563 results on '"Philippe, M."'
Search Results
2. Impact of COVID-19 Vaccination on Short-Term Perceived Change in Physical Performance among Elite Athletes: An International Survey
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Olivier Bruyère, Géraldine Martens, Céline Demonceau, Axel Urhausen, Romain Seil, Suzanne Leclerc, Sébastien Le Garrec, Philippe Le Van, Pascal Edouard, Philippe M Tscholl, François Delvaux, Jean-François Toussaint, and Jean-François Kaux
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SARS-CoV-2 ,sports ,immunization ,athletes ,elite ,athletic performance ,Medicine - Abstract
COVID-19 vaccination raised concerns about its potential effects on physical performance. To assess the impact of COVID-19 vaccination on the perceived change in physical performance, we conducted an online survey among elite athletes from Belgium, Canada, France and Luxembourg, with questions about socio-demographics, COVID-19 vaccination, perceived impact on physical performance and perceived pressure to get vaccinated. Full vaccination was defined as two doses of mRNA or vector vaccine or a heterologous vaccine scheme. Among 1106 eligible athletes contacted, 306 athletes answered the survey and were included in this study. Of these, 72% perceived no change in their physical performance, 4% an improvement and 24% a negative impact following full COVID-19 vaccination. For 82% of the included athletes, the duration of the negative vaccine reactions was ≤3 days. After adjustment for potential confounding variables, practicing an individual sport, a duration of vaccine reactions longer than 3 days, a high level of vaccine reaction and the perceived pressure to get vaccinated were independently associated with a perceived negative impact on physical performance of more than 3 days after the vaccination. The perceived pressure to get vaccinated appears to be a parameter associated with the negative perceived change in the physical performance and deserves further consideration.
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- 2023
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3. Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome
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Mary E. McQuaid, Kashif Ahmed, Stephanie Tran, Justine Rousseau, Ranad Shaheen, Kristin D. Kernohan, Kyoko E. Yuki, Prerna Grover, Ema S. Dreseris, Sameen Ahmed, Lucie Dupuis, Jennifer Stimec, Mary Shago, Zuhair N. Al-Hassnan, Roch Tremblay, Philipp G. Maass, Michael D. Wilson, Eyal Grunebaum, Kym M. Boycott, François-Michel Boisvert, Sateesh Maddirevula, Eissa A. Faqeih, Fahad Almanjomi, Zaheer Ullah Khan, Fowzan S. Alkuraya, Philippe M. Campeau, Peter Kannu, Eric I. Campos, and Hugo Wurtele
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Cell biology ,Medicine - Abstract
The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome–like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.
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- 2022
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4. Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study
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Lina Moisan, David Iannuzzi, Bruno Maranda, Philippe M. Campeau, and John J. Mitchell
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Canada ,Founder effects ,Genetic disorders ,Mucopolysaccharidosis IVA ,Activities of daily living ,Walk test ,Medicine - Abstract
Abstract Background Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa. Results A total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease. Conclusions In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.
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- 2020
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5. Inhibition of in vitro Ebola infection by anti-parasitic quinoline derivatives [version 1; peer review: 2 approved]
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Shawn Goyal, Beth Binnington, Stephen D.S. McCarthy, Didier Desmaële, Laurent Férrié, Bruno Figadère, Philippe M. Loiseau, and Donald R. Branch
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Medicine ,Science - Abstract
There continues to be no approved drugs for the treatment of Ebola virus disease (EVD). Despite a number of candidate drugs showing limited efficacy in vitro and/or in non-human primate studies, EVD continues to plaque certain areas of Africa without any efficacious treatments yet available. Recently, we have been exploring the potential for anti-malarial drugs to inhibit an in vitro model of Ebola Zaire replication using a transcription-competent virus-like particle (trVLP) assay. We examined the efficacy of chloroquine, amodiaquine and 36 novel anti-parasite quinoline derivatives at inhibiting Ebola virus replication. Drug efficacy was tested by trVLP assay and toxicity by MTT assay. Both chloroquine and amodiaquine were effective for inhibition of Ebola virus replication without significant toxicity. The half-maximal inhibitory concentration (IC50) of chloroquine and amodiaquine to inhibit Ebola virus replication were IC50, Chl = 3.95 µM and IC50, Amo = 1.45 µM, respectively. Additionally, three novel quinoline derivatives were identified as having inhibitory activity and low toxicity for Ebola trVLP replication, with 2NH2Q being the most promising derivative, with an IC50 of 4.66 µM. Quinoline compounds offer many advantages for disease treatment in tropical climates as they are cheap to produce, easy to synthesize and chemically stable. In this report, we have demonstrated the potential of anti-parasite quinolines for further investigation for use in EVD.
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- 2020
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6. Diversity of Pneumocystis jirovecii Across Europe: A Multicentre Observational Study
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Alexandre Alanio, Maud Gits-Muselli, Nicolas Guigue, Marie Desnos-Ollivier, Enrique J. Calderon, David Di Cave, Damien Dupont, Axel Hamprecht, Philippe M. Hauser, Jannik Helweg-Larsen, Marta Kicia, Katrien Lagrou, Martina Lengerova, Olga Matos, Willem J.G. Melchers, Florent Morio, Gilles Nevez, Anne Totet, Lewis P. White, and Stéphane Bretagne
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Pneumocystis jirovecii ,Genotyping ,Europe ,Transmission ,Mixed infection ,MLS typing ,Microsatellites ,Medicine ,Medicine (General) ,R5-920 - Abstract
Pneumocystis jirovecii is an airborne human-specific ascomycetous fungus responsible for Pneumocystis pneumonia (PCP) in immunocompromised patients, affecting >500,000 patients per year (www.gaffi.org). The understanding of its epidemiology is limited by the lack of standardised culture. Recent genotyping data suggests a limited genetic diversity of P. jirovecii. The objective of the study was to assess the diversity of P. jirovecii across European hospitals and analyse P. jirovecii diversity in respect to clinical data obtained from the patients. Genotyping was performed using six already validated short tandem repeat (STR) markers on 249 samples (median: 17 per centre interquartile range [11−20]) from PCP patients of 16 European centres. Mixtures of STR markers (i.e., ≥2 alleles for ≥1 locus) were detected in 67.6% (interquartile range [61.4; 76.5]) of the samples. Mixture was significantly associated with the underlying disease of the patient, with an increased proportion in HIV patients (78.3%) and a decreased proportion in renal transplant recipients (33.3%) (p
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- 2017
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7. Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
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Wei Mao, Pierre Daligaux, Noureddine Lazar, Tâp Ha-Duong, Christian Cavé, Herman van Tilbeurgh, Philippe M. Loiseau, and Sébastien Pomel
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Medicine ,Science - Abstract
Abstract Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal. GDP-Mannose Pyrophosphorylase (GDP-MP) is a prominent therapeutic target involved in host-parasite recognition which has been described to be essential for parasite survival. In this work, we produced and purified GDP-MPs from L. mexicana (LmGDP-MP), L. donovani (LdGDP-MP), and human (hGDP-MP), and compared their enzymatic properties. From a rationale design of 100 potential inhibitors, four compounds were identified having a promising and specific inhibitory effect on parasite GDP-MP and antileishmanial activities, one of them exhibits a competitive inhibition on LdGDP-MP and belongs to the 2-substituted quinoline series.
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- 2017
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8. Stabilization of primary cilia reduces abortive cell cycle re-entry to protect injured adult CNS neurons from apoptosis.
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Brian K A Choi, Philippe M D'Onofrio, Alireza P Shabanzadeh, and Paulo D Koeberle
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Medicine ,Science - Abstract
Abortive cell cycle (ACC) re-entry of apoptotic neurons is a recently characterized phenomenon that occurs after central nervous system (CNS) injury or over the course of CNS disease. Consequently, inhibiting cell cycle progression is neuroprotective in numerous CNS pathology models. Primary cilia are ubiquitous, centriole-based cellular organelles that prevent cell cycling, but their ability to modulate abortive cell cycle has not been described. Here, we show that neuronal cilia are ablated in-vitro and in-vivo following injury by hypoxia or optic nerve transection (ONT), respectively. Furthermore, forced cilia resorption sensitized neurons to these injuries and enhanced cell death. In contrast, pharmacological inhibition or shRNA knockdown of the proteins that disassemble the cilia increased neuron survival and decreased the phosphorylation of retinoblastoma (Rb), a master switch for cell cycle re-entry. Our findings show that the stabilization of neuronal primary cilia inhibits, at least transiently, apoptotic cell cycling, which has implications for future therapeutic strategies that halt or slow the progression of neurodegenerative diseases and acute CNS injuries.
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- 2019
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9. A Discussion With Dr. Philippe Campeau, Medical Geneticist and Clinician-Scientist
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Danny Jomaa and Philippe M. Campeau
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Canada ,Biomedical Research ,Physicians ,Mentors ,Humans ,Medicine ,General Medicine - Abstract
Dr. Philippe Campeau is the recipient of the 2021 Canadian Society for Clinical Investigation (CSCI) Joe Doupe Young Investigator Award—given in recognition of his early career achievements as a clinician-scientist and his mentorship to trainees. In honor of his success, this article discusses Dr. Campeau’s journey to a career as clinician-scientist and his successes and challenges along the way. In answering these questions, Dr. Campeau shares encouraging insights and advice for clinician-scientist trainees who are building the foundations of their own careers in medicine and research.
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- 2022
10. Establishing a core outcome set for mucopolysaccharidoses (MPS) in children: study protocol for a rapid literature review, candidate outcomes survey, and Delphi surveys
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Alexandra Wyatt, Michal Inbar-Feigenberg, Aizeddin A. Mhanni, Kim Angel, Pranesh Chakraborty, Jenifer Gentle, Alison H. Howie, Beth K. Potter, Philippe M. Campeau, Rebecca Sparkes, Farah El Turk, Maureen Smith, Martin Offringa, John J. Mitchell, Sylvia Stockler, Kylie Tingley, Nancy J. Butcher, Becky Skidmore, Eva Mamak, Alicia Chan, and University of Manitoba
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medicine.medical_specialty ,Medicine (General) ,Psychological intervention ,Medicine (miscellaneous) ,Outcome (game theory) ,Pediatrics ,law.invention ,Study Protocol ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,R5-920 ,Randomized controlled trial ,law ,030225 pediatrics ,Health care ,Medicine ,Pharmacology (medical) ,030212 general & internal medicine ,computer.programming_language ,Protocol (science) ,business.industry ,Mucopolysaccharidoses ,3. Good health ,Rare diseases ,Outcomes research ,Family medicine ,business ,computer ,Delphi - Abstract
Background Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases characterized by chronic, progressive multi-system manifestations with varying degrees of severity. Disease-modifying therapies exist to treat some types of MPS; however, they are not curative, underscoring the need to identify and evaluate co-interventions that optimize functioning, participation in preferred activities, and quality of life. A Canadian pediatric MPS registry is under development and may serve as a platform to launch randomized controlled trials to evaluate such interventions. To promote the standardized collection of patient/family-reported and clinical outcomes considered important to patients/families, health care providers (HCPs), and policymakers, the choice of outcomes to include in the registry will be informed by a core outcome set (COS). We aim to establish a patient-oriented COS for pediatric MPS using a multi-stakeholder approach. Methods In step 1 of the six-step process to develop the COS, we will identify relevant outcomes through a rapid literature review and candidate outcomes survey. A two-phase screening approach will be implemented to identify eligible publications, followed by extraction of outcomes and other pre-specified data elements. Simultaneously, we will conduct a candidate outcomes survey with children with MPS and their families to identify outcomes most important to them. In step 2, HCPs experienced in treating patients with MPS will be invited to review the list of outcomes generated in step 1 and identify additional clinically relevant outcomes. We will then ask patients/families, HCPs, and policymakers to rate the outcomes in a set of Delphi Surveys (step 3), and to participate in a subsequent consensus meeting to finalize the COS (step 4). Step 5 involves establishing a set of outcome measurement instruments for the COS. Finally, we will disseminate the COS to knowledge users (step 6). Discussion The proposed COS will inform the choice of outcomes to include in the MPS registry and, more broadly, promote the standardized collection of patient-oriented outcomes for pediatric MPS research. By involving patients/families from the earliest stage of the research, we will ensure that the COS will be relevant to those who will ultimately benefit from the research. Trial registration PROSPERO CRD42021267531, COMET
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- 2021
11. PIGG variant pathogenicity assessment reveals characteristic features within 19 families
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Anna Lehman, Christina T. Rüsch, Angela F. Brady, Julie S. Cohen, Millan S. Patel, Rani Sachdev, Usha Kini, Elizabeth E. Palmer, Reza Maroofian, Sonal Mahida, Karen Stals, Roger L. Ladda, Yoshiko Murakami, Camille Tremblay-Laganière, Tahsin Stefan Barakat, Scott D. McLean, Fizza Akbar, Marilena Christoforou, Farah Ashrafzadeh, Melissa A. Walker, Grazia M.S. Mancini, Salman Kirmani, Kimberly Nugent, Philippe M. Campeau, Fatima Y. Ismail, Amanda Nagy, Sian Ellard, Stephanie Efthymiou, Bushra Afroze, Rebecca Macintosh, Saskia B. Wortmann, Danilo Bernardo, Rebecca Truty, Matias Wagner, Shahnaz Ibrahim, Tipu Sultan, Kristin W. Barañano, Stylianos E. Antonarakis, Yuta Maki, Thi Tuyet Mai Nguyen, Henry Houlden, Robert Steinfeld, Saadet Mercimek-Andrews, Taroh Kinoshita, Georg M. Stettner, Andrew C. Edmondson, Naila Ismayilova, Meisam Babaei, Heather M. McLaughlin, Mohammad Doosti, Ehsan Ghayoor Karimiani, and Clinical Genetics
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Autism Spectrum Disorder ,Immunoglobulin D ,Article ,Cell membrane ,chemistry.chemical_compound ,Biosynthesis ,Seizures ,Intellectual Disability ,medicine ,Humans ,Transferase ,Gene ,Genetics (clinical) ,Genetics ,chemistry.chemical_classification ,Virulence ,biology ,Membrane Proteins ,Hypotonia ,In vitro ,Pedigree ,Phosphotransferases (Alcohol Group Acceptor) ,Enzyme ,medicine.anatomical_structure ,chemistry ,biology.protein ,medicine.symptom - Abstract
Purpose Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions. Unlabelled Image
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- 2021
12. An adamantamine derivative as a drug candidate for the treatment of visceral leishmaniasis
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Joël Vacus, Daniel Gillet, Julien Barbier, Laetitia Nguyen, Valérie Pons, Sébastien Pomel, Jean-Christophe Cintrat, Philippe M. Loiseau, Sandrine Cojean, and Alain Pruvost
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0301 basic medicine ,Microbiology (medical) ,030231 tropical medicine ,Antiprotozoal Agents ,ADME Study ,Drug resistance ,Pharmacology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Pharmacology (medical) ,Leishmania infantum ,ADME ,Mice, Inbred BALB C ,Miltefosine ,biology ,Chemistry ,biology.organism_classification ,030104 developmental biology ,Infectious Diseases ,Pharmaceutical Preparations ,Drug development ,Leishmaniasis, Visceral ,medicine.drug - Abstract
Background This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania. Objectives To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages. Methods In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development. Results VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline. Conclusions VP343 has the properties of a good drug candidate and merits further investigations.
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- 2021
13. Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy
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Parenti, Ilaria, Lehalle, Daphné, Nava, Caroline, Torti, Erin, Leitão, Elsa, Person, Richard, Mizuguchi, Takeshi, Matsumoto, Naomichi, Kato, Mitsuhiro, Nakamura, Kazuyuki, de Man, Stella A., Cope, Heidi, Shashi, Vandana, Friedman, Jennifer, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Muffels, Irena, van Hasselt, Peter M., Petit, Florence, Smol, Thomas, Le Guyader, Gwenaël, Bilan, Frédéric, Sorlin, Arthur, Vitobello, Antonio, Philippe, Christophe, van de Laar, Ingrid M. B. H., van Slegtenhorst, Marjon A., Campeau, Philippe M., Au, Ping Yee Billie, Nakashima, Mitsuko, Saitsu, Hirotomo, Yamamoto, Tatsuya, Nomura, Yumiko, Louie, Raymond J., Lyons, Michael J., Dobson, Amy, Plomp, Astrid S., Motazacker, M. Mahdi, Kaiser, Frank J., Timberlake, Andrew T., Fuchs, Sabine A., Depienne, Christel, Mignot, Cyril, Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Deardorff, Matthew, Dell’Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldrich, Madison P., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Huryn, Laryssa, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Karaviti, Lefkothea, Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, LaMoure, Grace L., Lanpher, Brendan C., Lanza, Ian R., Latham, Lea, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., MacDowall, John, Macnamara, Ellen F., Mac-Rae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan C., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Mosbrook-Davis, Deborah, Mulvihill, John J., Murdock, David R., Nagy, Anna, Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Power, Bradley, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Shin, Jimann, Signer, Rebecca, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Jennifer A., Sullivan, Kathleen, Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Amelia L. M., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Thurm, Audrey, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yousef, Muhammad, Zastrow, Diane B., Zein, Wadih, Zhao, Chunli, Zuchner, Stephan, Clinical Genetics, Human Genetics, ACS - Pulmonary hypertension & thrombosis, and ANS - Complex Trait Genetics
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Male ,Adolescent ,Mutation, Missense ,Medizin ,Nerve Tissue Proteins ,Biology ,Frameshift mutation ,Chromodomain ,Cohort Studies ,Young Adult ,Epilepsy ,Neurodevelopmental disorder ,Catalytic Domain ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Missense mutation ,Child ,Genetics (clinical) ,Exome sequencing ,Original Investigation ,Genes, Dominant ,DNA Helicases ,medicine.disease ,Pedigree ,Neurodevelopmental Disorders ,Child, Preschool ,Speech delay ,Female ,medicine.symptom - Abstract
Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
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- 2021
14. Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability [version 1; referees: 2 approved]
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Erika Banuelos, Keri Ramsey, Newell Belnap, Malavika Krishnan, Chris Balak, Szabolcs Szelinger, Ashley L. Siniard, Megan Russell, Ryan Richholt, Matt De Both, Ignazio Piras, Marcus Naymik, Ana M. Claasen, Sampathkumar Rangasamy, Matthew J. Huentelman, David W. Craig, Philippe M. Campeau, Vinodh Narayanan, and Isabelle Schrauwen
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Medical Genetics ,Medicine ,Science - Abstract
Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy
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- 2017
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15. Drugs used for the treatment of cerebral and disseminated infections caused by free‐living amoebae
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Philippe M. Loiseau, Zineb Fechtali-Moute, Alexandre Taravaud, and Sébastien Pomel
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Drug ,030213 general clinical medicine ,media_common.quotation_subject ,Reviews ,Central Nervous System Protozoal Infections ,RM1-950 ,Balamuthia ,Review ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,Balamuthia mandrillaris ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,Medicine ,Humans ,Amebicides ,General Pharmacology, Toxicology and Pharmaceutics ,Granulomatous amoebic encephalitis ,Amoeba ,media_common ,Naegleria fowleri ,biology ,business.industry ,General Neuroscience ,Meningoencephalitis ,Acanthamoeba infection ,General Medicine ,Amebiasis ,biology.organism_classification ,medicine.disease ,Acanthamoeba ,Survival Rate ,Treatment Outcome ,Immunology ,Drug Therapy, Combination ,Therapeutics. Pharmacology ,Public aspects of medicine ,RA1-1270 ,business - Abstract
Free‐living amoebae (FLAs) are protozoa developing autonomously in diverse natural or artificial environments. The FLAs Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri represent a risk for human health as they can become pathogenic and cause severe cerebral infections, named granulomatous amoebic encephalitis (GAE), Balamuthia amoebic encephalitis (BAE), and primary amoebic meningoencephalitis (PAM), respectively. Additionally, Acanthamoeba sp. can also rarely disseminate to diverse organs, such as the skin, sinuses, or bones, and cause extracerebral disseminated acanthamebiasis (EDA). No consensus treatment has been established for cerebral FLA infections or EDA. The therapy of cerebral and disseminated FLA infections often empirically associates a large diversity of drugs, all exhibiting a high toxicity. Nevertheless, these pathologies lead to a high mortality, above 90% of the cases, even in the presence of a treatment. In the present work, a total of 474 clinical cases of FLA infections gathered from the literature allowed to determine the frequency of usage, as well as the efficacy of the main drugs and drug combinations used in the treatment of these pathologies. The efficacy of drug usage was determined based on the survival rate after drug administration. The most efficient drugs, drug combinations, and their mechanism of action were discussed in regard to the present recommendations for the treatment of GAE, EDA, BAE, and PAM. At the end, this review aims to provide a useful tool for physicians in their choice to optimize the treatment of FLA infections.
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- 2021
16. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome
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Ange Line Bruel, Katherine A. Bosanko, Abeltje M. Polstra, Agne Liedén, Marcel M.A.M. Mannens, R. Pfundt, Frédérick A. Mallette, Britt-Marie Anderlid, Kieran B. Pechter, Louise Rafael-Croes, Madhura Bakshi, Saskia M. Maas, Dagmar Glatz, R. Frank Kooy, Natalie Lippa, Philippe M. Campeau, Yuri A. Zarate, Jade England, Mieke M. van Haelst, Megan Boothe, Kosuke Izumi, Manon van Ginkel, Vimla Aggarwal, Anna Lehman, Eline A. Verberne, Zornitza Stark, Christopher M. Richmond, Marije Meuwissen, Darryl C. De Vivo, Pankaj B. Agrawal, Shuxiang Goh, Jennifer M. Lemons, Bertrand Isidor, Ayeshah Chaudhry, Causes Study, Emma Bedoukian, Nathaniel H. Robin, David A. Koolen, Sylvia Stockler, David Rodriguez-Buritica, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human Genetics, Graduate School, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and ACS - Pulmonary hypertension & thrombosis
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0301 basic medicine ,Heterozygote ,Haploinsufficiency ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,Exome Sequencing ,Intellectual disability ,medicine ,Humans ,Copy-number variation ,Gene ,Genetics (clinical) ,Exome sequencing ,Genetics ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,neurodevelopment ,Microarray analysis techniques ,Polycomb Repressive Complex 2 ,Chromosome ,Syndrome ,medicine.disease ,developmental delay ,Phenotype ,030104 developmental biology ,Neurodevelopmental Disorders ,intellectual disability ,Histone methyltransferase ,Human medicine ,JARID2 - Abstract
Item does not contain fulltext PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.
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- 2021
17. Abdominal Decompression after Cardiac Surgery: Outcome of 42 Patients with Abdominal Compartment Syndrome
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Michaela Ramser, Philipp Kirchhoff, Philippe M. Glauser, Tracy R. Glass, Henry Hoffmann, Benjamin Weixler, and Martin Grapow
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medicine.medical_specialty ,Abdominal compartment syndrome ,business.industry ,medicine.medical_treatment ,Vascular surgery ,medicine.disease ,Surgery ,Cardiac surgery ,03 medical and health sciences ,Abdominal decompression ,0302 clinical medicine ,Cardiothoracic surgery ,030220 oncology & carcinogenesis ,Laparotomy ,Intensive care ,medicine ,030211 gastroenterology & hepatology ,business ,Abdominal surgery - Abstract
Up to 50% of patients in intensive care units develop intraabdominal hypertension (IAH) in the course of medical treatment. If not detected on time and treated adequately, IAH may develop into an abdominal compartment syndrome (ACS) which is associated with a high mortality rate. Patients undergoing cardiac surgery are especially prone to develop ACS due to several risk factors including intraoperative hypothermia, fluid resuscitation and acidosis. We investigated patients who developed ACS after cardiac surgery and analyzed potential risk factors, treatment and outcome. From 2011 to 2016, patients with ACS after cardiac surgery requiring decompressive laparotomy were prospectively recorded. Patient characteristics, details on the cardiac surgery, mortality rate and type of treatment of the open abdomen were analyzed. Incidence of ACS in cardiac surgery patients was 1.0% (n = 42/4128), with a mortality rate of 57%. Ejection fraction, Euroscore2 as well as the perfusion time are independent risk factors for the development of ACS. The outcome of patients with ACS was independent of elective versus emergency surgery, gender, age, BMI or ASA score. In the 18 surviving patients, fascial closure was achieved in 72% after a median of 9 days. Abdominal compartment syndrome is a rare but serious complication after cardiac surgery with a high mortality rate. Independent risk factors for ACS were identified. Negative pressure wound therapy seems to promote and allow early fascia closure of the abdomen and represents therefore a likely benefit for the patient.
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- 2021
18. In vitro antileishmanial potentialities of essential oils from Citrus limon and Pistacia lentiscus harvested in Tunisia
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Marwa Yahyaoui, Ghozlene Mekhloufi, Florence Agnely, Sandrine Cojean, Zeineb Maaroufi, Philippe M. Loiseau, and Manef Abderraba
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Citrus ,Tunisia ,030231 tropical medicine ,Antiprotozoal Agents ,Leishmaniasis, Cutaneous ,Gas Chromatography-Mass Spectrometry ,030308 mycology & parasitology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Phenols ,law ,Oils, Volatile ,medicine ,Animals ,Humans ,Plant Oils ,Leishmania major ,Amastigote ,Axenic ,Essential oil ,0303 health sciences ,Miltefosine ,General Veterinary ,biology ,Pistacia ,Traditional medicine ,food and beverages ,Leishmaniasis ,General Medicine ,biology.organism_classification ,medicine.disease ,Plant Leaves ,Infectious Diseases ,Insect Science ,Pistacia lentiscus ,Parasitology ,medicine.drug - Abstract
Leishmaniasis is a tropical parasitic disease that affects up to 12 million people worldwide. Current chemotherapies have limitations such as toxicity, high cost, and parasite resistance. This work aims to select an essential oil (EssOil) isolated from the Tunisian flora as a new antileishmanial candidate. Two plants were chosen for their antileishmanial potential: Citrus limon (Citrus) and Pistacia lentiscus (Pistacia). Each of these plants was harvested from two different sites (area 1 and area 2). Extracted EssOils were characterized using GC-MS. Their antiparasitic activity against axenic and intracellular Leishmania major amastigotes and their cytotoxicity were assessed. Citrus EssOil from area 1 displayed an interesting activity against L. major intramacrophage amastigotes with IC50 value at 4.2 ± 1.3 μg/mL. Interestingly, this activity was close to that of miltefosine. Moderate activities against intracellular amastigote were observed for Pistacia EssOil from area 1 and Citrus EssOil from area 2. However, low cytotoxicity with high selectivity index was proved only for Citrus EssOil from area 1, revealing its safety for macrophages. This study also demonstrated for the first time the antileishmanial activity of EssOil extracted from Citrus limon leaves. The EssOil interesting activity could be related to the lipophilic properties of terpenes that were shown in literature to contribute to the disruption of parasite intracellular metabolic pathways.
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- 2021
19. Pneumocystis jirovecii Genotype Associated with Increased Death Rate of HIV-infected Patients with Pneumonia
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Meja Rabodonirina, Laetitia Vaillant, Patrick Taffé, Aimable Nahimana, René-Pierre Gillibert, Philippe Vanhems, and Philippe M. Hauser
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Pneumocystis jirovecii pneumonia ,HIV ,dihydropteroate synthase mutations ,opportunistic infection ,immunocompromised ,virus ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations have been associated with failure of sulfa prophylaxis; their effect on the outcome of patients with P. jirovecii pneumonia (PCP) remains controversial. P. jirovecii DHPS polymorphisms and genotypes were identified in 112 cases of PCP in 110 HIV-infected patients by using PCR single-strand conformation polymorphism. Of the 110 patients observed, 21 died; 18 of those deaths were attributed to PCP. Thirty-three percent of the PCP cases involved a P. jirovecii strain that had 1 or both DHPS mutations. The presence or absence of DHPS mutations had no effect on the PCP mortality rate within 1 month, whereas P.jirovecii type 7 and mechanical ventilation at PCP diagnosis were associated with an increased risk of death caused by PCP. Mechanical ventilation at PCP diagnosis was also associated with an increased risk of sulfa treatment failure at 5 days.
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- 2013
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20. The ARID1B spectrum in 143 patients
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Catherine Vincent-Delorme, Claudia A. L. Ruivenkamp, Marjan De Rademaeker, Francisco Martínez, Tracy Dudding-Byth, Marianne McGuire, Bert B.A. de Vries, Mitsuhiro Kato, Levinus A. Bok, Hülya Kayserili, Jeff M. Milunsky, Suzanne C E H Sallevelt, Alwin F. J. Brouwer, Jill Clayton-Smith, Emilia K. Bijlsma, Miranda Splitt, Patricia G. Wheeler, Philippe M. Campeau, Fatma Mujgan Sonmez, Kylin Lammers, Stefanie Beck-Wödl, Caroline Rooryck, Louise C. Wilson, Evan E. Eichler, Sarina G. Kant, Johanna C. Herkert, Karin R. Heitink, Eyyup Uctepe, Pleuntje J. van der Sluijs, Miho Adachi-Fukuda, Lone W. Laulund, Sandra Jansen, Nicolette S. den Hollander, Damien Lederer, Tomoki Kosho, Constance T. R. M. Stumpel, Saskia M. Maas, Esra Kılıç, Erica H. Gerkes, Duco Steenbeek, Melissa Lees, Kay Metcalfe, Karin Dahan, Ineke van der Burgt, Isabelle Maystadt, Christian Netzer, Ute Grasshoff, Carmen Orellana, Mahmut Şamil Sağıroğlu, Gijs W. E. Santen, Pelin Ozlem Simsek-Kiper, Mónica Roselló, Gabriela Soares, Alexander P.A. Stegmann, Stephen P. Robertson, Adila Al-Kindy, Maian Roifman, Saori Tanabe, Vera Riehmer, Brain H Y Chung, Arie van Haeringen, G. Eda Utine, Yasemin Alanay, Rogier Kersseboom, John B. Moeschler, Barbara Oehl-Jaschkowitz, Katherine Berry, Denise Horn, Alice Gardham, Shane McKee, Anwar Baban, Amparo Sanchis Calvo, Golder N. Wilson, Krystyna H. Chrzanowska, G. M. S. Mancini, Ellen R. Elias, Małgorzata Krajewska-Walasek, Rolph Pfundt, Sarju G. Mehta, Fabienne G. Ropers, Seiji Mizuno, David Hunt, Caroline Pottinger, Dagmar Wieczorek, Yoyo W. Y. Chu, Laurent Pasquier, Bernd Wollnik, Nobuhiko Okamoto, Sunita Venkateswaran, Vanesa López-González, Natalie Canham, Blanca Gener, Anne Destree, Christina Fagerberg, Rachel K. Earl, Sharon N M Olminkhof, Nursel Elcioglu, Charlotte W. Ockeloen, Carlo Marcelis, Samantha A. Vergano, Hermine E. Veenstra-Knol, Anneke T. Vulto-van Silfhout, Allan Bayat, Catheline Vilain, Lucia Solaeche, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), Klinische Genetica, van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Woedl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F. J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W. Y., Chung, Brain H. Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hulya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, Lopez-Gonzalez, Vanesa, Maas, Saskia, Mancini, Grazia M. S., Marcelis, Carlo, Martinez, Francisco, Maystadt, Isabelle, McGuire, Marianne, McKee, Shane, Mehta, Sarju, Metcalfe, Kay, Milunsky, Jeff, Mizuno, Seiji, Moeschler, John B., Netzer, Christian, Ockeloen, Charlotte W., Oehl-Jaschkowitz, Barbara, Okamoto, Nobuhiko, Olminkhof, Sharon N. M., Orellana, Carmen, Pasquier, Laurent, Pottinger, Caroline, Riehmer, Vera, Robertson, Stephen P., Roifman, Maian, Rooryck, Caroline, Ropers, Fabienne G., Rosello, Monica, Ruivenkamp, Claudia A. L., Sagiroglu, Mahmut S., Sallevelt, Suzanne C. E. H., Sanchis Calvo, Amparo, Simsek-Kiper, Pelin O., Soares, Gabriela, Solaeche, Lucia, Sonmez, Fatma Mujgan, Splitt, Miranda, Steenbeek, Duco, Stegmann, Alexander P. A., Stumpel, Constance T. R. M., Tanabe, Saori, Uctepe, Eyyup, Utine, G. Eda, Veenstra-Knol, Hermine E., Venkateswaran, Sunita, Vilain, Catheline, Vincent-Delorme, Catherine, Vulto-van Silfhout, Anneke T., Wheeler, Patricia, Wilson, Golder N., Wilson, Louise C., Wollnik, Bernd, Kosho, Tomoki, Wieczorek, Dagmar, Eichler, Evan, Pfundt, Rolph, de Vries, Bert B. A., Clayton-Smith, Jill, Santen, Gijs W. E., Erasmus MC other, Clinical Genetics, Human Genetics, and Acibadem University Dspace
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Male ,0301 basic medicine ,Hypertrichosis ,Pediatrics ,cuello ,bias ,Coffin–Siris syndrome ,Chromosomal Proteins, Non-Histone ,humanos ,adolescente ,Penetrance ,PHENOTYPE ,0302 clinical medicine ,Genotype ,Intellectual disability ,Exome ,Coffin-Siris syndrome ,Child ,mediana edad ,Genetics (clinical) ,Exome sequencing ,factores de transcripción ,adulto ,Middle Aged ,estudios de asociación genética ,3. Good health ,DNA-Binding Proteins ,intellectual disability ,Child, Preschool ,discapacidad intelectual ,penetrancia ,Female ,Hand Deformities, Congenital ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Adult ,medicine.medical_specialty ,Adolescent ,Micrognathism ,Article ,CHROMATIN-REMODELING COMPLEX ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,cara ,micrognatismo ,Human Phenotype Ontology ,medicine ,Humans ,Abnormalities, Multiple ,mutación ,Long eyelashes ,Genetic Association Studies ,lactante ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,MUTATIONS ,proteínas de unión al ADN ,Infant, Newborn ,Genetic Variation ,Infant ,ARID1B ,Hand Deformities ,Phalanx ,medicine.disease ,variación genética ,deformidades de la mano ,exoma ,030104 developmental biology ,Face ,Mutation ,business ,Neck ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)
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- 2019
21. The influence of a meniscal bucket handle tear on the Posterior Cruciate Ligament Angle in Anterior Cruciate Ligament Rupture – A case report
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Amine M. Korchi, Sana Boudabbous, Julien Billières, Oscar Vazquez, and Philippe M. Tscholl
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medicine.medical_specialty ,Anterior cruciate ligament ,Physical examination ,Case Report ,03 medical and health sciences ,0302 clinical medicine ,Chronic knee instability ,Medicine ,Anterior cruciate ligament rupture ,Bucket Handle ,medicine.diagnostic_test ,business.industry ,musculoskeletal, neural, and ocular physiology ,ACL ,Locked knee ,Arthroscopy ,musculoskeletal system ,Kinking ,Surgery ,medicine.anatomical_structure ,surgical procedures, operative ,PCL ,Clinical exam ,030220 oncology & carcinogenesis ,Posterior cruciate ligament ,030211 gastroenterology & hepatology ,business ,Medial meniscus ,human activities - Abstract
Highlights • The PCL angle in ACL-deficient knee might be false-negative in the presence of bucket handle tear. • There must be always high suspicious of ACL insufficiency in case of medial bucket handle tear. • Profound knowledge of clinical examination patient’s history is absolutely mandatory to examine ACL insufficiency., Introduction Chronic anterior cruciate ligament (ACL) tear might be difficult to diagnose on MRI. Indirect signs might be a typical meniscal or cartilage lesion, or a spontaneous anterior drawer visualized by a decreased angle of the posterior cruciate ligament (PCL). Presentation of case A 27-year-old former ballet dancer was admitted to the emergency department for a locked left knee, without never having experienced previous symptoms of giving way or locking. The MRI performed revealed a medial meniscus bucket handle tear, without traumatic bone marrow oedema or ligament injury. The PCL angle was 130°. A former MRI of her left knee performed 1 year previously to investigate on the recurrent catching of her left knee showed a grade III medial meniscal tear of the posterior horn, and buckling of the PCL angle of 100°, as a sign of chronic ACL rupture. During arthroscopy and medial meniscal repair, the ACL showed complete loss of tension, and was therefore reconstructed simultaneously to enable proper meniscal healing. Discussion and conclusion Chronic ACL insuffiency is a major risk factor for subsequent medial meniscus tear, especially bucket handle tear. The locked knee might unable proper pre-operative clinical examination. The preoperative MRI therefore being the only possibility to diagnose concomitant ligamentous injury. This is the first case reported in literature showing, that a positive PCL angle sign might be falsely negative due to a locked medial meniscus bucket handle tear.
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- 2020
22. Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study
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David Iannuzzi, Bruno Maranda, Philippe M. Campeau, John J. Mitchell, and Lina Moisan
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medicine.medical_specialty ,Canada ,Mucopolysaccharidosis ,Population ,lcsh:Medicine ,Physical examination ,chemistry.chemical_compound ,Elosulfase alfa ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Respiratory function ,Medical history ,Mucopolysaccharidosis IVA ,education ,Genetics (clinical) ,Retrospective Studies ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Research ,lcsh:R ,Quebec ,Founder effects ,Activities of daily living ,Mucopolysaccharidosis IV ,General Medicine ,Enzyme replacement therapy ,medicine.disease ,Natural history ,chemistry ,Walk test ,business ,Genetic disorders - Abstract
Background Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa. Results A total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease. Conclusions In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.
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- 2020
23. Early infantile epileptic encephalopathy due to biallelic pathogenic variants in <scp> PIGQ </scp> : Report of seven new subjects and review of the literature
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Rebecca C. Spillmann, Nissan V. Baratang, Kym M. Boycott, Karen W. Gripp, Taila Hartley, Anik St-Denis, Philippe M. Campeau, Kristin D. Kernohan, Erik A. Eklund, Jessica L. Zambonin, Loren D M Pena, Michael T. Geraghty, Andrew C. Edmondson, Jacek Majewski, Hugh J. McMillan, Allan Bayat, Miao He, Manuela Pendziwiat, Eric Bareke, Andrea Guerin, Thi Tuyet Mai Nguyen, Julie Richer, Devon L. Johnstone, and Hilde M. H. Braakman
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HYPERPHOSPHATASIA ,Male ,GLYCOSYLPHOSPHATIDYLINOSITOL ,Disease ,Immunoglobulin D ,Fatal Outcome ,0302 clinical medicine ,1ST STEP ,PIGQ ,Child ,Genetics (clinical) ,Exome sequencing ,0303 health sciences ,biology ,medicine.diagnostic_test ,rare diseases ,DEFECTS ,Transfection ,Phenotype ,3. Good health ,epileptic encephalopathy ,Child, Preschool ,Muscle Hypotonia ,Original Article ,Female ,medicine.symptom ,Spasms, Infantile ,DISORDERS ,Mutation, Missense ,Status epilepticus ,Flow cytometry ,03 medical and health sciences ,Seizures ,Exome Sequencing ,Genetics ,medicine ,Humans ,BIOSYNTHESIS ,Abnormalities, Multiple ,IGD ,Gene ,030304 developmental biology ,MUTATIONS ,business.industry ,Infant, Newborn ,Infant ,Membrane Proteins ,Original Articles ,GENE ,GPI ,Immunology ,biology.protein ,business ,exome sequencing ,030217 neurology & neurosurgery - Abstract
We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)‐anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ‐related disease and provide the first functional evidence in human cells of defective GPI‐anchoring due to pathogenic variants in PIGQ.
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- 2020
24. Apoprunellelactone (APL), an antiprotozoal lactone from the stem barks of Isolona cooperi Hutch. & Dalziel (Annonaceae)
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Venance Martial Say, Philippe M. Loiseau, Pierre Champy, Faustin Aka Kabran, Laurent Evanno, Bruno Figadère, Timothée Aboua Okpekon, and Alexandre Maciuk
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chemistry.chemical_classification ,Bioassay guided fractionation ,Traditional medicine ,010405 organic chemistry ,medicine.drug_class ,Organic Chemistry ,Plant Science ,Biology ,biology.organism_classification ,01 natural sciences ,Biochemistry ,Isolona cooperi ,0104 chemical sciences ,Analytical Chemistry ,010404 medicinal & biomolecular chemistry ,chemistry ,Annonaceae ,Antiprotozoal ,medicine ,Lactone - Abstract
Bioassay guided fractionation of the stem barks of Isolona cooperi led to the isolation of a new lactone, apoprunellelactone (APL, 1), and two known compounds, 5-[1-hydroxyhexyl]-2H-furan-2-one (2) and oleic acid (3). Their structures were elucidated by spectral analysis including MS, UV, IR, 1D and 2D-NMR spectroscopy. Evaluated for its antiprotozoal activities, APL (1) was found to be the most active on Leishmania donovani and L. major promastigotes with EC50 values of 16.3 and 8.2 µM, respectively. Against Trypanosoma brucei brucei trypomastigote forms, the activity of APL was moderated (MEC = 38.0 µM). Its hemisynthetic ester acetic derivative (1c) was 2-42 times more active than that of the APL and reference drugs, justifying further in vivo evaluation of the two compounds (1 and 1c) on Leishmania sp and Trypanosoma brucei brucei/mice models.
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- 2020
25. Complete response to talimogene laherparepvec in a primary acral lentiginous melanoma
- Author
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Alexander C.J. van Akkooi, Jacqueline E. van der Wal, Philippe M G Smeets, and Viola Franke
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Herpesvirus 1, Human ,Dermatology ,medicine.disease_cause ,Acral lentiginous melanoma ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Humans ,Medicine ,Stage (cooking) ,Melanoma ,Aged, 80 and over ,Biological Products ,business.industry ,medicine.disease ,Oncolytic virus ,030104 developmental biology ,Herpes simplex virus ,Lymphatic system ,Oncology ,030220 oncology & carcinogenesis ,Female ,Talimogene laherparepvec ,business - Abstract
Talimogene laherparepvec (T-VEC) is an oncolytic virus, approved for the treatment of stage IIIb-IVM1a melanoma with injectable disease (cutaneous, subcutaneous or lymphatic). It is a modified herpes simplex virus type 1 that induces tumor-specific T-cell responses via reduction of virally mediated suppression of antigen presentation, stimulation of viral pathogenicity and enhancement of tumor-selective replication. Response rates up to 82.6% have been reported for stage III disease. Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with a poor prognosis. Here, we present a case of an elderly and frail patient with primary ALM who refused surgical treatment and consented to receive T-VEC as first-line drug therapy. After 10 courses of treatment, a histopathologically confirmed complete response was achieved. To our knowledge, this is the first case ever reported in which a primary ALM is (successfully) treated with T-VEC.
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- 2020
26. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome
- Author
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Ann Seman, Rixa Woitschach, Duygu Selcen, Divya Nair, Lauren Gunderson, Mahim Jain, Sha Tang, Giuseppe Zampino, Julien L. Marcadier, Marielle Alders, Jason Pinner, Melanie Napier, Linda Hasadsri, Marina Macchiaiolo, Alyssa Blesson, Pavel N. Pichurin, Joseph T. Alaimo, Arjan Bouman, Philippe M. Campeau, Catherine Karimov, Chitra Prasad, Anne Dieux-Coeslier, Nicole L. Bertsch, Bernd Wollnik, Janine Altmüller, Zöe Powis, Holly Dubbs, Tahsin Stefan Barakat, Gregory M. Cooper, Kristen J. Rasmussen, Perrine Brunelle, Patrick R. Blackburn, Erica D. Smith, Jeff M. Milunsky, Katja Kloth, E. Martina Bebin, Lot Snijders Blok, Knut Brockmann, Karin Weiss, Xilma R. Ortiz-Gonzalez, Danna Gal, Dong Li, Francesca Clementina Radio, Joan M. Stoler, Elaine H. Zackai, Jiddeke M. van de Kamp, Deepali N. Shinde, Huifang Yan, Thomas Smol, Alejandro Ferrer, Dagmar Weise, Baiba Lace, Deborah L. Renaud, Lauren E. Bartik, Beth Keena, Michelle L. Thompson, Carol J Saunders, Theodore G. Drivas, Elizabeth J. Bhoj, Eric T. Rush, Marco Tartaglia, Eric W. Klee, Margit Burmeister, Jingmin Wang, Jonas Denecke, Clinical genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, and Clinical Genetics
- Subjects
Adult ,Male ,CHD3 variants ,Genetic testing ,Adolescent ,Snijders Blok-Campeau syndrome ,Developmental Disabilities ,medicine.disease_cause ,Pediatrics ,Article ,Chromodomain ,Craniofacial Abnormalities ,Catalytic Domain ,Intellectual Disability ,Genetics ,medicine ,Missense mutation ,Humans ,Child ,Genetics (clinical) ,Mutation ,medicine.diagnostic_test ,biology ,Significant difference ,DNA Helicases ,Helicase ,Infant ,Syndrome ,Autism spectrum disorders ,Phenotype ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,Cohort ,biology.protein ,Female ,Mi-2 Nucleosome Remodeling and Deacetylase Complex - Abstract
There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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- 2020
27. Inguinal and femoral hernia repair in octogenarians and nonagenarians – A population-based analysis
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Philipp Kirchhoff, Henry Hoffmann, Ralph F. Staerkle, Joana Pina-Vaz, Marco von Strauss und Torney, and Philippe M. Glauser
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medicine.medical_specialty ,octogenarians ,medicine.medical_treatment ,Population ,lcsh:Surgery ,femoral hernia ,elderly ,medicine ,education ,education.field_of_study ,Groin ,business.industry ,emergency ,Bowel resection ,Perioperative ,lcsh:RD1-811 ,Femoral hernia ,medicine.disease ,Hernia repair ,humanities ,Surgery ,Inguinal hernia ,medicine.anatomical_structure ,nonagenarians ,inguinal hernia ,business ,Watchful waiting - Abstract
PURPOSE: Our primary aim was to evaluate the inhospital mortality (IHM) of elderly patients undergoing inguinal or femoral hernia repair (groin hernia repair GHR), since this growing population is associated with increased perioperative risks. MATERIALS AND METHODS: Totally 179,806 patients undergoing GHR between 2005 and 2015 in Switzerland were divided into three cohorts: 80 years) represent 8.86% (n = 15,750) of our sample. The IHM for elective GHR in these patients is low (0.15% for octogenarians and 0.8% for nonagenarians). For emergency surgery, it increases substantially (4.1% and 7.5%, respectively). In emergency cases with a combined bowel resection (n = 755), the IHM has a fivefold increase for nonagenarians when compared to the younger population. The IHM was significantly higher with femoral hernia repair, especially in the elderly (4.75% – octogenarians and 11.4% – nonagenarians). When adjusting for other variables, there is a twofold risk of death with femoral hernia repair. Patients with a Charlson Comorbidity Index (CCI) ≥2 have a 7.5 times higher risk of dying after GHR. All of these results were statistically significant (P < 0.0001). CONCLUSIONS: This retrospective analysis highlights the increased operative risk in emergency compared to elective GHR in the elderly. This should be considered when opting for watchful waiting in minimally symptomatic octo- and nonagenarians.
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- 2020
28. Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction
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Caroline Nava, Justine Rousseau, Hugo J. Bellen, Yi Ting Cheng, Jiani Chen, Julia Wang, Philippe M. Campeau, Zhongyuan Zuo, Fowzan S. Alkuraya, Weimin Bi, Eissa Faqeih, Alexandra Afenjar, Lee-Jun C. Wong, Klaas J. Wierenga, Jill A. Rosenfeld, Jane Juusola, Joseph G. Gleeson, Sophie Ehresmann, Boris Keren, Diane Doummar, David Li-Kroeger, Ye Jin Park, Emily Kim, Markus Grompe, and Lita Duraine
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,Mutant ,Biology ,medicine.disease_cause ,Article ,Mitochondrial Proteins ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cerebellar Diseases ,Genetics ,medicine ,Animals ,Humans ,V-ATPase ,Global developmental delay ,Child ,Gene ,Genetics (clinical) ,Fibroblasts ,Phenotype ,Pedigree ,Cell biology ,Oxidative Stress ,Drosophila melanogaster ,030104 developmental biology ,Speech delay ,Female ,Cerebellar atrophy ,Atrophy ,Nervous System Diseases ,medicine.symptom ,Lysosomes ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.
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- 2019
29. Trichomonas vaginalis Motility Is Blocked by Drug-Free Thermosensitive Hydrogel
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Philippe M. Loiseau, Sophia Malli, and Kawthar Bouchemal
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0301 basic medicine ,Infectivity ,biology ,Chemistry ,Cilium ,030106 microbiology ,Cell ,Motility ,Flagellum ,biology.organism_classification ,medicine.disease_cause ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,medicine ,Parasite hosting ,Trichomonas vaginalis ,Bacteria - Abstract
Trichomonas vaginalis motility in biological fluids plays a prominent, but understudied, role in parasite infectivity. In this study, the ability of a thermosensitive hydrogel (pluronic F127) to physically immobilize T. vaginalis was investigated. Blocking parasite motility could prevent its attachment to the mucosa, thus reducing the acquisition of the infection. The trajectory of individual parasites was monitored by multiple particle tracking. Mean square displacement, diffusivity, and velocity were calculated from x, y coordinates during time. Major results are that T. vaginalis exhibited different types of trajectories in a diluted solution composed of lactate buffer similar to "run-and-tumble" motion reported for flagellated bacteria. The fastest T. vaginalis specimen moves with a velocity of 19 μm/s. Observation of T. vaginalis movements showed that the cell body remains rigid during swimming and that the propulsive forces necessary to generate the movement are the result of flagellar beating. Parasite motility was partially slowed down using hydroxyethylcellulose hydrogel, used as a reference for the development of vaginal microbicides, while 100% of T. vaginalis were immobile in F127 hydrogel. Once completed by biological investigations on mice, this report suggests using drug-free formulation composed of F127 as a new strategy to prevent T. vaginalis attachment to the mucosa. The concept will be extended to other flagellated organisms where the motility is driven by cilia and flagella.
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- 2019
30. A variant of neonatal progeroid syndrome, or Wiedemann–Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL
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Sophie Ehresmann, Hyunyun Kim, Virginie Saillour, Smrithi Salian, Guylaine DʹAmours, Philippe M. Campeau, Julie Gauthier, Jean-François Soucy, Grant A. Mitchell, Eliane Beauregard-Lacroix, Geneviève Bernard, and Jacques L. Michaud
- Subjects
media_common.quotation_subject ,Nonsense ,Biology ,Article ,Neonatal Progeroid Syndrome ,03 medical and health sciences ,Progeria ,0302 clinical medicine ,Protein Domains ,Genetics ,medicine ,Humans ,Allele ,Gene ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,media_common ,0303 health sciences ,Fetal Growth Retardation ,RNA Polymerase III ,RNA ,medicine.disease ,Phenotype ,3. Good health ,Codon, Nonsense ,Child, Preschool ,Female ,Lipodystrophy ,030217 neurology & neurosurgery - Abstract
Neonatal progeroid syndrome, also known as Wiedemann–Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.
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- 2019
31. Heterozygous variant in WNT1 gene in two brothers with early onset osteoporosis
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Philippe M. Campeau, Mona Al Mukaddam, Amna Khan, Stephanie Byers Asher, Kyu Sang Joeng, Christie Gloria Turin, Staci Kallish, and Anna Raper
- Subjects
medicine.medical_specialty ,VUS, variant of unknown significance ,Early osteoporosis ,ACMG, American College of Medical Genetics ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Case Report ,Diseases of the musculoskeletal system ,WNT1 pathway ,Bone resorption ,Frameshift mutation ,Bone remodeling ,Internal medicine ,medicine ,BMD, Bone mineral density ,Orthopedics and Sports Medicine ,WNT1 ,Gene ,Genetic variant ,business.industry ,Wnt signaling pathway ,DXA, dual-energy X-ray absorptiometry ,medicine.disease ,Endocrinology ,RC925-935 ,business ,Fragility fractures ,Homeostasis - Abstract
Osteoporosis is a multifactorial disorder characterized by low bone mass and strength, leading to increased risk of fracture. The WNT pathway plays a critical role in bone remodeling by enhancing osteoblastic differentiation, which promotes bone formation, and inhibiting osteoclastic differentiation, decreasing bone resorption. Therefore, genetic alterations of this pathway will lead to impaired bone homeostasis and could contribute to varying response to treatment. We present the case of two brothers with early osteoporosis who were found to have a heterozygous variant of unknown significance in the WNT1 gene, c.1060_1061delCAinsG (p.H354Afs*39). This finding demonstrates that frameshift variants in WNT1 may also act in a dominant fashion leading to decreased bone mass.
- Published
- 2021
32. Endograft apposition and infrarenal neck enlargement after endovascular aortic aneurysm repair
- Author
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Nada Y. Elzefzaf, Philippe M. de Rooy, Claire van der Riet, Rogier H.J. Kropman, Ranjeet Narlawar, Jan Wille, George A. Antoniou, Ignace F.J. Tielliu, Jean-Paul P.M. de Vries, Richte C.L. Schuurmann, Multi-Modality Medical Imaging, TechMed Centre, and Robotics and image-guided minimally-invasive surgery (ROBOTICS)
- Subjects
Time Factors ,Computed Tomography Angiography ,medicine.medical_treatment ,Prosthesis Design ,Endovascular aneurysm repair ,Aortography ,Neck enlargement ,Blood Vessel Prosthesis Implantation ,Interquartile range ,Predictive Value of Tests ,medicine.artery ,Multidetector Computed Tomography ,medicine ,Humans ,Aorta, Abdominal ,Renal artery ,Abdominal ,imaging ,Neck diameter ,Computed tomography angiography ,Retrospective Studies ,Three-dimensional ,stents ,Aortic aneurysm repair ,Aortic aneurysm ,medicine.diagnostic_test ,business.industry ,Endovascular Procedures ,General Medicine ,Blood Vessel Prosthesis ,Apposition ,Treatment Outcome ,Surgery ,Cardiology and Cardiovascular Medicine ,Nuclear medicine ,business ,Aortic Aneurysm, Abdominal - Abstract
BACKGROUND: Sufficient apposition and oversizing of the endograft in the aortic neck are both essential for durable endovascular aneurysm repair (EVAR). These measures are however not regularly stated on post-EVAR computed tomography angiography (CTA) scan reports. In this study endograft apposition and neck enlargement (NE) after EVAR with an Endurant II(s) endograft were analyzed and associated with supra- and infrarenal aortic neck morphology.METHODS: In 97 consecutive elective patients, the aortic neck morphology was measured on the pre-EVAR CTA scan on a 3mensio vascular workstation. The distance between the lowest renal artery and the proximal edge of the fabric (shortest fabric distance, SFD), and the shortest length of circumferential apposition between endograft and aortic wall (shortest apposition length, SAL) was determined on the early post-EVAR CTA scan. NE, defined as the aortic diameter change between pre- and post-EVAR CTA scan, was determined at eight levels: +40, +30, +20, +15, +10, 0, -5 and -10 mm relative to the lowest renal artery baseline. The aortic neck diameter and preoperative oversizing were correlated to NE with the Pearson correlation coefficient. The effective post-EVAR endograft oversizing is calculated from the nominal endograft diameter and the post-EVAR neck diameter where the endograft is circumferentially apposed.RESULTS: The median time (interquartile range, IQR) between the EVAR procedure and the pre- and post-EVAR CTA scan was 40 (25, 71) days and 36 (30, 46) days, respectively. The Endurant II(s) endograft was deployed with a median (IQR) SFD of 1.0 (0.0, 3.0) mm. The SAL was CONCLUSIONS: Circumferential apposition between an endograft and the infrarenal aortic neck, SAL, and NE can be derived from standard postoperative CT scans. These variables provide essential information about the post-procedural endograft and aortic neck morphology regardless of the preoperative measurements. Patients with SAL
- Published
- 2021
33. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia
- Author
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Virginia Fano, Martyn T. Cobourne, Patricia Carl-Innig, Michael B. Bober, Melita Irving, Fabio Mazzoleni, Jeffrey W. Campbell, Brigitte Fauroux, Dominic Thompson, Judith P Rossiter, Jenna W. Briddell, Yosha Prasad, Mary C. Theroux, Geert Mortier, Antonio Leiva-Gea, Amaka C. Offiah, Klaus Mohnike, Penny Ireland, James A. Betts, Juan Llerena, Steven Powell, Heather Elphick, Pablo Rosselli, Wagner A.R. Baratela, Therese Hannon, Kenneth W. Martin, Marco Sessa, Natsuo Yasui, Michael Wright, Moira Cheung, Matthew Thomas, Inês Alves, Jonathan Gibbins, Cathleen L. Raggio, Muriel Deladure-Molla, Angelo Selicorni, Lars Hagenäs, Sharon McDonnell, William G. Mackenzie, Morrys Kaisermann, Maria Costanza Meazzini, Svein O. Fredwall, Laura Trespedi, Ravi Savarirayan, Philippe M. Campeau, Mari L. Groves, Valérie Cormier-Daire, Keiichi Ozono, Julie Hoover-Fong, David E. Tunkel, John A. Phillips, Josef Milerad, Silvio Boero, C Wallis, and Mariana del Pino
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Consensus ,Statement (logic) ,Endocrinology, Diabetes and Metabolism ,MEDLINE ,Achondroplasia ,Endocrinology ,Quality of life (healthcare) ,SDG 3 - Good Health and Well-being ,Multidisciplinary approach ,Osteogenesis ,Medicine ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Intensive care medicine ,business.industry ,medicine.disease ,Life stage ,Optimal management ,Mutation ,Quality of Life ,Human medicine ,business ,Psychosocial - Abstract
Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life. Achondroplasia is the most common skeletal dysplasia and is characterized by various lifelong clinical, functional and psychosocial challenges for affected individuals. This first International Consensus Statement on the care of children and adults with achondroplasia aims to facilitate the global standardization and improvement of achondroplasia clinical care.
- Published
- 2021
34. Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index
- Author
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Syed Zahed Rasheed, Sean Richards, Asif Rasheed, Nabi Shah, Anastasia Gurinovich, Treeve Currie, Shahid Abbas, Shari L. Caplan, Subhan Saeed, Shareef Khalid, Amit Khera, John Dominy, Linh Vong, Allan Gurtan, Sekar Kathiresan, Daniel Denning, Fazal-ur-Rehman Memon, Lindsey Lamarche, Philippe M. Frossard, Anjum Jalal, John Danesh, Raffat Sultana, Shahid Hameed, M. Ishaq, Danish Saleheen, Imran Saleem, and Diana Shpektor
- Subjects
business.industry ,Medicine ,Physiology ,Type 2 diabetes ,Odds ratio ,Allele ,business ,medicine.disease ,Body mass index ,Allele frequency ,Obesity ,Exome ,Gene knockout - Abstract
Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we follow up on GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify 3 GPR151 putative loss-of-function (plof) variants (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7) with a cumulative allele frequency of 2.2% and present at homozygosity. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits. GPR151 deficiency in complete human knockouts is not associated with a clinically significant difference in BMI. Moreover, loss of GPR151 confers a nominally significant increase in risk of T2D (odds ratio = 1.2, p value = 0.03). Relative to wild-type mice, Gpr151-/- animals exhibit no difference in body weight on normal chow, and higher body weight on a high-fat diet, consistent with the findings in humans. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach for obesity.
- Published
- 2021
35. Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1
- Author
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Delphine Héron, Wendy Mears, Smrithi Salian, William Boyce Burns, Julia Russo, Elliot S. Stolerman, Valentina Serpieri, David A. Dyment, Philippe M. Campeau, Susanne Morlot, Kristin Herman, Thi Tuyet Mai Nguyen, Ginevra Zanni, Boris Keren, Rachel Rock, Raffaella Cusmai, Efrat Sofrin-Drucker, Hannah Wallaschek, Alison M.R. Castle, Julie R. Jones, Devon L. Johnstone, Haim Bassan, Children's Hospital of Eastern Ontario, CHU Sainte Justine [Montréal], Tel Aviv University [Tel Aviv], University of California, Bambino Gesù Children’s Hospital [Rome, Italy], Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], 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), Service de Génétique médicale [CHU Pitié-Salpêtrière], Hannover Medical School [Hannover] (MHH), BC Children's Hospital Research Institute [Vancouver, BC, Canada] (BCCHR), University of British Columbia (UBC), The Greenwood Genetic Center, University of Pavia, and IRCCS Mondino Foundation
- Subjects
Genetics ,0303 health sciences ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,medicine.diagnostic_test ,Glycosylphosphatidylinositol ,Developmental disorders ,Biology ,Phenotype ,Hypotonia ,Clinical knowledge ,Flow cytometry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Neuroimaging ,All Genetics ,medicine ,Alkaline phosphatase ,Neurology (clinical) ,Functional studies ,medicine.symptom ,030217 neurology & neurosurgery ,Genetics (clinical) ,030304 developmental biology - Abstract
Background and ObjectivesTo expand the clinical knowledge of GPAA1-related glycosylphosphatidylinositol (GPI) deficiency.MethodsAn international case series of 7 patients with biallelic GPAA1 variants were identified. Clinical, biochemical, and neuroimaging data were collected for comparison. Where possible, GPI-anchored proteins were assessed using flow cytometry.ResultsTen novel variants were identified in 7 patients. Flow cytometry samples of 3 available patients confirmed deficiency of several GPI-anchored proteins on leukocytes. Extensive phenotypic information was available for each patient. The majority experienced developmental delay, seizures, and hypotonia. Neuroimaging revealed cerebellar anomalies in the majority of the patients. Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects. We notably describe individuals either less affected or older than the ones published previously.DiscussionClinical features of the cases reported broaden the spectrum of the known phenotype of GPAA1-related GPI deficiency, while outlining the importance of using functional studies such as flow cytometry to aid in variant classification.
- Published
- 2021
36. BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
- Author
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Øyvind L. Busk, Kimberley Bradbury, Arjan Bouman, Philippe M. Campeau, Lynne M. Bird, Cornelia Kraus, Colleen Carlston, Rong Mao, Juliette Piard, Laurence Faivre, Amanda Openshaw, Catherine Ward Melver, Mohnish Suri, Christiane Zweier, François Guillemot, Rolph Pfundt, Janice C. Palumbos, Parthiv Haldipur, Jane A. Hurst, Kimberly McDonald, Margaux Serey-Gaut, Luitgard Graul-Neumann, Karen J. Low, Jenny Carmichael, Patrick Ferrerira, Birgit Elisabeth Kristiansen, Ange-Line Bruel, Constance Motter, Andrea Accogli, Darrah N. Haffner, Suhair Hanna, Ruta Marcinkute, Angela Peron, Marcella Zollino, Sofia Maia, James Lespinasse, Claire E. Turner, Sally Ann Lynch, Richard E. Person, Valeria Capra, Kimberly A. Aldinger, Constance Smith-Hicks, Gyri Aasland Gradek, Ingrid M. Wentzensen, Megha Desai, Manuela Morleo, Aditi Shah Parikh, Marcello Scala, Cristina Dias, Gunnar Houge, Telethon Undiagnosed Disease Program, Anne Slavotinek, Roberta Battini, Mary J. Green, Anna Chassevent, Tara Montgomery, David Viskochil, Tatiana Tvrdik, Dawn L. Earl, Karin Weiss, Felice D'Arco, William B. Dobyns, Ping Yee Billie Au, Daniah Beleford, Erica F. Andersen, Bert B.A. de Vries, Jill Clayton-Smith, Christophe Philippe, and Michael J. Bamshad
- Subjects
business.industry ,Postnatal microcephaly ,Microdeletion syndrome ,medicine.disease ,Bioinformatics ,Hypotonia ,Developmental disorder ,Autism spectrum disorder ,Intellectual disability ,Fetal hemoglobin ,medicine ,Missense mutation ,medicine.symptom ,business - Abstract
PurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.MethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.ResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.ConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.
- Published
- 2021
37. Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci
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Zoubia Hina, Julian L. Griffin, Asif Rasheed, Nadeem Qamar, Danish Saleheen, Dirk S. Paul, Imran Saleem, Taniya Sattar, M. Ishaq, Nadeem Hayat Mallick, Adam S. Butterworth, Philippe M. Frossard, Daniel Ziemek, Fazal-ur-Rehman Memon, Syed Nadeem Hasan Rizvi, Albert Koulman, Anjum Jalal, Tahir Saghir, John Danesh, Angela M. Wood, David Stacey, Eric B. Fauman, Unzila Ishtiaq, Anis Memon, Rachel M. Y. Ong, Eric L. Harshfield, Shahid Abbas, Zameer-ul-Asar, Zia Yaqub, Syed Zahed Rasheed, Harshfield, Eric [0000-0001-8767-0928], Paul, Dirk [0000-0002-8230-0116], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], Wood, Angela [0000-0002-7937-304X], Koulman, Albert [0000-0001-9998-051X], Apollo - University of Cambridge Repository, and Paul, Dirk S [0000-0002-8230-0116]
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South asia ,Population ,Myocardial Infarction ,Blood lipids ,Disease ,Gaussian Graphical Modelling ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Lipidomics ,Genetics ,Medicine ,South Asian ,Humans ,Genetic Predisposition to Disease ,education ,Gene ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,business.industry ,General Medicine ,Lipidome ,Lipids ,Genetic architecture ,3. Good health ,Network analysis ,business ,030217 neurology & neurosurgery ,Research Article ,Genome-Wide Association Study - Abstract
Background Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. Methods We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. Results We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. Conclusions Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.
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- 2021
38. 'What Really Matters When Performing a Laparoscopic Roux-en Y Gastric Bypass?' Literature-Based Key Steps Towards Success and Standardization of the Procedure
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Jean-Philippe M. M. K. Magema, Jacques Himpens, UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service de chirurgie
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Gastric bypass ,Nutrition and Dietetics ,Standardization ,Gastroplasty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Gastric Bypass ,Literature based ,Reference Standards ,Limb length ,Roux-en-Y anastomosis ,Obesity, Morbid ,Treatment Outcome ,Key steps ,Weight regain ,Key (cryptography) ,Medicine ,Humans ,Surgery ,Operations management ,Laparoscopy ,business - Abstract
Lack of standardization in the Roux-en-Y gastric bypass (RY-GBP) is quite well established. We all learned the basics of the technique, but a lot of differences do exist in performing each step of the procedure. Based on scientific evidences, coming from an extensive and meticulous review of the literature of the last 20 years, we thus address the different technical steps of the procedure and their importance to try and propose a standardization of RYGBP. A lot of possibilities exist at each and every step of a RYGBP. They influence the postoperative complications, the end weight loss (EWL), weight regain, and resolution of obesity bounded comorbidities. Furthermore, lack of standardization leads to problems regarding comparison of scientific data in the related literature.
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- 2021
39. Validation of two contrasting capturing mechanisms for gaseous formaldehyde between two different types of strong metal-organic framework adsorbents
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Sherif A. Younis, Thi Yen Tran, Philippe M. Heynderickx, and Ki-Hyun Kim
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Environmental Engineering ,Aqueous solution ,Chemistry ,Health, Toxicology and Mutagenesis ,Formaldehyde ,Analytical chemistry ,Partial pressure ,Pollution ,chemistry.chemical_compound ,Adsorption ,medicine ,Environmental Chemistry ,Metal-organic framework ,Relative humidity ,Benzene ,Waste Management and Disposal ,Activated carbon ,medicine.drug - Abstract
In this research, the adsorption behavior of formaldehyde (FA) onto two types of metal-organic frameworks (MOFs: MOF-199 [M199] and UiO-66-NH2 [U6N]) is investigated against changes in the key process variables (e.g., FA partial pressure (0.5–10 Pa), temperature (30–120 °C), and relative humidity (RH: 0%, 50%, and 100%)). The results revealed that the FA adsorption behavior onto both MOFs is exothermic in nature. Besides, their relative dominance for FA uptake varies interactively with the changes in RH and FA partial pressure levels. As the FA levels increase in dry conditions, their breakthrough volumes (BTV (100% BT)) exhibit contrasting trends: The values of U6N decreased noticeably from 5232 and 3792 L·atm·g−1, while those of M199 increased from 4152 to 5772 L·atm·g−1. The superiority of U6N over M199 in the lower FA level (at
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- 2021
40. Intranasal vaccine from whole Leishmania donovani antigens provides protection and induces specific immune response against visceral leishmaniasis
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Doumet Georges Helou, François Fasquelle, Juliane Sousa Lanza, Aurélie Mauras, Didier Betbeder, Philippe M. Loiseau, and Sandrine Cojean
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Life Cycles ,Physiology ,RC955-962 ,Antibodies, Protozoan ,Protozoology ,Adaptive Immunity ,White Blood Cells ,Mice ,Medical Conditions ,Animal Cells ,Bone Marrow ,Arctic medicine. Tropical medicine ,Zoonoses ,Immune Physiology ,Medicine and Health Sciences ,Cytotoxic T cell ,Leishmaniasis ,Immune Response ,Vaccines ,Mice, Inbred BALB C ,T Cells ,Acquired immune system ,Infectious Diseases ,Liver ,Leishmaniasis, Visceral ,Protozoan Life Cycles ,Female ,Public aspects of medicine ,RA1-1270 ,Cellular Types ,Research Article ,Neglected Tropical Diseases ,Infectious Disease Control ,Immune Cells ,Immunology ,Leishmania donovani ,Cytotoxic T cells ,Antigens, Protozoan ,Biology ,Microbiology ,Interferon-gamma ,Immune system ,Antigen ,Adjuvants, Immunologic ,medicine ,Parasitic Diseases ,Animals ,Leishmaniasis Vaccines ,Administration, Intranasal ,Protozoan Infections ,Blood Cells ,Promastigotes ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Cell Biology ,biology.organism_classification ,medicine.disease ,Leishmania ,Tropical Diseases ,Visceral leishmaniasis ,Immunization ,Spleen ,Developmental Biology - Abstract
Visceral leishmaniasis is a protozoan disease associated with high fatality rate in developing countries. Although the drug pipeline is constantly improving, available treatments are costly and live-threatening side effects are not uncommon. Moreover, an approved vaccine against human leishmaniasis does not exist yet. Using whole antigens from Leishmania donovani promastigotes (LdAg), we investigated the protective potential of a novel adjuvant-free vaccine strategy. Immunization of mice with LdAg via the intradermal or the intranasal route prior to infection decreases the parasitic burden in primary affected internal organs, including the liver, spleen, and bone marrow. Interestingly, the intranasal route is more efficient than the intradermal route, leading to better parasite clearance and remarkable induction of adaptive immune cells, notably the helper and cytotoxic T cells. In vitro restimulation experiments with Leishmania antigens led to significant IFN-γ secretion by splenocytes; therefore, exemplifying specificity of the adaptive immune response. To improve mucosal delivery and the immunogenic aspects of our vaccine strategy, we used polysaccharide-based nanoparticles (NP) that carry the antigens. The NP-LdAg formulation is remarkably taken up by dendritic cells and induces their maturation in vitro, as revealed by the increased expression of CD80, CD86 and MHC II. Intranasal immunization with NP-LdAg does not improve the parasite clearance in our experimental timeline; however, it does increase the percentage of effector and memory T helper cells in the spleen, suggesting a potential induction of long-term memory. Altogether, this study provides a simple and cost-effective vaccine strategy against visceral leishmaniasis based on LdAg administration via the intranasal route, which could be applicable to other parasitic diseases., Author summary Visceral leishmaniasis is a neglected tropical disease caused by specific species of Leishmania parasites that affect internal organs including spleen, liver, and bone marrow. The infective stage called promastigote, is transmitted into the host skin via sandfly bites. Visceral leishmaniasis is usually associated with high mortality rate in poor and developing countries, lacking proper health assistance. Moreover, treatments are expensive while no approved vaccines exist to prevent infection and avoid disease outbreaks. This study suggests an affordable and adjuvant-free vaccine formulation made from the total lysate of promastigotes. Vaccine administration via the intranasal route, ensures a remarkable clearance of Leishmania parasites from the internal organs of infected experimental mice. In particular, intranasal route known to be not invasive, is efficient in inducing adequate immune response against the infective form of the parasite. Further studies are now required to improve this prophylactic vaccine and provide therefore the basis for a promising translational approach.
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- 2021
41. Calvarial doughnut lesions with bone fragility in a French-Canadian family; case report and review of the literature
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Valancy Miranda, Melissa Fiscaletti, Philippe M. Campeau, Johanne Dubé, Shuaa Basalom, Elise Monceau, Céline Huber, Régen Drouin, Outi Mäkitie, Guillaume Couture, Valérie Cormier-Daire, and Sandrine Wavrant
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Proband ,Pathology ,medicine.medical_specialty ,Calvarial doughnut lesions with bone fragility ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Nonsense ,Case Report ,Diseases of the musculoskeletal system ,Metacarpal bones ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Bone fragility ,Orthopedics and Sports Medicine ,030304 developmental biology ,media_common ,Genetic testing ,Bone mineral ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Penetrance ,SGMS2 ,3. Good health ,Osteopenia ,Skull ,medicine.anatomical_structure ,RC925-935 ,Skeletal dysplasia ,business - Abstract
Calvarial Doughnut Lesions with Bone Fragility (CDL) is an autosomal dominant genetic disease, characterized by low bone mineral density, multiple fractures starting in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Aubé and colleagues described in 1988 a French-Canadian family of 12 affected members who had a clinical diagnosis of doughnut lesions of the skull, with pathological fractures, osteopenia, “bone in bone” in the vertebral bodies and squaring of metatarsal and metacarpal bones. Herein we study new members of this family. Sequential genetic testing identified a nonsense variant c.148C>T, p. Arg50⁎ in SGMS2 previously reported in other families. SGMS2 encodes Sphingomyelin Synthase 2, which produces Sphingomyelin (SM), a major lipid component of the plasma membrane that plays a role in bone mineralization. The nonsense variant is associated with milder phenotype. The proband presents with bone in bone vertebral appearance that had been defined uniquely in the first cases described in the same family. The proband's son was identified to carry the same variant, which makes him the sixth generation with the diagnosis of CDL. We also report that the same pathogenic variant was identified in another previously described family, from France. These reports further confirm the genetic basis of CDL, the recurrence of the same variant (p.Arg50*) in individuals of the same ancestry, and the variable penetrance of some of the clinical findings.
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- 2021
42. Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection [v2; ref status: indexed, http://f1000r.es/53d]
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Veljko Veljkovic, Philippe M. Loiseau, Bruno Figadere, Sanja Glisic, Nevena Veljkovic, Vladimir R. Perovic, David P. Cavanaugh, and Donald R. Branch
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Antimicrobials & Drug Resistance ,Bioinformatics ,Tropical & Travel-Associated Diseases ,Virology ,Medicine ,Science - Abstract
The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD). Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.
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- 2015
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43. Pneumocystis Mating-Type Locus and Sexual Cycle during Infection
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Philippe M. Hauser
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Homothallism ,Review ,Microbiology ,Airborne transmission ,03 medical and health sciences ,medicine ,Antigenic variation ,Pneumocystis jirovecii ,Animals ,Humans ,DNA, Fungal ,Molecular Biology ,Lung ,030304 developmental biology ,0303 health sciences ,Life Cycle Stages ,biology ,Obligate ,030306 microbiology ,Pneumocystis ,Reproduction ,biology.organism_classification ,medicine.disease ,Sexual reproduction ,Obligate parasite ,Pneumocystis Infections ,Infectious Diseases ,Genome, Fungal ,Pneumonia (non-human) - Abstract
Pneumocystis species colonize mammalian lungs and cause deadly pneumonia if the immune system of the host weakens. Each species presents a specificity for a single mammalian host species. Pneumocystis jirovecii infects humans and provokes pneumonia, which is among the most frequent invasive fungal infections. The lack of in vitro culture methods for these fungi complicates their study. Recently, high-throughput sequencing technologies followed by comparative genomics have allowed a better understanding of the mechanisms involved in the sexuality of Pneumocystis organisms. The structure of their mating-type locus corresponding to a fusion of two loci, Plus and Minus, and the concomitant expression of the three mating-type genes revealed that their mode of sexual reproduction is primarily homothallism. This mode is favored by microbial pathogens and involves a single self-compatible mating type that can enter into the sexual cycle on its own. Pneumocystis sexuality is obligatory within the host's lungs during pneumonia in adults, primary infection in children, and possibly colonization. This sexuality participates in cell proliferation, airborne transmission to new hosts, and probably antigenic variation, processes that are crucial to ensure the survival of the fungus. Thus, sexuality is central in the Pneumocystis life cycle. The obligate biotrophic parasitism with obligate sexuality of Pneumocystis is unique among fungi pathogenic to humans. Pneumocystis organisms are similar to the plant fungal obligate biotrophs that complete their entire life cycle within their hosts, including sex, and that are also difficult to grow in vitro.
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- 2021
44. Nineteen percent of meniscus repairs are being revised and failures frequently occur after the second postoperative year: a systematic review and meta-analysis with a minimum follow-up of 5 years
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Robin Ristl, Wenzel Waldstein, Reinhard Windhager, Conradin Schweizer, Sebastian Apprich, Philippe M. Tscholl, and Carola Hanreich
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Knee arthritis ,medicine.medical_specialty ,Sports medicine ,Anterior cruciate ligament reconstruction ,medicine.medical_treatment ,Meniscus (anatomy) ,Menisci, Tibial ,Arthroscopy ,medicine ,Humans ,Orthopedics and Sports Medicine ,Meniscus ,Retrospective Studies ,Lateral meniscus ,business.industry ,Anterior Cruciate Ligament Injuries ,musculoskeletal system ,medicine.disease ,Surgery ,Tibial Meniscus Injuries ,medicine.anatomical_structure ,Orthopedic surgery ,Tears ,business ,Medial meniscus ,Follow-Up Studies - Abstract
Purpose Meniscus repair has gained increasing interest over the last two decades as loss of meniscus tissue predisposes to early onset knee arthritis. Although there are many reports of meniscus repair outcome in short-term studies, data on the long-term outcome of meniscus repair are still scarce. The purpose of this meta-analysis was to evaluate the overall failure rate of meniscus repair with a minimum follow-up of 5 years. Additionally, possible factors influencing meniscus repair outcome were assessed. Methods PubMed and Scopus were searched for studies of the last 20 years reporting on meniscus repair outcome with a minimum follow-up of 5 years. The study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search terms used for this study were ([meniscus OR meniscal] AND repair). Titles and abstracts were evaluated by two authors independently. Using meta package of R (version 3.6.2), random-effect models were performed to pool failure rates. Subgroup analyses were performed and effect estimates in form of an odds ratio with 95% CIs were established. Results In total, 12 studies with 864 patients were included. Degenerative tears were excluded in two studies and one study only included traumatic meniscus tears. Other studies did not state whether the cause of meniscus tear was degenerative or traumatic. Studies reporting meniscus repair outcome on root repairs, revision anterior cruciate ligament reconstruction, discoid menisci or ramp lesions were excluded. Revision surgery was used as failure definition in all included studies. The overall failure rate of meniscal repair at a mean follow-up of 86 months was 19.1%. There was no significant difference in meniscus repair outcome when performed in combination with anterior cruciate ligament reconstruction compared to isolated meniscus repair (18.7% vs. 28%; n.s.) or when performed on the lateral meniscus compared to the medial meniscus (19.5% vs. 24.4%; n.s.). There was no significant difference of meniscus repair outcome between vertical/longitudinal tears and bucket-handle tears (n.s.). Thirty-six percent of meniscus repair failures occur after the second postoperative year. The only significant finding was that inside-out repair results in a lower failure rate compared to all-inside repair (5.6% vs. 22.3%; p = 0.009) at 5 years. Conclusion The overall meniscus repair failure rate remains nineteen percent in long-term studies. The cause of failure is poorly documented, and it remains unclear whether failure of the meniscus repair itself or additional adjacent tears lead to revision surgery. Despite the given technical advantages of all-inside repair devices, this meta-analysis cannot demonstrate superior outcomes compared to inside-out or outside-in repair at 5 years. Level of evidence IV.
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- 2021
45. Rickets manifestations in a child with metaphyseal anadysplasia, report of a spontaneously resolving case
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Patricia Olivier, Patricia Diaz Escagedo, Philippe M. Campeau, Nathalie Alos, Melissa Fiscaletti, Valancy Miranda, Marie-Claude Miron, and Chloé Hudon
- Subjects
0301 basic medicine ,Rickets mimicking presentation disease ,Pediatrics ,medicine.medical_specialty ,Heterozygote ,Metaphyseal anadysplasia ,Costochondral junctions ,Limb Deformities, Congenital ,Rickets ,Case Report ,030105 genetics & heredity ,Osteochondrodysplasias ,Short stature ,RJ1-570 ,03 medical and health sciences ,medicine ,Humans ,Toddler ,Child ,business.industry ,Metaphyseal flaring ,medicine.disease ,030104 developmental biology ,Pediatrics, Perinatology and Child Health ,Regressive course ,Autosomal dominant variant ,Differential diagnosis ,medicine.symptom ,business ,Rachitic rosary - Abstract
Introduction Rickets is not an unusual diagnosis for pediatricians even currently in developed countries. Children typically present with leg bowing, enlargement of wrists, rachitic rosary (swelling of costochondral junctions) and/or waddling gait. But not every child with growth delay and enlarged metaphyses is diagnosed with rickets. Metaphyseal anadysplasia (MAD) is a disorder of variable severity with metaphyseal flaring and irregularities, without vertebral abnormalities. MAD is characterized by an early onset and a regressive course in late childhood without treatment, despite persistent short stature. Autosomal dominant or recessive variants in the matrix metalloproteinase 13 gene (MMP13) are responsible for these transient metaphyseal changes. Case presentation We report a new pathogenic heterozygous variant in MMP13 (NM_002427.4: c.216G>C, p.Gln72His) in a toddler, initially thought to have rickets, and his father, with MAD phenotypes. Additionally, we review the seven reported MMP13 variants. Conclusion One should keep a wide differential diagnosis in cases of suspected rickets, including skeletal dysplasias which might have a regressive course.
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- 2021
46. Strain Typing Methods and Molecular Epidemiology of Pneumocystis Pneumonia
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Charles Ben Beard, Patricia Roux, Gilles Nevez, Philippe M. Hauser, Joseph A. Kovacs, Thomas R. Unnasch, and Bettina Lundgren
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Pneumocystis ,PCP ,molecular epidemiology ,typing methods ,perspective ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Pneumocystis pneumonia (PCP) caused by the opportunistic fungal agent Pneumocystis jirovecii (formerly Pneumocystis carinii) continues to cause illness and death in HIV-infected patients. In the absence of a culture system to isolate and maintain live organisms, efforts to type and characterize the organism have relied on polymerase chain reaction–based approaches. Studies using these methods have improved understanding of PCP epidemiology, shedding light on sources of infection, transmission patterns, and potential emergence of antimicrobial resistance. One concern, however, is the lack of guidance regarding the appropriateness of different methods and standardization of these methods, which would facilitate comparing results reported by different laboratories.
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- 2004
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47. Molecular Evidence of Interhuman Transmission of Pneumocystis Pneumonia among Renal Transplant Recipients Hospitalized with HIV-Infected Patients
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Meja Rabodonirina, Philippe Vanhems, Sandrine Couray-Targe, René-Pierre Gillibert, Christell Ganne, Nathalie Nizard, Cyrille Colin, Jacques Fabry, Jean-Louis Touraine, Guy van Melle, Aimable Nahimana, Patrick Francioli, and Philippe M. Hauser
- Subjects
Epidemiology ,Pneumocystis carinii ,Pneumocystis jirovecii ,interhuman transmission ,cluster analysis ,sulfa drug resistance ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Ten Pneumocystis jirovecii pneumonia (PCP) cases were diagnosed in renal transplant recipients (RTRs) during a 3-year period. Nosocomial transmission from HIV-positive patients with PCP was suspected because the these patients shared the same hospital building, were not isolated, and were receiving no or suboptimal anti-PCP prophylaxis. P. jirovecii organisms were typed with the multitarget polymerase chain reaction–single-strand conformation polymorphism method. Among the 45 patients with PCP hospitalized during the 3-year period, 8 RTRs and 6 HIV-infected patients may have encountered at least 1 patient with active PCP within the 3 months before the diagnosis of their own PCP episode. In six instances (five RTRs, one HIV-infected patient), the patients harbored the same P. jirovecii molecular type as that found in the encountered PCP patients. The data suggest that part of the PCP cases observed in this building, particularly those observed in RTRs, were related to nosocomial interhuman transmission.
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- 2004
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48. Sulfa Resistance and Dihydropteroate Synthase Mutants in Recurrent Pneumocystis carinii Pneumonia
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Aimable Nahimana, Meja Rabodonirina, Jannik Helweg-Larsen, Isabelle Meneau, Patrick Francioli, Jacques Bille, and Philippe M. Hauser
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Pneumocystis carinii ,pneumonia ,fungal typing ,drug resistance ,drug pressure ,mutation ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Failure of sulfa or sulfone prophylaxis is associated with mutations in Pneumocystis carinii gene coding for dihydropteroate synthase (DHPS). The DHPS genotype was analyzed in AIDS patients who had two separate episodes of P. carinii pneumonia. The results suggest that DHPS mutations can be selected de novo within patients by the pressure of a sulfa or sulfone drug.
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- 2003
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49. Nonsyndromic erythrodermic ichthyosis resulting from a homozygous mutation in PIGL
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J.K. Simpson, John A. McGrath, Michael A. Simpson, Anna E. Martinez, Alexandros Onoufriadis, C. McDonald, T. T. M. Nguyen, and Philippe M. Campeau
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Genetics ,Ichthyosis ,business.industry ,Homozygote ,Infant ,Dermatology ,N-Acetylglucosaminyltransferases ,medicine.disease ,Pedigree ,Child, Preschool ,Mutation ,Mutation (genetic algorithm) ,medicine ,Humans ,Female ,business ,Dermatitis, Exfoliative - Published
- 2019
50. The calcium‐activated protease calpain regulates netrin‐1 receptor deleted in colorectal cancer‐induced axon outgrowth in cortical neurons
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Nathalie Lamarche-Vane and Philippe M. Duquette
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0301 basic medicine ,Deleted in Colorectal Cancer ,Neurogenesis ,Growth Cones ,Neuronal Outgrowth ,Biochemistry ,Rats, Sprague-Dawley ,Focal adhesion ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Netrin ,medicine ,Animals ,Spectrin ,Axon ,Growth cone ,Cerebral Cortex ,Neurons ,biology ,Calpain ,Chemistry ,fungi ,Netrin-1 ,DCC Receptor ,Actin cytoskeleton ,Rats ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,biology.protein ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
During development, neurons extend axons toward their appropriate synaptic targets to establish functional neuronal connections. The growth cone, a highly motile structure at the tip of the axon, is capable of recognizing extracellular guidance cues and translating them into directed axon outgrowth through modulation of the actin cytoskeleton. Netrin-1 mediates its attractive function through the receptor deleted in colorectal cancer (DCC) to promote axon outgrowth and guidance. The calcium-activated protease calpain is involved in the cleavage of cytoskeletal proteins, which plays an important role during adhesion turnover and cell migration. However, its function during neuronal development is less understood. Here we demonstrate that netrin-1 activated calpain in embryonic rat cortical neurons in an extracellular-regulated kinase 1/2-dependent manner. In addition, we found that netrin-1 stimulation led to an increase in calpain-1 localization in the axon, whereas its endogenous inhibitor calpastatin was decreased in the growth cones of cortical neurons by indirect immunofluorescence. Interestingly, calpain-1 was able to cleave DCC in vitro. Furthermore, netrin-1 induced the cleavage of the cytoskeletal proteins spectrin and focal adhesion kinase concomitantly with the intracellular domain of DCC in a calpain-dependent manner in embryonic rat cortical neurons. Cortical neurons over-expressing calpastatin or calpain-depleted neurons displayed increased basal axon length and were unresponsive to netrin-1 stimulation. Altogether, we propose a novel model whereby netrin-1/DCC-mediated axon outgrowth is modulated by calpain-mediated proteolysis of DCC and cytoskeletal targets in embryonic cortical neurons. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.
- Published
- 2019
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