freeman JL, Caldwell PHY, and Scott KM
- Subjects
- Humans, Adolescent, Communication, Advertising, Friends, Social Support, Social Media
- Abstract
Background: Given the potential for social media to spread health misinformation, it is important to understand how trusts impact adolescents' engagement with health content on social media., Objective: To explore the concept of trust when adolescents (13-18 years) engage with health information on social media. Five relevant databases (MEDLINE, EMBASE, PsycINFO, ERIC, and CINAHL) were systematically searched alongside Google Scholar and reference lists of included papers. Studies were included if they examined adolescents' trust when engaging with health information on social media., Study Appraisal and Synthesis Methods: Thematic analysis was used to synthesize the findings from this review., Results: Thirty-four papers were included. Three key domains were explored: trust in the social media platform/service (general distrust of social media for health information; safety and privacy); trust in other users (mistrust of unknown users; fear of bullying or judgment; trust in friends or peers; celebrities and popularity; trust in others' experience and the importance of social support); trust in content (tone and appearance of health information; expertise and verification; advertising, pushed, and suggested content)., Limitations: Narrow geographic representation of papers and limited quantitative studies., Conclusions and Implications of Key Findings: Adolescents' trust in health information on social media involves a complex interplay between trust in: social media platforms, other users, and health content. Central to many of the findings is the social and identity work done by adolescents on and through social media., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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77. Microbial endophytes and compost improve plant growth in two contrasting types of hard rock mining waste.
- Author
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Creamer CA, Leewis MC, Governali FC, Freeman JL, Gray F, Wright EG, and Foster AL
- Subjects
- Endophytes, Lead, Biodegradation, Environmental, Poaceae, Plants, Soil chemistry, Composting, Trace Elements, Soil Pollutants analysis
- Abstract
The re-vegetation of mining wastes with native plants is a comparatively low-cost solution for mine reclamation. However, re-vegetation fails when extreme pH values, low organic matter, or high concentrations of phytotoxic elements inhibit plant establishment and growth. Our aim was to determine whether the combined addition of municipal waste compost and diazotrophic endophytes (i.e., microorganisms that fix atmospheric N
2 and live within plants) could improve plant growth, organic matter accumulation, and phytostabilization of trace element contaminants in two types of hard rock mine waste. We grew a widespread native perennial grass, Bouteloua curtipendula , for one month in alkaline waste rock (porphyry copper mine) and tailings (Ag-Pb-Au mine, amended with dolomite) sourced from southeastern Arizona, United States. B. curtipendula tolerated elevated concentrations of multiple phytotoxic trace elements in the tailings (Mn, Pb, Zn), stabilizing them in roots without foliar translocation. Adding compost and endophyte seed coats improved plant growth, microbial biomass, and organic matter accumulation despite stark differences in the geochemical and physical characteristics of the mining wastes. The widespread grass B. curtipendula is a potential candidate for re-vegetating mine wastes when seeded with soil additives to increase pH and with microbial and organic amendments to increase plant growth.- Published
- 2023
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78. Joint Action Toxicity of Arsenic (As) and Lead (Pb) Mixtures in Developing Zebrafish.
- Author
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Kiper K and Freeman JL
- Subjects
- Animals, Zebrafish, Lead toxicity, Arsenic toxicity, Environmental Pollutants
- Abstract
Arsenic (As) and lead (Pb) are environmental pollutants found in common sites and linked to similar adverse health effects. Multiple studies have investigated the toxicity of each metal individually or in complex mixtures. Studies defining the joint interaction of a binary exposure to As and Pb, especially during the earliest stages of development, are limited and lack confirmation of the predicted mixture interaction. We hypothesized that a mixture of As (iAsIII) and Pb will have a concentration addition (CA) interaction informed by common pathways of toxicity of the two metals. To test this hypothesis, developing zebrafish (1-120 h post fertilization; hpf) were first exposed to a wide range of concentrations of As or Pb separately to determine 120 hpf lethal concentrations. These data were then used in the CA and independent action (IA) models to predict the type of mixture interaction from a co-exposure to As and Pb. Three titration mixture experiments were completed to test prediction of observed As and Pb mixture interaction by keeping the Pb concentration constant and varying As concentrations in each experiment. The prediction accuracy of the two models was then calculated using the prediction deviation ratio (PDR) and Chi-square test and regression modeling applied to determine type of interaction. Individual metal exposures determined As and Pb concentrations at which 25% (39.0 ppm Pb, 40.2 ppm As), 50% (73.8 ppm Pb, 55.4 ppm As), 75% (99.9 ppm Pb, 66.6 ppm As), and 100% (121.7 ppm Pb, 77.3 ppm As) lethality was observed at 120 hpf. These data were used to graph the predicted mixture interaction using the CA and IA models. The titration experiments provided experimental observational data to assess the prediction. PDR values showed the CA model approached 1, whereas all PDR values for the IA model had large deviations from predicted data. In addition, the Chi-square test showed most observed results were significantly different from the predictions, except in the first experiment (Pb LC
25 held constant) with the CA model. Regression modeling for the IA model showed primarily a synergistic response among all exposure scenarios, whereas the CA model indicated additive response at lower exposure concentrations and synergism at higher exposure concentrations. The CA model was a better predictor of the Pb and As binary mixture interaction compared to the IA model and was able to delineate types of mixture interactions among different binary exposure scenarios.- Published
- 2022
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79. Assessment of unique behavioral, morphological, and molecular alterations in the comparative developmental toxicity profiles of PFOA, PFHxA, and PFBA using the zebrafish model system.
- Author
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Wasel O, Thompson KM, and Freeman JL
- Subjects
- Animals, Zebrafish
- Abstract
Perfluoroalkyl substances (PFAS) are a class of synthetic chemicals that are persistent in the environment. Due to adverse health outcomes associated with longer chain PFAS, shorter chain chemicals were used as replacements, but developmental toxicity assessments of the shorter chain chemicals are limited. Toxicity of three perfluoroalkyl acids (PFAAs) [perfluorooctanoic acid (PFOA), composed of 8 carbon (C8), perfluorohexanoic acid (PFHxA, C6), and perfluorobutanoic acid (PFBA, C4)] was compared in developing zebrafish (Danio rerio). LC
50 s at 120 h post fertilization (hpf) assessed potency of each PFAA by exposing developing zebrafish (1-120 hpf) to range of concentrations. Zebrafish were then exposed to sublethal concentrations (0.4-4000 ppb, µg/L) throughout embryogenesis (1-72 hpf). Effects of the embryonic exposure on locomotor activities was completed with the visual motor response test at 120 hpf. At 72 hpf, morphological changes (total body length, head length, head width) and transcriptome profiles to compare altered molecular and disease pathways were determined. The LC50 ranking followed trend as expected based on chain length. PFOA caused hyperactivity and PFBA hypoactivity, while PFHxA did not change behavior. PFOA, PFHxA, and PFBA caused morphological and transcriptomic alterations that were unique for each chemical and were concentration-dependent indicating different toxicity mechanisms. Cancer was a top disease for PFOA and FXR/RXR activation was a top canonical pathway for PFBA. Furthermore, comparison of altered biological and molecular pathways in zebrafish exposed to PFOA matched findings reported in prior epidemiological studies and other animal models, supporting the predictive value of the transcriptome approach and for predicting adverse health outcomes associated with PFHxA or PFBA exposure., 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., (Copyright © 2022. Published by Elsevier Ltd.)- Published
- 2022
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80. Anxiety-related behavior and associated brain transcriptome and epigenome alterations in adult female zebrafish exposed to atrazine during embryogenesis.
- Author
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Horzmann KA, Lin LF, Taslakjian B, Yuan C, and Freeman JL
- Subjects
- Animals, Anxiety, Brain metabolism, Embryo, Nonmammalian metabolism, Embryonic Development, Epigenome, Estradiol metabolism, Female, Gene Expression Regulation, Developmental, Male, Receptors, Estrogen metabolism, Serotonin metabolism, Transcriptome, Zebrafish metabolism, Atrazine metabolism, Atrazine toxicity, Drinking Water metabolism, Herbicides metabolism, Herbicides toxicity, Neoplasms genetics
- Abstract
Atrazine often contaminates drinking water sources, exceeding the maximum contaminant level established by the US Environmental Protection Agency at 3 parts per billion (ppb; μg/L). Atrazine is linked to endocrine disruption, neurotoxicity, and cancer, with delayed health effects observed after developmental exposure in line with the developmental origins of health and disease (DOHaD) hypothesis. To test the hypothesis that embryonic atrazine exposure induces delayed neurotoxicity in adult female zebrafish (Danio rerio), embryos were exposed to 0, 0.3, 3, or 30 ppb atrazine during embryogenesis (1-72 h post fertilization (hpf)) and raised to adults with no additional atrazine exposure. Behavioral outcomes were tested through a novel tank test, light-dark box, and open field test and indicated female zebrafish had more anxious phenotypes at 9 months post fertilization (mpf). Female brain transcriptomic analysis at 9 mpf found altered gene expression pathways related to organismal injury and cancer with beta-estradiol and estrogen receptor as top upstream regulators. These results were compared to 9 mpf male and 6 mpf female groups with the same atrazine embryonic exposures and showed differences in specific genes that were altered, but similarities in top molecular pathways. Molecular pathways associated with behavior were observed only in the 6 mpf transcriptomic profiles, suggesting prediction of observed behavioral outcomes at 9 mpf. The expression of genes associated with serotonin neurotransmission was also evaluated at 14 mpf to determine persistence; however, no significant changes were observed. Brain global methylation in 12 mpf zebrafish observed an increased percent 5 mC in females with embryonic 0.3 ppb atrazine exposure. Finally, the body length, body weight, and brain weight were determined at 14 mpf and were altered in all treatment groups. These results indicate that embryonic atrazine exposure does cause delayed neurotoxicity within the DOHaD framework, which is significant given atrazine's presence and persistence in the environment., 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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81. Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.
- Author
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McKnight D, Morales A, Hatchell KE, Bristow SL, Bonkowsky JL, Perry MS, Berg AT, Borlot F, Esplin ED, Moretz C, Angione K, Ríos-Pohl L, Nussbaum RL, Aradhya S, Haldeman-Englert CR, Levy RJ, Parachuri VG, Lay-Son G, de Montellano DJD, Ramirez-Garcia MA, Benítez Alonso EO, Ziobro J, Chirita-Emandi A, Felix TM, Kulasa-Luke D, Megarbane A, Karkare S, Chagnon SL, Humberson JB, Assaf MJ, Silva S, Zarroli K, Boyarchuk O, Nelson GR, Palmquist R, Hammond KC, Hwang ST, Boutlier SB, Nolan M, Batley KY, Chavda D, Reyes-Silva CA, Miroshnikov O, Zuccarelli B, Amlie-Wolf L, Wheless JW, Seinfeld S, Kanhangad M, Freeman JL, Monroy-Santoyo S, Rodriguez-Vazquez N, Ryan MM, Machie M, Guerra P, Hassan MJ, Candee MS, Bupp CP, Park KL, Muller E 2nd, Lupo P, Pedersen RC, Arain AM, Murphy A, Schatz K, Mu W, Kalika PM, Plaza L, Kellogg MA, Lora EG, Carson RP, Svystilnyk V, Venegas V, Luke RR, Jiang H, Stetsenko T, Dueñas-Roque MM, Trasmonte J, Burke RJ, Hurst ACE, Smith DM, Massingham LJ, Pisani L, Costin CE, Ostrander B, Filloux FM, Ananth AL, Mohamed IS, Nechai A, Dao JM, Fahey MC, Aliu E, Falchek S, Press CA, Treat L, Eschbach K, Starks A, Kammeyer R, Bear JJ, Jacobson M, Chernuha V, Meibos B, Wong K, Sweney MT, Espinoza AC, Van Orman CB, Weinstock A, Kumar A, Soler-Alfonso C, Nolan DA, Raza M, Rojas Carrion MD, Chari G, Marsh ED, Shiloh-Malawsky Y, Parikh S, Gonzalez-Giraldo E, Fulton S, Sogawa Y, Burns K, Malets M, Montiel Blanco JD, Habela CW, Wilson CA, Guzmán GG, and Pavliuk M
- Subjects
- Humans, Female, Infant, Newborn, Infant, Child, Preschool, Child, Adolescent, Young Adult, Adult, Middle Aged, Male, Retrospective Studies, Cross-Sectional Studies, Seizures genetics, Genetic Testing methods, Epilepsy drug therapy, Epilepsy genetics
- Abstract
Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes., Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes., Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals., Exposures: Genetic test results., Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms., Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%)., Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.
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- 2022
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82. Preferences of parents for mental health services to suit children with chronic medical conditions.
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Ride J, Cameron L, Jones R, Dalziel K, Wurzel D, Kao KT, Freeman JL, and Hiscock H
- Subjects
- Child, Humans, Travel, Mental Health Services, Parents
- Abstract
Objectives To identify features of mental health services that affect the uptake of services among parents of children with chronic medical conditions, to inform the design of pathways into mental health care. Methods A discrete choice experiment in which participants made choices between hypothetical mental health services described in terms of service features: cost, wait time, provider knowledge of chronic medical conditions, recommendations, opening hours, and travel time. Participants were parents of children attending The Royal Children's Hospital outpatient clinics for the management of a chronic medical condition who completed the online survey between August 2020 and January 2021. The uptake of mental health services with differing features was predicted based on regression models examining the relationship between choice and service features, and accounting for participant characteristics and unobserved heterogeneity. Results The sample comprised 112 parents, of whom 52% reported unmet needs. The most influential service features were wait times, cost, recommendation from medical specialists, and mental health provider knowledge of chronic medical conditions. Predicted uptake of a realistic service showed inequalities across income, parental education, and single parent status. A service comprising preferred features was predicted to eliminate these inequalities. Conclusions Reducing cost and wait time for mental health services could reduce unmet need among children with chronic medical conditions. Specific approaches to tackle the high levels of unmet needs in this group include equipping medical specialists to recommend mental health providers and training mental health providers on the impacts of chronic medical conditions on children. Offering preferred services could increase uptake and reduce inequalities in mental health care.
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- 2022
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83. Acetylenotrophic and Diazotrophic Bradyrhizobium sp. Strain I71 from TCE-Contaminated Soils.
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Akob DM, Sutton JM, Bushman TJ, Baesman SM, Klein E, Shrestha Y, Andrews R, Fierst JL, Kolton M, Gushgari-Doyle S, Oremland RS, and Freeman JL
- Subjects
- Nitrogen Fixation genetics, Soil chemistry, Acetylene metabolism, Phylogeny, Symbiosis, RNA, Ribosomal, 16S genetics, Root Nodules, Plant microbiology, DNA, Bacterial genetics, Sequence Analysis, DNA, Bradyrhizobium, Trichloroethylene metabolism
- Abstract
Acetylene (C
2 H2 ) is a molecule rarely found in nature, with very few known natural sources, but acetylenotrophic microorganisms can use acetylene as their primary carbon and energy source. As of 2018 there were 15 known strains of aerobic and anaerobic acetylenotrophs; however, we hypothesize there may yet be unrecognized diversity of acetylenotrophs in nature. This study expands the known diversity of acetylenotrophs by isolating the aerobic acetylenotroph, Bradyrhizobium sp. strain I71, from trichloroethylene (TCE)-contaminated soils. Strain I71 is a member of the class Alphaproteobacteria and exhibits acetylenotrophic and diazotrophic activities, the only two enzymatic reactions known to transform acetylene. This unique capability in the isolated strain may increase the genus' economic impact beyond agriculture as acetylenotrophy is closely linked to bioremediation of chlorinated contaminants. Computational analyses indicate that the Bradyrhizobium sp. strain I71 genome contains 522 unique genes compared to close relatives. Moreover, applying a novel hidden Markov model of known acetylene hydratase (AH) enzymes identified a putative AH enzyme. Protein annotation with I-TASSER software predicted the AH from the microbe Syntrophotalea acetylenica as the closest structural and functional analog. Furthermore, the putative AH was flanked by horizontal gene transfer (HGT) elements, like that of AH in anaerobic acetylenotrophs, suggesting an unknown source of acetylene or acetylenic substrate in the environment that is selecting for the presence of AH. IMPORTANCE The isolation of Bradyrhizobium strain I71 expands the distribution of acetylene-consuming microbes to include a group of economically important microorganisms. Members of Bradyrhizobium are well studied for their abilities to improve plant health and increase crop yields by providing bioavailable nitrogen. Additionally, acetylene-consuming microbes have been shown to work in tandem with other microbes to degrade soil contaminants. Based on genome, cultivation, and protein prediction analysis, the ability to consume acetylene is likely not widespread within the genus Bradyrhizobium . These findings suggest that the suite of phenotypic capabilities of strain I71 may be unique and make it a good candidate for further study in several research avenues.- Published
- 2022
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84. Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.
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Stutterd CA, Vanderver A, Lockhart PJ, Helman G, Pope K, Uebergang E, Love C, Delatycki MB, Thorburn D, Mackay MT, Peters H, Kornberg AJ, Patel C, Rodriguez-Casero V, Waak M, Silberstein J, Sinclair A, Nolan M, Field M, Davis MR, Fahey M, Scheffer IE, Freeman JL, Wolf NI, Taft RJ, van der Knaap MS, Simons C, and Leventer RJ
- Subjects
- Flavoproteins, Genetic Testing methods, High-Throughput Nucleotide Sequencing, Humans, Mitochondrial Proteins, Phenotype, Phosphoric Monoester Hydrolases, Tubulin, Leukoencephalopathies diagnostic imaging, Leukoencephalopathies genetics, White Matter diagnostic imaging
- Abstract
Background: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended., Aim: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic., Methods: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance., Results: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test., Discussion: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses., Conclusions: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling., (Copyright © 2022. Published by Elsevier Masson SAS.)
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- 2022
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85. Pre-differentiation exposure of PFOA induced persistent changes in DNA methylation and mitochondrial morphology in human dopaminergic-like neurons.
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Zhao H, Xie J, Wu S, Sánchez OF, Zhang X, Freeman JL, and Yuan C
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- Biomarkers metabolism, Caprylates metabolism, Caprylates toxicity, DNA Methylation, Dopamine metabolism, Epigenesis, Genetic, Humans, Mitochondria metabolism, Neurons metabolism, Fluorocarbons metabolism, Fluorocarbons toxicity, Neuroblastoma metabolism
- Abstract
Perfluorooctanoic acid (PFOA) is abundant in environment due to its historical uses in consumer products and industrial applications. Exposure to low doses of PFOA has been associated with various disease risks, including neurological disorders. The underlying mechanism, however, remains poorly understood. In this study, we examined the effects of low dose PFOA exposure at 0.4 and 4 μg/L on the morphology, epigenome, mitochondrion, and neuronal markers of dopaminergic (DA)-like SH-SY5Y cells. We observed persistent decreases in H3K4me3, H3K27me3 and 5 mC markers in nucleus along with alterations in nuclear size and chromatin compaction percentage in DA-like neurons differentiated from SH-SY5Y cells exposed to 0.4 and 4 μg/L PFOA. Among the selected epigenetic features, DNA methylation pattern can be used to distinguish between PFOA-exposed and naïve populations, suggesting the involvement of epigenetic regulation. Moreover, DA-like neurons with pre-differentiation PFOA exposure exhibit altered network connectivity, mitochondrial volume, and TH expression, implying impairment in DA neuron functionality. Collectively, our results revealed the prolonged effects of developmental PFOA exposure on the fitness of DA-like neurons and identified epigenome and mitochondrion as potential targets for bearing long-lasting changes contributing to increased risks of neurological diseases later in life., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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86. Neurospecific fabrication and toxicity assessment of a PNIPAM nanogel encapsulated with trans -tephrostachin for blood-brain-barrier permeability in zebrafish model.
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Arjun P, Freeman JL, and Kannan RR
- Abstract
Biocompatible Poly(N-isopropylacrylamide) (PNIPAM) nanogels (NGs) were developed at 40-65 nm to deliver Trans -Tephrostachin (TT) in zebrafish brain. Neurospecific PNIPAM NGs are functionalized with polysorbate 80 (PS80) to overcome the Blood Brain Barrier (BBB). The TT loaded with NG (NG + TT) was confirmed in UV-spectroscopy and transmission electron microscopy (TEM) with 90% efficiency of controlled release at 37 °C. The neurospecificity of NG was confirmed in 144 hours post fertilization (hpf) larvae with PS80 surface-treated rhodamine-B (Rh-B) conjugated NG and visualized in the zebrafish CNS. Oral gavaging of TT loaded NG with PS80 surface treatment (NG + TT + PS80) was confirmed to cross the BBB in adult zebrafish at 37 °C. TT release was detected by RP-HPLC. LC
50 was determined as 250 μg/ml for NG, 172 μg/ml for NG + TT, and 0.9 μg/ml for TT at 96 hpf and confirmed the lesser toxicity in TT bound NG. Delays in growth and malformations were observed at concentrations above the 96 hpf-LC50 . The behavior outcomes were varied with phase - and concentration-dependent hypo- or hyperactivity. The altered expression of genes associated with Alzheimer's disease (AD) was found at 96 hpf of its LC50 concentration. The expression of appa was significantly increased for TT and supporting the TT to bind NG without altering the AD genes. Thus the study suggests the biocompatible potential of PNIPAM and its neurospecific delivery to the brain., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)- Published
- 2022
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87. Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions.
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Green TE, Motelow JE, Bennett MF, Ye Z, Bennett CA, Griffin NG, Damiano JA, Leventer RJ, Freeman JL, Harvey AS, Lockhart PJ, Sadleir LG, Boys A, Scheffer IE, Major H, Darbro BW, Bahlo M, Goldstein DB, Kerrigan JF, Heinzen EL, Berkovic SF, and Hildebrand MS
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- Hedgehog Proteins metabolism, Humans, Magnetic Resonance Imaging, Ciliopathies genetics, Hamartoma genetics, Hypothalamic Diseases complications, Hypothalamic Diseases genetics
- Abstract
Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2022
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88. Atrazine exposure in zebrafish induces aberrant genome-wide methylation.
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Wang S, Bryan C, Xie J, Zhao H, Lin LF, Tai JAC, Horzmann KA, Sanchez OF, Zhang M, Freeman JL, and Yuan C
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- Animals, DNA Methylation, Female, Zebrafish, Atrazine metabolism, Atrazine toxicity, Endocrine Disruptors toxicity, Herbicides toxicity
- Abstract
Atrazine (ATZ) is the second most common agricultural herbicide used in the United States and is an endocrine disrupting chemical (EDC). Developmental exposure to ATZ can lead to significant behavioral and morphological alterations in exposed animals and their progeny suggesting the involvement of an epigenetic mechanism. Specific epigenetic mechanisms responsible for these alterations, however, are yet to be elucidated. In this study, we exposed zebrafish embryos to 0, 0.3, 3, or 30 ppb (μg/L) of ATZ from 1 to 72 h post fertilization (hpf). Chemical exposure was ceased and zebrafish maintained until 9 months post fertilization (mpf), when whole-genome bisulfite sequencing (WGBS) was performed to assess the effects of embryonic ATZ exposure on DNA methylation in female fish brains. The number of differentially methylated genes (DMGs) increased with increasing treatment concentration. DMGs were enriched in neurological pathways with extensive methylation changes consistently observed in neuroendocrine pathways. Specifically, DMGs with methylation changes in promoter regions showed hypomethylation in estrogen receptor signaling and hypermethylation in androgen signaling. DMGs with methylation changes in genebody were primarily enriched for mitochondrion-related pathways associated with healthy aging. Integrated analysis with transcriptomic data at 9 mpf exhibited a similar trend identifying CABLES1 and NDUFA4 as shared targets at all concentrations. We then compared the predicted upstream regulators of transcriptomic changes with DMGs and identified CALML3 as a common upstream regulator at both 0.3 and 30 ppb that exhibit significant methylation changes. Collectively, our study identified long-lasting DNA methylation changes in genome after embryonic ATZ exposure and elucidated potential gene targets whose aberrant methylation features may drive alterations in gene transcription in long-term., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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89. Elastin Insufficiency Confers Proximal and Distal Pulmonary Vasculopathy in Mice, Partially Remedied by the K ATP Channel Opener Minoxidil: Considerations and Cautions for the Treatment of People With Williams-Beuren Syndrome.
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Knutsen RH, Gober LM, Kronquist EK, Kaur M, Donahue DR, Springer D, Yu ZX, Chen MY, Fu YP, Choobdar F, Nguyen ML, Osgood S, Freeman JL, Raja N, Levin MD, and Kozel BA
- Abstract
Background: Williams Beuren syndrome (WBS) is a recurrent microdeletion disorder that removes one copy of elastin ( ELN ), resulting in large artery vasculopathy. Early stenosis of the pulmonary vascular tree is common, but few data are available on longer-term implications of the condition., Methods: Computed tomography (CT) angiogram ( n = 11) and echocardiogram ( n = 20) were performed in children with WBS aged 3.4-17.8 years. Controls ( n = 11, aged 4.4-16.8 years) also underwent echocardiogram. Eln
+/- mice were analyzed by invasive catheter, echocardiogram, micro-CT (μCT), histology, and pressure myography. We subsequently tested whether minoxidil resulted in improved pulmonary vascular endpoints., Results: WBS participants with a history of main or branch pulmonary artery (PA) stenosis requiring intervention continued to exhibit increased right ventricular systolic pressure (RVSP, echocardiogram) relative to their peers without intervention ( p < 0.01), with no clear difference in PA size. Untreated Eln+/- mice also show elevated RVSP by invasive catheterization ( p < 0.0001), increased normalized right heart mass ( p < 0.01) and reduced caliber branch PAs by pressure myography ( p < 0.0001). Eln+/- main PA medias are thickened histologically relative to Eln+/+ ( p < 0.0001). Most Eln+/- phenotypes are shared by both sexes, but PA medial thickness is substantially greater in Eln+/- males ( p < 0.001). Eln+/- mice showed more acute proximal branching angles ( p < 0.0001) and longer vascular segment lengths ( p < 0.0001) (μCT), with genotype differences emerging by P7. Diminished PA acceleration time ( p < 0.001) and systolic notching ( p < 0.0001) were also observed in Eln+/- echocardiography. Vascular casting plus μCT revealed longer generation-specific PA arcade length ( p < 0.0001), with increased PA branching detectable by P90 ( p < 0.0001). Post-weaning minoxidil decreased RVSP ( p < 0.01) and normalized PA caliber ( p < 0.0001) but not early-onset proximal branching angle or segment length, nor later-developing peripheral branch number., Conclusions: Vascular deficiencies beyond arterial caliber persist in individuals with WBS who have undergone PA stenosis intervention. Evaluation of Eln+/- mice reveals complex vascular changes that affect the proximal and distal vasculatures. Minoxidil, given post-weaning, decreases RVSP and improves lumen diameter, but does not alter other earlier-onset vascular patterns. Our data suggest additional therapies including minoxidil could be a useful adjunct to surgical therapy, and future trials should be considered., 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 © 2022 Knutsen, Gober, Kronquist, Kaur, Donahue, Springer, Yu, Chen, Fu, Choobdar, Nguyen, Osgood, Freeman, Raja, Levin and Kozel.)- Published
- 2022
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90. Use of Zebrafish Genetic Models to Study Etiology of the Amyloid-Beta and Neurofibrillary Tangle Pathways in Alzheimer's Disease.
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Kiper K and Freeman JL
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- Animals, Disease Models, Animal, Models, Genetic, Neurofibrillary Tangles metabolism, Zebrafish, tau Proteins metabolism, Alzheimer Disease metabolism, Neurodegenerative Diseases pathology
- Abstract
The prevalence of neurodegenerative diseases is increasing globally, with an imperative need to identify and expand the availability of pharmaceutical treatment strategies. Alzheimer's disease is the most common neurodegenerative disease for which there is no cure and limited treatments. Rodent models are primarily used in Alzheimer's disease research to investigate causes, pathology, molecular mechanisms, and pharmaceutical therapies. However, there is a lack of a comprehensive understanding of Alzheimer's disease causes, pathogenesis, and optimal treatments due in part to some limitations of using rodents, including higher economic cost, which can influence sample size and ultimately statistical power. It is necessary to expand our animal model toolbox to provide alternative strategies in Alzheimer's disease research. The zebrafish application in neurodegenerative disease research and neuropharmacology is greatly expanding due to several vital strengths spanning lower economic costs, the smaller size of the organism, a sequenced characterized genome, and well described anatomical structures. These characteristics are coupled to the conserved molecular function and disease pathways in humans. The existence of orthologs for genes associated with Alzheimer's disease in zebrafish is also confirmed. While wild-type zebrafish appear to lack some of the neuropathological features of Alzheimer's disease, the advent of genetic editing technologies has expanded the evaluation of the amyloid and neurofibrillary tangle hypotheses using the zebrafish and exploration of pharmaceutical molecular targets. An overview of how genetic editing technologies are being used on the zebrafish to create models to investigate the causes, pathology, molecular mechanisms, and pharmaceutical targets of Alzheimer's disease is detailed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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- 2022
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91. Mental healthcare for children with chronic conditions: a qualitative study.
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Jones R, Hiscock H, Wurzel D, Kao KT, Freeman JL, and Ride J
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- Adolescent, Adult, Child, Chronic Disease therapy, Humans, Needs Assessment, Parents, Qualitative Research, Young Adult, Chronic Disease psychology, Health Services Accessibility organization & administration, Mental Health Services organization & administration
- Abstract
Objective: To explore parent perspectives on accessing mental healthcare for children with a chronic physical health condition., Design: Qualitative research using semistructured interviews and Framework Analysis. Rankings were used to select attributes for a Discrete Choice Experiment (DCE)., Setting: Four specialty outpatient clinics (diabetes, epilepsy, bronchiectasis unrelated to cystic fibrosis and epidermolysis bullosa) at an Australian tertiary paediatric hospital., Participants: Eighteen parents of children with a chronical physical health condition., Results: Most parents identified the child's general practitioner and/or hospital team as an initial pathway to seek help if they were worried about their child's mental health. Parents see mental healthcare as part of care for the whole child and want the outpatient clinics to proactively discuss child and family mental health, as well as refer to appropriate services as needed. The hospital being a familiar, child-friendly environment was identified as a key reason the hospital might be a desired place to access mental healthcare, as previous research has found. Six attributes of mental health services were identified as important and will be included in an upcoming DCE: travel time, cost, wait time, available hours, knowledge of physical health condition, and recommendation., Conclusions: This study highlights the opportunity presented in specialist outpatient clinics to address the often unmet mental healthcare needs of children with chronic physical health conditions. Parents identified practical ways for outpatient clinics to better facilitate access to mental healthcare. These will be further explored through a quantitative study of parent preferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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92. Lead exposure induces dysregulation of constitutive heterochromatin hallmarks in live cells.
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Sánchez OF, Lin LF, Xie J, Freeman JL, and Yuan C
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Lead (Pb) is a heavy metal contaminant commonly found in air, soil, and drinking water due to legacy uses. Excretion of ingested Pb can result in extensive kidney damages due to elevated oxidative stress. Epigenetic alterations induced by exposure to Pb have also been implied but remain poorly understood. In this work, we assessed changes in repressive epigenetic marks, namely DNA methylation (
me CpG) and histone 3 lysine 9 tri-methylation (H3K9me3) after exposure to Pb. Live cell epigenetic probes coupled to bimolecular fluorescence complementation (BiFC) were used to monitor changes in the selected epigenetic marks. Exposure to Pb significantly loweredme CpG and H3K9me3 levels in HEK293T cells suggesting global changes in constitutive heterochromatin. A heterodimeric pair of probes that tags chromatin regions enriched in bothme CpG and H3K9me3 further confirmed our findings. The observed epigenetic changes can be partially attributed to aberrant transcriptional changes induced by Pb, such as overexpression of TET1 after Pb exposure. Lastly, we monitored changes in selected heterochromatin marks after removal of Pb and found that changes in these markers do not immediately recover to their original level suggesting potential long-term damages to chromatin structure., Competing Interests: 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., (© 2021 The Author(s).)- Published
- 2021
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93. Corrigendum to Thyroid disrupting effects of halogenated and next generation chemicals on the swim bladder development of zebrafish, Aquatic Toxicology, 193 (December 2017), 228-235/ doi.org/10.1016/j.aquatox.2017.10.024.
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Godfrey A, Hooser B, Abdelmoneim A, Horzmann KA, Freeman JL, and Sepúlveda MS
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- 2021
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94. An unexpected disease course for a patient with diffuse midline glioma.
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Malalasekera VS, D'Arcy CE, Mignone C, Wray AC, Nazarian J, Freeman JL, and Hansford JR
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- Histones genetics, Humans, Mutation, Brain Neoplasms diagnostic imaging, Glioma diagnostic imaging
- Published
- 2021
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95. Mechanisms of Neurotoxicity Associated with Exposure to the Herbicide Atrazine.
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Stradtman SC and Freeman JL
- Abstract
Atrazine is an herbicide commonly used on crops to prevent broadleaf weeds. Atrazine is an endocrine-disrupting chemical mainly targeting the neuroendocrine system and associated axes, especially as a reproductive toxicant through attenuation of the luteinizing hormone (LH). Current regulatory levels for chronic exposure are based on no observed adverse effect levels (NOAELs) of these LH alterations in rodent studies. Atrazine has also been studied for its effects on the central nervous system and neurotransmission. The European Union (EU) recognized the health risks of atrazine exposure as a public health concern with no way to contain contamination of drinking water. As such, the EU banned atrazine use in 2003. The United States recently reapproved atrazine's use in the fall of 2020. Research has shown that there is a wide array of adverse health effects that are seen across multiple models, exposure times, and exposure periods leading to dysfunction in many different systems in the body with most pointing to a neuroendocrine target of toxicity. There is evidence of crosstalk between systems that can be affected by atrazine exposure, causing widespread dysfunction and leading to changes in behavior even with no direct link to the hypothalamus. The hypothetical mechanism of toxicity of atrazine endocrine disruption and neurotoxicity can therefore be described as a web of pathways that are influenced through changes occurring in each and their multiple feedback loops with further research needed to refine NOAELs for neurotoxic outcomes.
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- 2021
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96. Risk of Fractures and Other Injuries in Children Treated with Antiseizure Medications for Epilepsy.
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Kumar SM, Simm PJ, De Silva L M, Gorelik A, Freeman JL, Mackay MT, Ahmad BS, Petty SJ, and Wark JD
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- Anticonvulsants adverse effects, Child, Cross-Sectional Studies, Humans, Prospective Studies, Seizures drug therapy, Seizures epidemiology, Epilepsy complications, Epilepsy drug therapy, Epilepsy epidemiology, Fractures, Bone drug therapy, Fractures, Bone epidemiology
- Abstract
This study aimed to investigate the prevalence of fractures and non-fracture injuries, including associated risk factors, in children with epilepsy prescribed antiseizure medications (ASM). A controlled, cross-sectional study was conducted in a hospital outpatient setting, comparing children with epilepsy prescribed ASMs with their non-epileptic siblings. Information was collected by questionnaire included history of fractures, non-fracture injuries and epilepsy, comorbidities and ASM use. 261 participants completed the questionnaire, 133 children with epilepsy (aged 10.7 ± 3.5 years, mean ± SD) and 128 siblings (10.1 ± 3.7 years). There were 49 non-seizure-related fractures in 34 ASM patients while prescribed ASMs, compared with 21 lifetime fractures in 15 controls, giving a 2.7 (95% CI 1.3-5.3, p = 0.007) times greater fracture prevalence in children treated with ASMs compared to healthy siblings. The rates of non-fracture injuries were similar across groups, except that concussion was more common in children taking ASMs (9.0% vs 1.6%, p = 0.026). Duration of ASM use and generalized tonic-clonic seizures (GTCS) were independent predictors of fractures (OR 1.55; 95% CI 1.03-2.31, p = 0.03; OR 2.50; 95% CI 1.05-5.94, p = 0.04, respectively). Fewer than 20% of participants and/or their families were aware that ASM use was related to bone health. Children with epilepsy treated with ASMs had a higher fracture prevalence than their sibling controls. Duration of ASM treatment and GTCS were associated with fracture risk. Longitudinal prospective studies are required to further explore risk and the direct impact of epilepsy on bone health., (© 2021. Crown.)
- Published
- 2021
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97. Feasibility and Safety of Outpatient Thyroidectomy: A Narrative Scoping Review.
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Philteos J, Baran E, Noel CW, Pasternak JD, Higgins KM, Freeman JL, Chiodo A, and Eskander A
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- Feasibility Studies, Humans, Thyroid Diseases pathology, Ambulatory Surgical Procedures standards, Length of Stay statistics & numerical data, Outpatients statistics & numerical data, Thyroid Diseases surgery, Thyroidectomy methods
- Abstract
Background: Outpatient thyroid surgery is gaining popularity as it can reduce length of hospital stay, decrease costs of care, and increase patient satisfaction. There remains a significant variation in the use of this practice including a perceived knowledge gap with regards to the safety of outpatient thyroidectomies and how to go about implementing standardized institutional protocols to ensure safe same-day discharge. This review summarizes the information available on the subject based on existing published studies and guidelines., Methods: This is a scoping review of the literature focused on the safety, efficacy and patient satisfaction associated with outpatient thyroidectomies. The review also summarizes and editorializes the most recent American Thyroid Association guidelines., Results: In total, 11 studies were included in the analysis: 6 studies were retrospective analyses, 3 were retrospective reviews of prospective data, and 2 were prospective studies. The relative contraindications to outpatient thyroidectomy have been highlighted, including: complex medical conditions, anticipated difficult surgical dissection, patients on anticoagulation, lack of home support, and patient anxiety toward an outpatient procedure. Utilizing these identified features, an outpatient protocol has been proposed., Conclusion: The salient features regarding patient safety and selection criteria and how to develop a protocol implementing ambulatory thyroidectomies have been identified and reviewed. In conclusion, outpatient thyroidectomy is safe, associated with high patient satisfaction and decreased health costs when rigorous institutional protocols are established and implemented. Successful outpatient thyroidectomies require standardized preoperative selection, clear discharge criteria and instructions, and interprofessional collaboration between the surgeon, anesthetist and same-day nursing staff., 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 © 2021 Philteos, Baran, Noel, Pasternak, Higgins, Freeman, Chiodo and Eskander.)
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- 2021
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98. One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.
- Author
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Macdonald-Laurs E, Maixner WJ, Bailey CA, Barton SM, Mandelstam SA, Yuan-Mou Yang J, Warren AEL, Kean MJ, Francis P, MacGregor D, D'Arcy C, Wrennall JA, Davidson A, Pope K, Leventer RJ, Freeman JL, Wray A, Jackson GD, and Harvey AS
- Subjects
- Adolescent, Cerebral Cortex diagnostic imaging, Cerebral Cortex physiopathology, Child, Epilepsy diagnostic imaging, Epilepsy physiopathology, Female, Humans, Magnetic Resonance Imaging, Male, Malformations of Cortical Development, Group I diagnostic imaging, Malformations of Cortical Development, Group I physiopathology, Monitoring, Physiologic, Neurosurgical Procedures methods, Preoperative Care, Treatment Outcome, Cerebral Cortex surgery, Epilepsy surgery, Malformations of Cortical Development, Group I surgery
- Abstract
Objective: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD)., Methods: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG., Results: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication., Conclusion: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping., Classification of Evidence: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures., (© 2021 American Academy of Neurology.)
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- 2021
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99. Diagnostic Value of Galectin-3 in Distinguishing Invasive Encapsulated Carcinoma from Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features (NIFTP).
- Author
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Fu G, Polyakova O, Chazen RS, Freeman JL, and Witterick IJ
- Abstract
Background : non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), which is considered as low-risk cancer, should be distinguished from the malignant invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Improved discrimination of NIFTPs from invasive EFVPTCs using a molecular biomarker test could provide useful insights into pre- and post-surgical management of the indeterminate thyroid nodule. Galectin-3 (Gal-3), a β-galactosyl-binding molecule in the lectin group, is involved in different biological functions in well differentiated thyroid carcinomas. The aim of this study was to determine whether Gal-3 expression as a diagnostic marker could distinguish indolent NIFTP from invasive EFVPTC on tissue specimens from surgical thyroid nodules. Methods : immunohistochemical (IHC) analysis of cytoplasmic and nuclear Gal-3 expression was performed in formalin-fixed paraffin-embedded (FFPE) surgical tissues in four specific diagnostic subgroups- benign nodules, NIFTPs, EFVPTCs and lymphocytic/Hashimoto's thyroiditis (LTs). Results : cytoplasmic Gal-3 expression (mean ± SD) was significantly increased in invasive EFVPTCs (4.80 ± 1.60) compared to NIFTPs (2.75 ± 1.58, p < 0.001) and benign neoplasms (2.09 ± 1.19, p < 0.001) with no significant difference between NIFTPs and benign lesions ( p = 0.064). The presence of LT enhanced cytoplasmic Gal-3 expression (3.80 ± 1.32) compared to NIFTPs ( p = 0.016) and benign nodules ( p < 0.001). Nuclear Gal-3 expression in invasive EFVPTCs (1.84 ± 1.30) was significantly higher than in NIFTPs (1.00 ± 0.72, p = 0.001), but similar to benign nodules (1.44 ± 1.77, p = 0.215), thereby obviating its potential clinical application. Conclusions : our observations have indicated that increased cytoplasmic Gal-3 expression shows diagnostic potential in distinguishing NIFTP among encapsulated follicular variant nodules thereby serving as a possible ancillary test to H&E histopathological diagnostic criteria when LT interference is absent, to assist in the detection of the invasive EFVPTC among such nodules.
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- 2021
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100. Embryonic atrazine exposure and later in life behavioral and brain transcriptomic, epigenetic, and pathological alterations in adult male zebrafish.
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Horzmann KA, Lin LF, Taslakjian B, Yuan C, and Freeman JL
- Subjects
- Animals, Brain pathology, Embryonic Development drug effects, Endocrine Disruptors adverse effects, Epigenesis, Genetic drug effects, Gene Expression Regulation drug effects, Gene Expression Regulation, Developmental drug effects, Humans, Larva drug effects, Larva genetics, Larva growth & development, Transcriptome drug effects, Water Pollutants, Chemical adverse effects, Zebrafish embryology, Zebrafish genetics, Zebrafish growth & development, Atrazine adverse effects, Brain drug effects, Pesticides adverse effects, Transcriptome genetics
- Abstract
Atrazine (ATZ), a commonly used pesticide linked to endocrine disruption, cancer, and altered neurochemistry, frequently contaminates water sources at levels above the US Environmental Protection Agency's 3 parts per billion (ppb; μg/L) maximum contaminant level. Adult male zebrafish behavior, brain transcriptome, brain methylation status, and neuropathology were examined to test the hypothesis that embryonic ATZ exposure causes delayed neurotoxicity, according to the developmental origins of health and disease paradigm. Zebrafish (Danio rerio) embryos were exposed to 0 ppb, 0.3 ppb, 3 ppb, or 30 ppb ATZ during embryogenesis (1-72 h post fertilization (hpf)), then rinsed and raised to maturity. At 9 months post fertilization (mpf), males had decreased locomotor parameters during a battery of behavioral tests. Transcriptomic analysis identified altered gene expression in organismal development, cancer, and nervous and reproductive system development and function pathways and networks. The brain was evaluated histopathologically for morphometric differences, and decreased numbers of cells were identified in raphe populations. Global methylation levels were evaluated at 12 mpf, and the body length, body weight, and brain weight were measured at 14 mpf to evaluate effects of ATZ on mature brain size. No significant difference in genome methylation or brain size was observed. The results demonstrate that developmental exposure to ATZ does affect neurodevelopment and neural function in adult male zebrafish and raises concern for possible health effects in humans due to ATZ's environmental presence and persistence. Graphical abstract.
- Published
- 2021
- Full Text
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