103 results on '"Disease Models, Animal"'
Search Results
2. INFRAFRONTIER: mouse model resources for modelling human diseases.
- Author
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Ali Khan A, Valera Vazquez G, Gustems M, Matteoni R, Song F, Gormanns P, Fessele S, Raess M, and Hrabĕ de Angelis M
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- Mice, Animals, Humans, Disease Models, Animal, Europe, Biomedical Research
- Abstract
Over the last decade, INFRAFRONTIER has positioned itself as a world-class Research Infrastructure for the generation, phenotyping, archiving, and distribution of mouse models in Europe. The INFRAFRONTIER network consists of 22 partners from 15 countries, and is continuously enhancing and broadening its portfolio of resources and services that are offered to the research community on a non-profit basis. By bringing together European rodent model expertise and providing valuable disease model services to the biomedical research community, INFRAFRONTIER strives to push the accessibility of cutting-edge human disease modelling technologies across the European research landscape. This article highlights the latest INFRAFRONTIER developments and informs the research community about its extensively utilised services, resources, and technical developments, specifically the intricacies of the INFRAFRONTIER database, use of Curated Disease Models, overview of the INFRAFRONTIER Cancer and Rare Disease resources, and information about its main state-of-the-art services., (© 2023. The Author(s).)
- Published
- 2023
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3. Comparison of Crimean-Congo Hemorrhagic Fever Virus and Aigai Virus in Life Cycle Modeling Systems Reveals a Difference in L Protein Activity.
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Pickin MJ, Devignot S, Weber F, and Groschup MH
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- Africa, Animals, Disease Models, Animal, Europe, Gene Expression Regulation, Viral, Genotype, Hemorrhagic Fever, Crimean virology, Humans, Species Specificity, Hemorrhagic Fever Virus, Crimean-Congo classification, Hemorrhagic Fever Virus, Crimean-Congo genetics, Hemorrhagic Fever Virus, Crimean-Congo pathogenicity, Virulence genetics
- Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne orthonairovirus that causes a severe, often fatal, hemorrhagic disease throughout Africa, Asia, and Southeast Europe. A wide variety of strains are circulating in the field which broadly correlate to their geographic distribution. The viral determinants of pathogenicity remain unclear, as does the contribution of strain-specific differences to pathology. Aigai virus (AIGV) is a closely related virus (formally designated CCHFV genotype VI, Europe II, or AP92-like virus), which has been proposed to be less virulent than CCHFV. However, the molecular details leading to potential differences in virulence are unknown. To explore if differences exist, life cycle modeling systems, including both a minigenome and a transcriptionally competent virus-like particle assay, were developed for AIGV to allow the comparison with the CCHFV reference IbAr10200 strain. Using this approach, we could demonstrate that AIGV exhibits lower viral gene expression than the reference strain of CCHFV. Subsequent systematic exchange of viral components revealed that the L protein is responsible for the observed differences in gene expression and that the interferon (IFN) antagonistic activity of the ovarian tumor-type protease domain is not responsible for this effect. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is the cause of severe hemorrhagic disease, which is often fatal. Present throughout Africa, Asia, and Southeast Europe, a diverse number of viral genotypes exist. However, the viral determinants of pathogenicity remain unclear. It has been proposed that the closely related Aigai virus (AIGV) may be a less virulent virus. Here, using newly developed and improved life cycle modeling systems we have examined potential differences between the CCHFV reference strain, IbAr10200, and AIGV. Using this approach, we identified lower viral gene expression driven by the AIGV viral polymerase as a major difference which may be indicative of lower virulence.
- Published
- 2022
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4. Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.
- Author
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Ferrua F, Bortolomai I, Fontana E, Di Silvestre D, Rigoni R, Marcovecchio GE, Draghici E, Brambilla F, Castiello MC, Delfanti G, Moshous D, Picard C, Taghon T, Bordon V, Schulz AS, Schuetz C, Giliani S, Soresina A, Gennery AR, Signa S, Dávila Saldaña BJ, Delmonte OM, Notarangelo LD, Roifman CM, Poliani PL, Uva P, Mauri PL, Villa A, and Bosticardo M
- Subjects
- Adolescent, Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, Case-Control Studies, Child, Child, Preschool, Disease Models, Animal, Epithelial Cells metabolism, Europe, Female, Hematopoietic Stem Cell Transplantation, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II metabolism, Homeodomain Proteins genetics, Humans, Infant, Male, Mice, Inbred C57BL, Mice, Knockout, North America, Proteome, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency metabolism, Severe Combined Immunodeficiency surgery, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Thymocytes, Thymus Gland metabolism, Transcriptome, Young Adult, Mice, Epithelial Cells immunology, Histocompatibility Antigens Class II immunology, Immune Tolerance, Severe Combined Immunodeficiency immunology, Thymus Gland immunology
- Abstract
Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII
-/- mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII-/- mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with one of the authors (CRM)., (Copyright © 2021 Ferrua, Bortolomai, Fontana, Di Silvestre, Rigoni, Marcovecchio, Draghici, Brambilla, Castiello, Delfanti, Moshous, Picard, Taghon, Bordon, Schulz, Schuetz, Giliani, Soresina, Gennery, Signa, Dávila Saldaña, Delmonte, Notarangelo, Roifman, Poliani, Uva, Mauri, Villa and Bosticardo.)- Published
- 2021
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5. Kpi, a chaperone-usher pili system associated with the worldwide-disseminated high-risk clone Klebsiella pneumoniae ST-15.
- Author
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Gato E, Vázquez-Ucha JC, Rumbo-Feal S, Álvarez-Fraga L, Vallejo JA, Martínez-Guitián M, Beceiro A, Ramos Vivas J, Sola Campoy PJ, Pérez-Vázquez M, Oteo Iglesias J, Rodiño-Janeiro BK, Romero A, Poza M, Bou G, and Pérez A
- Subjects
- A549 Cells, Animals, Anti-Bacterial Agents, Bacterial Adhesion drug effects, Bacterial Adhesion genetics, Biofilms drug effects, Biofilms growth & development, Carbapenems pharmacology, Cell Line, Disease Models, Animal, Drug Resistance, Multiple, Bacterial genetics, Epithelial Cells microbiology, Europe, Female, Gene Deletion, Genes, Bacterial genetics, Humans, Klebsiella Infections, Klebsiella pneumoniae cytology, Klebsiella pneumoniae drug effects, Mice, Mice, Inbred BALB C, Multilocus Sequence Typing, Operon, Phylogeny, Fimbriae, Bacterial genetics, Klebsiella pneumoniae genetics, Molecular Chaperones genetics
- Abstract
Control of infections caused by carbapenem-resistant Klebsiella pneumoniae continues to be challenging. The success of this pathogen is favored by its ability to acquire antimicrobial resistance and to spread and persist in both the environment and in humans. The emergence of clinically important clones, such as sequence types 11, 15, 101, and 258, has been reported worldwide. However, the mechanisms promoting the dissemination of such high-risk clones are unknown. Unraveling the factors that play a role in the pathobiology and epidemicity of K. pneumoniae is therefore important for managing infections. To address this issue, we studied a carbapenem-resistant ST-15 K. pneumoniae isolate (Kp3380) that displayed a remarkable adherent phenotype with abundant pilus-like structures. Genome sequencing enabled us to identify a chaperone-usher pili system (Kpi) in Kp3380. Analysis of a large K. pneumoniae population from 32 European countries showed that the Kpi system is associated with the ST-15 clone. Phylogenetic analysis of the operon revealed that Kpi belongs to the little-characterized γ
2 -fimbrial clade. We demonstrate that Kpi contributes positively to the ability of K. pneumoniae to form biofilms and adhere to different host tissues. Moreover, the in vivo intestinal colonizing capacity of the Kpi-defective mutant was significantly reduced, as was its ability to infect Galleria mellonella The findings provide information about the pathobiology and epidemicity of Kpi+ K. pneumoniae and indicate that the presence of Kpi may explain the success of the ST-15 clone. Disrupting bacterial adherence to the intestinal surface could potentially target gastrointestinal colonization., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)- Published
- 2020
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6. The people behind the papers - Roman Szabo and Thomas Bugge.
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- Animals, Cell Membrane metabolism, Developmental Biology methods, Disease Models, Animal, Europe, History, 20th Century, History, 21st Century, Humans, Intestinal Diseases metabolism, Intestines embryology, Membrane Glycoproteins metabolism, Mice, National Institutes of Health (U.S.), Serine Endopeptidases metabolism, United States, Developmental Biology history
- Abstract
Dysregulated activity of cell surface proteolytic enzymes has a wide range of developmental and pathological consequences, but the underlying mechanisms are often poorly understood. A new Development paper uses mice to model a severe inherited form of enteropathy and the role of the serine protease matriptase in the disease's progression. We caught up with first author Roman Szabo and his supervisor Thomas Bugge, Senior Investigator at the NIH National Institute of Dental and Craniofacial Research in Bethesda, Maryland, to find out more about the story., (© 2019. Published by The Company of Biologists Ltd.)
- Published
- 2019
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7. Pathogenicity and genomic changes of a 2016 European H5N8 highly pathogenic avian influenza virus (clade 2.3.4.4) in experimentally infected mallards and chickens.
- Author
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Leyson C, Youk SS, Smith D, Dimitrov K, Lee DH, Larsen LE, Swayne DE, and Pantin-Jackwood MJ
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- Animals, Chickens, Disease Models, Animal, Ducks, Europe, Influenza A Virus, H5N8 Subtype isolation & purification, Survival Analysis, Virulence, Whole Genome Sequencing, Genetic Variation, Genome, Viral, Influenza A Virus, H5N8 Subtype genetics, Influenza A Virus, H5N8 Subtype pathogenicity, Influenza in Birds virology
- Abstract
Highly pathogenic avian influenza H5N8 clade 2.3.4.4 virus caused outbreaks in poultry and unusually high mortality in wild birds in 2016-2017. The pathobiology of one of these viruses was examined in mallards and chickens. High mortality and transmission to direct contacts were observed in mallards inoculated with medium and high doses of the virus. However, in chickens, high mortality occurred only when birds are given the high virus dose and no transmission was observed, indicating that the virus was better adapted to mallards. In comparison with the virus inoculum, viral sequences obtained from the chickens had a higher number of nucleotide changes but lower intra-host genomic diversity than viral sequences obtained from the mallards. These observations are consistent with population bottlenecks occurring when viruses infect and replicate in a host that it is not well adapted to. Whether these observations apply to influenza viruses in general remains to be determined., (Published by Elsevier Inc.)
- Published
- 2019
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8. An outline on distribution and hosts of the cystoid nematodes of Ataloderinae Wouts, 1973 and Meloidoderinae Golden, 1971.
- Author
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Ghaderi R
- Subjects
- Africa, Animals, Asia, Disease Models, Animal, Europe, North America, South America, Nematoda
- Abstract
The cystoid nematodes of the subfamilies Ataloderinae and Meloidoderinae include 32 recognized species belonging to 10 genera. The geographical distribution and preferred hosts of these nematodes are reviewed in the present paper. Most genera in Ataloderinae are believed to have evolved in North America, but some genera currently show different or wider distributions. Although members of Bellodera, Ekphymatodera, Rhizonemella and Sarisodera have only been recovered from North America, those of Atalodera may be found in both North America and South America. Species of the other genera tend to occur in different geographical locations: Cryphodera species have been recorded in Asia and Oceania while Camelodera and Hylonema species have only reported from Asia and Africa, respectively. Members of Meloidoderinae (Meloidodera spp.) are distributed in North America, Asia and Europe. Plant hosts for the cystoid nematodes are distributed among both monocots and dicots. Nematologists suggest an ancient origin for genera such as Meloidodera, Cryphodera and Rhizonemella which can parasitize gymnosperms.
- Published
- 2019
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9. Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in human cardiovascular disease.
- Author
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Håkansson KEJ, Goossens EAC, Trompet S, van Ingen E, de Vries MR, van der Kwast RVCT, Ripa RS, Kastrup J, Hohensinner PJ, Kaun C, Wojta J, Böhringer S, Le Cessie S, Jukema JW, Quax PHA, and Nossent AY
- Subjects
- Aged, Aged, 80 and over, Animals, Apolipoprotein E3 genetics, Cardiovascular Diseases diagnosis, Cardiovascular Diseases mortality, Cardiovascular Diseases therapy, Disease Models, Animal, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Human Umbilical Vein Endothelial Cells metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, NIH 3T3 Cells, Phenotype, RNA, Small Nucleolar metabolism, Randomized Controlled Trials as Topic, Transcriptome, Up-Regulation, Cardiovascular Diseases genetics, Chromosomes, Human, Pair 14, Polymorphism, Single Nucleotide, RNA, Small Nucleolar genetics
- Abstract
Aims: We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 'orphan' small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease., Methods and Results: We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice., Conclusion: 14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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10. Detection and Characterization of Invertebrate Iridoviruses Found in Reptiles and Prey Insects in Europe over the Past Two Decades.
- Author
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Papp T and Marschang RE
- Subjects
- Animal Diseases virology, Animals, Base Sequence, Cell Line, DNA Virus Infections veterinary, DNA Virus Infections virology, DNA, Viral analysis, Disease Models, Animal, Europe, Genome, Viral, Gryllidae virology, Host Specificity, Iridovirus genetics, Lizards virology, Sequence Analysis, Virulence, Insecta virology, Invertebrates virology, Iridovirus classification, Iridovirus isolation & purification, Phylogeny, Reptiles virology
- Abstract
Invertebrate iridoviruses (IIVs), while mostly described in a wide range of invertebrate hosts, have also been repeatedly detected in diagnostic samples from poikilothermic vertebrates including reptiles and amphibians. Since iridoviruses from invertebrate and vertebrate hosts differ strongly from one another based not only on host range but also on molecular characteristics, a series of molecular studies and bioassays were performed to characterize and compare IIVs from various hosts and evaluate their ability to infect a vertebrate host. Eight IIV isolates from reptilian and orthopteran hosts collected over a period of six years were partially sequenced. Comparison of eight genome portions (total over 14 kbp) showed that these were all very similar to one another and to an earlier described cricket IIV isolate, thus they were given the collective name lizard-cricket IV (Liz-CrIV). One isolate from a chameleon was also subjected to Illumina sequencing and almost the entire genomic sequence was obtained. Comparison of this longer genome sequence showed several differences to the most closely related IIV, Invertebrate iridovirus 6 ) at 20 and 30 °C. Finally, the chameleon isolate used for the genome sequencing studies was also used in a transmission study with bearded dragons. The transmission studies showed large variability in virus replication and pathogenicity of the three tested viruses in crickets at the two temperatures. In the infection study with bearded dragons, lizards inoculated with a Liz-CrIV did not become ill, but the virus was detected in numerous tissues by qPCR and was also isolated in cell culture from several tissues. Highest viral loads were measured in the gastro-intestinal organs and in the skin. These studies demonstrate that Liz-CrIV circulates in the pet trade in Europe. This virus is capable of infecting both invertebrates and poikilothermic vertebrates, although its involvement in disease in the latter has not been proven.Iridovirus , including several deletions and possible recombination sites, as well as insertions of genes of non-iridoviral origin. Three isolates from vertebrate and invertebrate hosts were also used for comparative studies on pathogenicity in crickets ( Gryllus bimaculatus ) at 20 and 30 °C. Finally, the chameleon isolate used for the genome sequencing studies was also used in a transmission study with bearded dragons. The transmission studies showed large variability in virus replication and pathogenicity of the three tested viruses in crickets at the two temperatures. In the infection study with bearded dragons, lizards inoculated with a Liz-CrIV did not become ill, but the virus was detected in numerous tissues by qPCR and was also isolated in cell culture from several tissues. Highest viral loads were measured in the gastro-intestinal organs and in the skin. These studies demonstrate that Liz-CrIV circulates in the pet trade in Europe. This virus is capable of infecting both invertebrates and poikilothermic vertebrates, although its involvement in disease in the latter has not been proven.
- Published
- 2019
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11. HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response.
- Author
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Hamdane N, Jühling F, Crouchet E, El Saghire H, Thumann C, Oudot MA, Bandiera S, Saviano A, Ponsolles C, Roca Suarez AA, Li S, Fujiwara N, Ono A, Davidson I, Bardeesy N, Schmidl C, Bock C, Schuster C, Lupberger J, Habersetzer F, Doffoël M, Piardi T, Sommacale D, Imamura M, Uchida T, Ohdan H, Aikata H, Chayama K, Boldanova T, Pessaux P, Fuchs BC, Hoshida Y, Zeisel MB, Duong FHT, and Baumert TF
- Subjects
- Adult, Animals, Carcinoma, Hepatocellular genetics, Case-Control Studies, Cohort Studies, Disease Models, Animal, Epigenesis, Genetic, Europe, Female, Gene Expression Regulation, Neoplastic, Hepatitis C, Chronic complications, Hepatitis C, Chronic drug therapy, Humans, Japan, Liver Neoplasms pathology, Male, Mice, Mice, SCID, Random Allocation, Sustained Virologic Response, Antiviral Agents therapeutic use, Carcinoma, Hepatocellular virology, Hepatitis C, Chronic pathology, Liver Neoplasms genetics, Liver Neoplasms virology
- Abstract
Background & Aims: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the risk for HCC is decreased but not eliminated after a sustained virologic response (SVR) to direct-acting antiviral (DAA) agents, and the risk is higher in patients with advanced fibrosis. We investigated HCV-induced epigenetic alterations that might affect risk for HCC after DAA treatment in patients and mice with humanized livers., Methods: We performed genome-wide ChIPmentation-based ChIP-Seq and RNA-seq analyses of liver tissues from 6 patients without HCV infection (controls), 18 patients with chronic HCV infection, 8 patients with chronic HCV infection cured by DAA treatment, 13 patients with chronic HCV infection cured by interferon therapy, 4 patients with chronic hepatitis B virus infection, and 7 patients with nonalcoholic steatohepatitis in Europe and Japan. HCV-induced epigenetic modifications were mapped by comparative analyses with modifications associated with other liver disease etiologies. uPA/SCID mice were engrafted with human hepatocytes to create mice with humanized livers and given injections of HCV-infected serum samples from patients; mice were given DAAs to eradicate the virus. Pathways associated with HCC risk were identified by integrative pathway analyses and validated in analyses of paired HCC tissues from 8 patients with an SVR to DAA treatment of HCV infection., Results: We found chronic HCV infection to induce specific genome-wide changes in H3K27ac, which correlated with changes in expression of mRNAs and proteins. These changes persisted after an SVR to DAAs or interferon-based therapies. Integrative pathway analyses of liver tissues from patients and mice with humanized livers demonstrated that HCV-induced epigenetic alterations were associated with liver cancer risk. Computational analyses associated increased expression of SPHK1 with HCC risk. We validated these findings in an independent cohort of patients with HCV-related cirrhosis (n = 216), a subset of which (n = 21) achieved viral clearance., Conclusions: In an analysis of liver tissues from patients with and without an SVR to DAA therapy, we identified epigenetic and gene expression alterations associated with risk for HCC. These alterations might be targeted to prevent liver cancer in patients treated for HCV infection., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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12. Usutu virus: A new threat?
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Clé M, Beck C, Salinas S, Lecollinet S, Gutierrez S, Van de Perre P, Baldet T, Foulongne V, and Simonin Y
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- Animals, Birds, Communicable Diseases, Emerging prevention & control, Disease Models, Animal, Disease Vectors, Europe epidemiology, Flavivirus pathogenicity, Humans, South Africa epidemiology, Bird Diseases transmission, Communicable Disease Control, Communicable Diseases, Emerging epidemiology, Flavivirus isolation & purification, Flavivirus Infections epidemiology
- Abstract
Usutu virus (USUV) is an emerging arbovirus that was first isolated in South Africa in 1959. This Flavivirus is maintained in the environment through a typical enzootic cycle involving mosquitoes and birds. USUV has spread to a large part of the European continent over the two decades mainly leading to substantial avian mortalities with a significant recrudescence of bird infections recorded throughout Europe within the few last years. USUV infection in humans is considered to be most often asymptomatic or to cause mild clinical signs. Nonetheless, a few cases of neurological complications such as encephalitis or meningoencephalitis have been reported. USUV and West Nile virus (WNV) share many features, like a close phylogenetic relatedness and a similar ecology, with co-circulation frequently observed in nature. However, USUV has been much less studied and in-depth comparisons of the biology of these viruses are yet rare. In this review, we discuss the main body of knowledge regarding USUV and compare it with the literature on WNV, addressing in particular virological and clinical aspects, and pointing data gaps.
- Published
- 2019
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13. Quantifying the contribution of recessive coding variation to developmental disorders.
- Author
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Martin HC, Jones WD, McIntyre R, Sanchez-Andrade G, Sanderson M, Stephenson JD, Jones CP, Handsaker J, Gallone G, Bruntraeger M, McRae JF, Prigmore E, Short P, Niemi M, Kaplanis J, Radford EJ, Akawi N, Balasubramanian M, Dean J, Horton R, Hulbert A, Johnson DS, Johnson K, Kumar D, Lynch SA, Mehta SG, Morton J, Parker MJ, Splitt M, Turnpenny PD, Vasudevan PC, Wright M, Bassett A, Gerety SS, Wright CF, FitzPatrick DR, Firth HV, Hurles ME, and Barrett JC
- Subjects
- Animals, Disease Models, Animal, Eukaryotic Initiation Factor-3 genetics, Europe, Genome-Wide Association Study, Humans, Jumonji Domain-Containing Histone Demethylases genetics, Mice, Nuclear Proteins genetics, Pakistan, Phylogeny, Repressor Proteins genetics, Developmental Disabilities genetics, Genes, Recessive, Genetic Code, Genetic Variation, Penetrance
- Abstract
We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F , and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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14. Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia.
- Author
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Lee YM, Conlon TJ, Specht A, Coleman KE, Brown LM, Estrella AM, Dambska M, Dahlberg KR, and Weinstein DA
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- Animals, Blood Glucose metabolism, Dependovirus genetics, Disease Models, Animal, Dogs, Europe, Genetic Vectors, Glucose-6-Phosphatase genetics, Hypoglycemia genetics, Hypoglycemia metabolism, Kidney metabolism, Liver metabolism, Genetic Therapy methods, Glycogen Storage Disease Type I therapy
- Abstract
Background: Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy., Methods: A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed., Results: Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2-4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose., Conclusion: rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.
- Published
- 2018
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15. Development of an International Canine Spinal Cord Injury observational registry: a collaborative data-sharing network to optimize translational studies of SCI.
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Moore SA, Zidan N, Spitzbarth I, Nout-Lomas YS, Granger N, da Costa RC, Levine JM, Jeffery ND, Stein VM, Tipold A, and Olby NJ
- Subjects
- Animals, Cohort Studies, Cross-Over Studies, Dogs, Europe, Female, Male, United States, Disease Models, Animal, Information Dissemination, International Cooperation, Registries, Spinal Cord Injuries epidemiology, Spinal Cord Injuries therapy, Spinal Cord Injuries veterinary, Translational Research, Biomedical methods
- Abstract
Study Design: Prospective cross-sectional cohort study., Objectives: The canine spontaneous model of spinal cord injury (SCI) is as an important pre-clinical platform as it recapitulates key facets of human injury in a naturally occurring context. The establishment of an observational canine SCI registry constitutes a key step in performing epidemiologic studies and assessing the impact of therapeutic strategies to enhance translational research. Further, accumulating information on dogs with SCI may contribute to current "big data" approaches to enhance understanding of the disease using heterogeneous multi-institutional, multi-species datasets from both pre-clinical and human studies., Setting: Multiple veterinary academic institutions across the United States and Europe., Methods: Common data elements recommended for experimental and human SCI studies were reviewed and adapted for use in a web-based registry, to which all dogs presenting to member veterinary tertiary care facilities were prospectively entered over ~1 year., Results: Analysis of data accumulated during the first year of the registry suggests that 16% of dogs with SCI present with severe, sensorimotor-complete injury and that 15% of cases are seen by a tertiary care facility within 8 h of injury. Similar to the human SCI population, 34% were either overweight or obese., Conclusions: Severity of injury and timing of presentation suggests that neuroprotective studies using the canine clinical model could be conducted efficiently using a multi-institutional approach. Additionally, pet dogs with SCI experience similar comorbidities to people with SCI, in particular obesity, and could serve as an important model to evaluate the effects of this condition.
- Published
- 2018
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16. Optimising experimental research in respiratory diseases: an ERS statement.
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Bonniaud P, Fabre A, Frossard N, Guignabert C, Inman M, Kuebler WM, Maes T, Shi W, Stampfli M, Uhlig S, White E, Witzenrath M, Bellaye PS, Crestani B, Eickelberg O, Fehrenbach H, Guenther A, Jenkins G, Joos G, Magnan A, Maitre B, Maus UA, Reinhold P, Vernooy JHJ, Richeldi L, and Kolb M
- Subjects
- Advisory Committees, Animals, Europe, Humans, Societies, Medical, Animal Experimentation ethics, Biomedical Research standards, Disease Models, Animal, Respiration Disorders
- Abstract
Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.The objective of this task force was to issue a statement with research recommendations about lung disease models by facilitating in-depth discussions between respiratory scientists, and to provide an overview of the literature on the available models. Focus was put on their specific benefits and limitations. This will result in more efficient use of resources and greater reduction in the numbers of animals employed, thereby enhancing the ethical standards and translational capacity of experimental research.The task force statement addresses general issues of experimental research (ethics, species, sex, age, ex vivo and in vitro models, gene editing). The statement also includes research recommendations on modelling asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, lung infections, acute lung injury and pulmonary hypertension.The task force stressed the importance of using multiple models to strengthen validity of results, the need to increase the availability of human tissues and the importance of standard operating procedures and data quality., Competing Interests: Conflict of interest: P. Bonniaud reports personal fees (board/advice) from Roche, Boehringer, Novartis, TEVA and AstraZeneca, and travel reimbursement (ERS meetings) from Chiesi, outside the submitted work. Conflict of interest: A. Fabre reports grants from Pfizer, reagents from Roche, and personal fees from MSD (Merck Sharp & Dohme Corp.), outside the submitted work. Conflict of interest: T. Maes reports grants from Belgian Science Policy (Federal Government Belgium-Interuniversity attraction Poles), Ghent University (Concerted Research Action and Spearhead Immunology) and Novartis, and personal fees (GSK Clinical Science award: prize for best abstract presentation at Belgian Pulmonology Society Meeting 2015) and non-financial support (travel/accommodation/meeting expenses) from GlaxoSmithKline, outside the submitted work; and is shareholder of Oryzon Genomics. Conflict of interest: W. Shi reports grants from National Institute of Health and Department of Defense, outside the submitted work. Conflict of interest: M. Stampfli reports grants from RespiVert and MedImmune, and personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work. Conflict of interest: S. Uhlig reports grants from Germany Research Foundation (DFG), during the conduct of the study. Conflict of interest: E. White reports grants and other support from NIH, personal fees for consulting from Akcea Therapeutics and Kadmon Pharmaceuticals, and research grants and personal fees for consulting from Boehringer-Ingelheim, outside the submitted work. Conflict of interest: M. Witzenrath reports grants and personal fees from Bayer Health Care, Boehringer Ingelheim, Biotest and Vaxxilon, and personal fees from Actelion, Berlin Chemie, AstraZeneca, GlaxoSmithKline and Novartis, outside the submitted work. Conflict of interest: B. Crestani has receieved an honorarium for speaking from Aventis, honoraria for speaking, grants for research and congress travel support grants from Boehringer Ingelheim and Roche, grants for research from CARDIF and LVL, an honorarium for speaking and congress travel support from AstraZeneca, and a grant for research and congress travel support from MedImmune, outside the submitted work. Conflict of interest: O. Eickelberg reports grants from the Helmholtz Association, the German Center of Lung Research, Roche, and Bayer and consultancy/lecture fees from BMS, Novartis, Bayer, Intermune, McKinsey, and MorphoSys. Conflict of interest: A. Guenther reports research funding, and compensation for lectures and consulting from Roche, compensation for lectures and consulting from Boehringer Ingelheim and Teva, and research funding from Sanofi, outside the submitted work. Conflict of interest: G. Jenkins reports grants from GlaxoSmithKline (institutional funding for the PROFILE study) and the Medical Research Council (co-funder of the PROFILE study with GSK through MICA award), during the conduct of the study; grants from Biogen (SRA for work on integrins in IPF), personal fees (consulting and data monitoring committees on lung fibrosis) from Boehringer Ingelheim, grants (PhD studentship) from Galecto, personal fees (advisory board on IPF) from GlaxoSmithKline and Intermune, grants and personal fees (consulting on IPF, PhD studentship) from MedImmune, personal fees (consulting on IPF) from PharmAkea, personal fees (advisory board on IPF and lecture fees) from Roche, consulting on IPF (with no payment received to date) for Pliant Therapeutics, participating in scientific advisory boards (with no payment received to date) for NuMedii, and personal fees from Pulmatrix, outside the submitted work; and is a trustee for the charities Action for Pulmonary Fibrosis and the British Thoracic Society. Conflict of interest: G. Joos reports grants, personal fees and non-financial support from AstraZeneca, grants and personal fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis, and personal fees from Mundipharma, Sandoz and Teva, outside the submitted work. Conflict of interest: U.A. Maus reports grants from Federal Ministry of Education and Research, German Research Foundation and Lower Saxony Society for the Control of Tuberculosis and Bronchial Diseases, outside the submitted work. Conflict of interest: L. Richeldi reports grants and personal fees (for advisory board membership) from InterMune, personal fees (for advisory board membership) from Medimmune, Roche and FibroGen, personal fees (for consulting activity) from Biogen, Sanofi-Aventis, ImmuneWorks, Celgene and Nitto, personal fees (for speaking) from Shionogi, and personal fees (for membership of steering committee) from Boehringer Ingelheim, outside the submitted work. Conflict of interest: M. Kolb reports grants and personal fees from Roche, Boehringer Ingelheim, GSK, Gilead, Prometic and Alkermes, grants from Actelion, Respivert and Synairgen, and personal fees from AstraZeneca and Genoa, outside the submitted work., (Copyright ©ERS 2018.)
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- 2018
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17. The E glycoprotein plays an essential role in the high pathogenicity of European-Mediterranean IS98 strain of West Nile virus.
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Alsaleh K, Khou C, Frenkiel MP, Lecollinet S, Vàzquez A, de Arellano ER, Després P, and Pardigon N
- Subjects
- Animals, Disease Models, Animal, Europe epidemiology, Female, Humans, Immunization, Mediterranean Region epidemiology, Mice, Mice, Inbred BALB C, Protein Structure, Tertiary, Reassortant Viruses chemistry, Reassortant Viruses immunology, Survival Analysis, Vaccines, Attenuated, Viral Envelope Proteins chemistry, Viral Envelope Proteins immunology, West Nile Fever epidemiology, West Nile Fever immunology, West Nile Fever mortality, West Nile virus genetics, West Nile virus immunology, Reassortant Viruses genetics, Viral Envelope Proteins genetics, Viral Vaccines administration & dosage, West Nile Fever prevention & control, West Nile virus pathogenicity
- Abstract
West Nile virus (WNV) is the most widespread arbovirus in the world. Several recent outbreaks and epizootics have been reported in Europe and the Mediterranean basin with increased virulence. In contrast to the well-characterized American and Australian strains, little is known about the virulence determinants of the WNV European-Mediterranean strains. To investigate the viral factors involved in the virulence of these strains, we generated chimeras between the highly neuropathogenic Israel 1998 (IS-98-ST1, IS98) strain and the non-pathogenic Malaysian Kunjin virus (KJMP-502). In vivo analyses in a mouse model of WNV pathogenesis shows that chimeric virus where KJMP-502 E glycoprotein was replaced by that of IS98 is neuropathogenic, demonstrating that this protein is a major virulence determinant. Presence of the N-glycosylation site had limited impact on virus virulence and the 5'UTR does not seem to influence pathogenesis. Finally, mice inoculated with KJMP-502 virus were protected against lethal IS98 infection., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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18. Neisseria meningitidis Serogroup X in Sub-Saharan Africa.
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Agnememel A, Hong E, Giorgini D, Nuñez-Samudio V, Deghmane AE, and Taha MK
- Subjects
- Africa South of the Sahara epidemiology, Animals, Clone Cells, Disease Models, Animal, Europe epidemiology, Gene Expression, Genes, Reporter, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Luciferases genetics, Luciferases metabolism, Meningitis, Meningococcal microbiology, Meningitis, Meningococcal pathology, Mice, Mice, Inbred BALB C, Mice, Transgenic, Neisseria meningitidis classification, Operon, Optical Imaging, Serotyping, Virulence, Genome, Bacterial, Meningitis, Meningococcal epidemiology, Neisseria meningitidis genetics, Neisseria meningitidis pathogenicity, Phylogeny, Serogroup
- Abstract
The epidemiology of meningococcal disease varies by geography and time. Whole-genome sequencing of Neisseria meningitidis serogroup X isolates from sub-Saharan Africa and Europe showed that serogroup X emergence in sub-Saharan Africa resulted from expansion of particular variants within clonal complex 181. Virulence of these isolates in experimental mouse models was high.
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- 2016
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19. Age- and strain-dependent differences in the outcome of experimental infections of domestic pigs with wild boar pseudorabies virus isolates.
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Verpoest S, Cay AB, Van Campe W, Mostin L, Welby S, Favoreel H, and De Regge N
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- Animals, Disease Models, Animal, Disease Transmission, Infectious, Europe, Herpesvirus 1, Suid isolation & purification, Herpesvirus 1, Suid pathogenicity, Pseudorabies transmission, Swine, Swine Diseases transmission, Treatment Outcome, Herpesvirus 1, Suid growth & development, Pseudorabies pathology, Pseudorabies virology, Sus scrofa virology, Swine Diseases pathology, Swine Diseases virology
- Abstract
Although pseudorabies virus (PRV) has been eradicated in domestic swine in many countries, its presence in wild boars remains a threat for a reintroduction into the currently unprotected swine population. To assess the possible impact of such a reintroduction in a naive herd, an in vivo infection study using two genetically characterized wild boar PRV isolates (BEL24043 and BEL20075) representative for wild boar strains circulating in south-western and central Europe and the virulent NIA3 reference strain was performed in 2- and 15-week-old domestic pigs. Our study revealed an attenuated nature of both wild boar strains in 15-week-old pigs. In contrast, it showed the capacity of strain BEL24043 to induce severe clinical symptoms and mortality in young piglets, thereby confirming that the known age dependency of disease outcome after PRV infection also holds for wild boar isolates. Despite the absence of clinical disease in 15-week-old sows, both wild boar PRV strains were able to induce seroconversion, but to a different extent. Importantly, differences in infection and transmission capacity of both strains were observed in 15-week-old sows. Strain BEL24043 induced a more prolonged and disseminated infection than strain BEL20075 and was able to spread efficiently to contact animals, indicative of its capacity to induce a sustained infection. In conclusion, it was shown that a reintroduction of a wild boar isolate into the domestic swine population could have serious economic consequences due to the induction of clinical symptoms in piglets and by jeopardizing the PRV-negative status.
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- 2016
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20. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.
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Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, Kleinman A, Styrkarsdottir U, Liu CT, Uggla C, Evans DS, Nielson CM, Walter K, Pettersson-Kymmer U, McCarthy S, Eriksson J, Kwan T, Jhamai M, Trajanoska K, Memari Y, Min J, Huang J, Danecek P, Wilmot B, Li R, Chou WC, Mokry LE, Moayyeri A, Claussnitzer M, Cheng CH, Cheung W, Medina-Gómez C, Ge B, Chen SH, Choi K, Oei L, Fraser J, Kraaij R, Hibbs MA, Gregson CL, Paquette D, Hofman A, Wibom C, Tranah GJ, Marshall M, Gardiner BB, Cremin K, Auer P, Hsu L, Ring S, Tung JY, Thorleifsson G, Enneman AW, van Schoor NM, de Groot LC, van der Velde N, Melin B, Kemp JP, Christiansen C, Sayers A, Zhou Y, Calderari S, van Rooij J, Carlson C, Peters U, Berlivet S, Dostie J, Uitterlinden AG, Williams SR, Farber C, Grinberg D, LaCroix AZ, Haessler J, Chasman DI, Giulianini F, Rose LM, Ridker PM, Eisman JA, Nguyen TV, Center JR, Nogues X, Garcia-Giralt N, Launer LL, Gudnason V, Mellström D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren Ö, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussière J, Arp PP, Koromani F, Prince RL, Lewis JR, Langdahl BL, Hermann AP, Jensen JE, Kaptoge S, Khaw KT, Reeve J, Formosa MM, Xuereb-Anastasi A, Åkesson K, McGuigan FE, Garg G, Olmos JM, Zarrabeitia MT, Riancho JA, Ralston SH, Alonso N, Jiang X, Goltzman D, Pastinen T, Grundberg E, Gauguier D, Orwoll ES, Karasik D, Davey-Smith G, Smith AV, Siggeirsdottir K, Harris TB, Zillikens MC, van Meurs JB, Thorsteinsdottir U, Maurano MT, Timpson NJ, Soranzo N, Durbin R, Wilson SG, Ntzani EE, Brown MA, Stefansson K, Hinds DA, Spector T, Cupples LA, Ohlsson C, Greenwood CM, Jackson RD, Rowe DW, Loomis CA, Evans DM, Ackert-Bicknell CL, Joyner AL, Duncan EL, Kiel DP, Rivadeneira F, and Richards JB
- Subjects
- Animals, Bone and Bones metabolism, Disease Models, Animal, Europe ethnology, Exome genetics, Female, Gene Frequency genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Genomics, Genotype, Humans, Mice, Sequence Analysis, DNA, White People genetics, Wnt Proteins genetics, Bone Density genetics, Fractures, Bone genetics, Genome, Human genetics, Homeodomain Proteins genetics
- Abstract
The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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- 2015
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21. Retrograde Trafficking Inhibitor of Shiga Toxins Reduces Morbidity and Mortality of Mice Infected with Enterohemorrhagic Escherichia coli.
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Secher T, Shima A, Hinsinger K, Cintrat JC, Johannes L, Barbier J, Gillet D, and Oswald E
- Subjects
- Animals, Benzamides therapeutic use, Chlorocebus aethiops, Disease Models, Animal, Disease Outbreaks, Enterohemorrhagic Escherichia coli genetics, Enterohemorrhagic Escherichia coli pathogenicity, Escherichia coli Infections epidemiology, Europe, HeLa Cells, Hemolytic-Uremic Syndrome prevention & control, Humans, Mice, Mice, Inbred BALB C, Thiophenes therapeutic use, Vero Cells, Benzamides pharmacology, Enterohemorrhagic Escherichia coli drug effects, Escherichia coli Infections drug therapy, Hemolytic-Uremic Syndrome drug therapy, Shiga Toxin 2 antagonists & inhibitors, Thiophenes pharmacology
- Abstract
The most deadly outbreak of Escherichia coli O104:H4 occurred in Europe in 2011. Here, we evaluated the effects of the retrograde trafficking inhibitor Retro-2(cycl) in a murine model of E. coli O104:H4 infection. Systemic treatment with Retro-2(cycl) significantly reduced body weight loss and improved clinical scores and survival rates for O104:H4-infected mice. The present data established that Retro-2(cycl) contributes to the protection of mice against O104:H4 infection and may represent a novel approach to limit Shiga toxin-producing Escherichia coli (STEC)-induced toxicity., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
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- 2015
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22. Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.
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Villa F, Carrizzo A, Spinelli CC, Ferrario A, Malovini A, Maciąg A, Damato A, Auricchio A, Spinetti G, Sangalli E, Dang Z, Madonna M, Ambrosio M, Sitia L, Bigini P, Calì G, Schreiber S, Perls T, Fucile S, Mulas F, Nebel A, Bellazzi R, Madeddu P, Vecchione C, and Puca AA
- Subjects
- 14-3-3 Proteins metabolism, Age Factors, Aged, Aged, 80 and over, Animals, Blood Pressure, Cell Movement, Disease Models, Animal, Europe, Female, Genetic Association Studies, Genetic Therapy, Genotype, HEK293 Cells, HSP90 Heat-Shock Proteins metabolism, Hindlimb, Humans, Hypertension genetics, Hypertension metabolism, Hypertension physiopathology, Hypertension therapy, Intercellular Signaling Peptides and Proteins, Ischemia genetics, Ischemia metabolism, Ischemia physiopathology, Ischemia therapy, Male, Mice, Inbred C57BL, Middle Aged, Nitric Oxide Synthase Type III metabolism, Phenotype, Phosphorylation, RNA Interference, Rats, Inbred SHR, Signal Transduction, Stress, Mechanical, Transfection, United States, Vasodilation, eIF-2 Kinase metabolism, Endothelial Progenitor Cells metabolism, Human Umbilical Vein Endothelial Cells metabolism, Longevity genetics, Muscle, Skeletal blood supply, Neovascularization, Physiologic, Phosphoproteins genetics, Phosphoproteins metabolism
- Abstract
Rationale: Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury., Objective: Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease., Methods and Results: We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R-like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34(+) cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle., Conclusions: Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes., (© 2015 American Heart Association, Inc.)
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- 2015
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23. Regulatory acceptance of animal models of disease to support clinical trials of medicines and advanced therapy medicinal products.
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Cavagnaro J and Silva Lima B
- Subjects
- Animal Use Alternatives, Animals, Clinical Trials as Topic legislation & jurisprudence, Europe, Guidelines as Topic, Humans, Species Specificity, Toxicity Tests, Translational Research, Biomedical legislation & jurisprudence, United States, Clinical Trials as Topic methods, Disease Models, Animal, Drug Evaluation, Preclinical methods, Drug-Related Side Effects and Adverse Reactions, Government Regulation, Translational Research, Biomedical methods
- Abstract
The utility of animal models of disease for assessing the safety of novel therapeutic modalities has become an increasingly important topic of discussion as research and development efforts focus on improving the predictive value of animal studies to support accelerated clinical development. Medicines are approved for marketing based upon a determination that their benefits outweigh foreseeable risks in specific indications, specific populations, and at specific dosages and regimens. No medicine is 100% safe. A medicine is less safe if the actual risks are greater than the predicted risks. The purpose of preclinical safety assessment is to understand the potential risks to aid clinical decision-making. Ideally preclinical studies should identify potential adverse effects and design clinical studies that will minimize their occurrence. Most regulatory documents delineate the utilization of conventional "normal" animal species to evaluate the safety risk of new medicines (i.e., new chemical entities and new biological entities). Animal models of human disease are commonly utilized to gain insight into the pathogenesis of disease and to evaluate efficacy but less frequently utilized in preclinical safety assessment. An understanding of the limitations of the animal disease models together with a better understanding of the disease and how toxicity may be impacted by the disease condition should allow for a better prediction of risk in the intended patient population. Importantly, regulatory authorities are becoming more willing to accept and even recommend data from experimental animal disease models that combine efficacy and safety to support clinical development., (Copyright © 2015 Elsevier B.V. All rights reserved.)
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- 2015
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24. New reassortant and enzootic European swine influenza viruses transmit efficiently through direct contact in the ferret model.
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Fobian K, Fabrizio TP, Yoon SW, Hansen MS, Webby RJ, and Larsen LE
- Subjects
- Animals, Cell Line, Disease Models, Animal, Epithelial Cells virology, Europe epidemiology, Ferrets, Humans, Influenza A Virus, H1N2 Subtype genetics, Influenza A Virus, H1N2 Subtype physiology, Influenza A Virus, H3N2 Subtype genetics, Influenza A Virus, H3N2 Subtype physiology, Molecular Sequence Data, Polysaccharides metabolism, RNA, Viral genetics, Reassortant Viruses genetics, Reassortant Viruses physiology, Receptors, Virus metabolism, Sequence Analysis, DNA, Swine, Swine Diseases epidemiology, Viral Load, Virus Attachment, Virus Replication, Influenza A Virus, H1N2 Subtype isolation & purification, Influenza A Virus, H3N2 Subtype isolation & purification, Orthomyxoviridae Infections transmission, Orthomyxoviridae Infections virology, Reassortant Viruses isolation & purification, Swine Diseases virology
- Abstract
The reverse zoonotic events that introduced the 2009 pandemic influenza virus into pigs have drastically increased the diversity of swine influenza viruses in Europe. The pandemic potential of these novel reassortments is still unclear, necessitating enhanced surveillance of European pigs with additional focus on risk assessment of these new viruses. In this study, four European swine influenza viruses were assessed for their zoonotic potential. Two of the four viruses were enzootic viruses of subtype H1N2 (with avian-like H1) and H3N2, and two were new reassortants, one with avian-like H1 and human-like N2 and one with 2009 pandemic H1 and swine-like N2. All viruses replicated to high titres in nasal wash and nasal turbinate samples from inoculated ferrets and transmitted efficiently by direct contact. Only the H3N2 virus transmitted to naïve ferrets via the airborne route. Growth kinetics using a differentiated human bronchial epithelial cell line showed that all four viruses were able to replicate to high titres. Further, the viruses revealed preferential binding to the 2,6-α-silalylated glycans and investigation of the antiviral susceptibility of the viruses revealed that all were sensitive to neuraminidase inhibitors. These findings suggested that these viruses have the potential to infect humans and further underline the need for continued surveillance as well as biological characterization of new influenza A viruses.
- Published
- 2015
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25. Host-pathogen interactions during porcine reproductive and respiratory syndrome virus 1 infection of piglets.
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Salguero FJ, Frossard JP, Rebel JM, Stadejek T, Morgan SB, Graham SP, and Steinbach F
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- Animals, Disease Models, Animal, Europe, North America, Porcine respiratory and reproductive syndrome virus classification, Porcine respiratory and reproductive syndrome virus genetics, Porcine respiratory and reproductive syndrome virus isolation & purification, Swine, Swine Diseases virology, Host-Pathogen Interactions, Porcine Reproductive and Respiratory Syndrome pathology, Porcine Reproductive and Respiratory Syndrome virology, Porcine respiratory and reproductive syndrome virus physiology
- Abstract
Porcine reproductive and respiratory syndrome (PRRS) is a major disease affecting pigs worldwide and resulting in considerable economic losses. While PRRS is a global phenomenon, the causative viruses PRRSV-1 (first detected in Europe) and PRRSV-2 (isolated in North America) are genetically and biologically distinct. In addition, the disease outcome is directly linked to co-infections associated with the porcine respiratory disease complex and the host response is variable between different breeds of pigs. It is therefore warranted when studying the pathogenesis of PRRS to consider each viral genotype separately and apply careful consideration to the disease model studied. We here review the respiratory pig model for PRRSV-1, with a focus on a recent set of studies conducted with carefully selected virus strains and pigs, which may serve as both a baseline and benchmark for future investigation., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
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26. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies.
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Shaheen R, Schmidts M, Faqeih E, Hashem A, Lausch E, Holder I, Superti-Furga A, Mitchison HM, Almoisheer A, Alamro R, Alshiddi T, Alzahrani F, Beales PL, and Alkuraya FS
- Subjects
- Amino Acid Sequence, Animals, Bone and Bones metabolism, Cell Cycle Proteins metabolism, Centrioles metabolism, Chromosome Mapping, Chromosomes, Human, Pair 5 genetics, Chromosomes, Human, Pair 5 metabolism, Cilia pathology, Cohort Studies, Disease Models, Animal, Europe, Female, Fibroblasts cytology, Fibroblasts metabolism, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Pedigree, Phenotype, Saudi Arabia, Zebrafish, Bone and Bones abnormalities, Cell Cycle Proteins genetics, Centrioles genetics, Ellis-Van Creveld Syndrome genetics, Mutation, Missense
- Abstract
Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies., (© The Author 2014. Published by Oxford University Press.)
- Published
- 2015
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27. Mission critical: mobilization of essential animal models for Ebola, Nipah, and Machupo virus infections.
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Zumbrun EE
- Subjects
- Animals, Arenaviruses, New World drug effects, Climate Change, Compassionate Use Trials, Disease Outbreaks, Ebolavirus drug effects, Epidemics, Europe epidemiology, Hemorrhagic Fever, American drug therapy, Hemorrhagic Fever, American virology, Hemorrhagic Fever, Ebola drug therapy, Hemorrhagic Fever, Ebola virology, Henipavirus Infections drug therapy, Henipavirus Infections virology, Humans, Internationality, Nipah Virus drug effects, United States epidemiology, United States Food and Drug Administration, Arenaviruses, New World physiology, Disease Models, Animal, Ebolavirus physiology, Hemorrhagic Fever, American epidemiology, Hemorrhagic Fever, Ebola epidemiology, Henipavirus Infections epidemiology, Nipah Virus physiology
- Abstract
The reports for Ebola virus Zaire (EBOV), Nipah virus, and Machupo virus (MACV) pathogenesis, in this issue of Veterinary Pathology, are timely considering recent events, both nationally and internationally. EBOV, Nipah virus, and MACV cause highly lethal infections for which no Food and Drug Administration (FDA) licensed vaccines or therapies exist. Not only are there concerns that these agents could be used by those with malicious intent, but shifts in ecological distribution of viral reservoirs due to climate change or globalization could lead to more frequent infections within remote regions than previously seen as well as outbreaks in more populous areas. The current EBOV epidemic shows no sign of abating across 3 West African nations (as of October 2014), including densely populated areas, far outpacing infection rates of previous outbreaks. A limited number of cases have also arisen in the United States and Europe. With few treatment options for these deadly viruses, development of animal models reflective of human disease is paramount to combat these diseases. As an example of this potential, a new treatment compound, ZMapp, that had demonstrated efficacy against EBOV infection in nonhuman primates (NHPs) received an emergency compassionate use exception from the FDA for the treatment of 2 American medical workers infected with EBOV, and they are currently virus free and recovering., (© The Author(s) 2014.)
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- 2015
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28. Mucormycoses caused by Lichtheimia species.
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Schwartze VU and Jacobsen ID
- Subjects
- Animals, Clinical Trials as Topic, Disease Models, Animal, Europe, Humans, Immunocompromised Host, Mucorales classification, Mucormycosis pathology, Mucorales pathogenicity, Mucormycosis microbiology
- Abstract
Mucormycoses are life-threatening infections with fungi from the order Mucorales (Mucoromycotina). Although mucormycoses are uncommon compared to other fungal infections, e.g. aspergillosis and candidiasis, the number of cases is increasing especially in immunocompromised patients. Lichtheimia (formerly Absidia) species represent the second to third most common cause of mucormycoses in Europe. This mini review presents current knowledge about taxonomy and clinical relevance of Lichtheimia species. In addition, clinical presentation and risk factors will be discussed. Proper animal infection models are essential for the understanding of the pathogenesis and the identification of virulence factors of fungal pathogens. To date, several animal models have been used to study Lichtheimia infection. A brief overview of the different models and the main conclusions from the infection experiments is summarised in this review., (© 2014 Blackwell Verlag GmbH.)
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- 2014
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29. European perspective and update on the management of nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid.
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Chastre J, Blasi F, Masterton RG, Rello J, Torres A, and Welte T
- Subjects
- Acetamides pharmacokinetics, Animals, Anti-Bacterial Agents pharmacokinetics, Cross Infection diagnosis, Cross Infection drug therapy, Cross Infection economics, Cross Infection epidemiology, Cross Infection microbiology, Disease Models, Animal, Europe, Humans, Linezolid, Oxazolidinones pharmacokinetics, Pneumonia, Staphylococcal diagnosis, Pneumonia, Staphylococcal economics, Pneumonia, Staphylococcal epidemiology, Pneumonia, Staphylococcal microbiology, Pneumonia, Ventilator-Associated mortality, Practice Guidelines as Topic, Risk Factors, Vancomycin therapeutic use, Acetamides therapeutic use, Anti-Bacterial Agents therapeutic use, Methicillin-Resistant Staphylococcus aureus, Oxazolidinones therapeutic use, Pneumonia, Staphylococcal drug therapy
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant hospital-acquired infections worldwide and remains a public health priority in Europe. Nosocomial pneumonia (NP) involving MRSA often affects patients in intensive care units with substantial morbidity, mortality and associated costs. A guideline-based approach to empirical treatment with an antibacterial agent active against MRSA can improve the outcome of patients with MRSA NP, including those with ventilator-associated pneumonia. New methods may allow more rapid or sensitive diagnosis of NP or microbiological confirmation in patients with MRSA NP, allowing early de-escalation of treatment once the pathogen is known. In Europe, available antibacterial agents for the treatment of MRSA NP include the glycopeptides (vancomycin and teicoplanin) and linezolid (available as an intravenous or oral treatment). Vancomycin has remained a standard of care in many European hospitals; however, there is evidence that it may be a suboptimal therapeutic option in critically ill patients with NP because of concerns about its limited intrapulmonary penetration, increased nephrotoxicity with higher doses, as well as the emergence of resistant strains that may result in increased clinical failure. Linezolid has demonstrated high penetration into the epithelial lining fluid of patients with ventilator-associated pneumonia and shown statistically superior clinical efficacy versus vancomycin in the treatment of MRSA NP in a phase IV, randomized, controlled study. This review focuses on the disease burden and clinical management of MRSA NP, and the use of linezolid after more than 10 years of clinical experience., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)
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- 2014
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30. Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.
- Author
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Harper JC, Geraedts J, Borry P, Cornel MC, Dondorp W, Gianaroli L, Harton G, Milachich T, Kääriäinen H, Liebaers I, Morris M, Sequeiros J, Sermon K, Shenfield F, Skirton H, Soini S, Spits C, Veiga A, Vermeesch JR, Viville S, de Wert G, and Macek M Jr
- Subjects
- Animals, Congenital Abnormalities epidemiology, Disease Models, Animal, Embryonic Stem Cells, Epigenesis, Genetic, Europe, Female, Fertilization in Vitro methods, Genetic Counseling, Genetic Testing, Genetic Variation, Genetics, Medical, Guidelines as Topic, Humans, Infertility genetics, Infertility therapy, Male, Medical Tourism, Policy, Pregnancy, Preimplantation Diagnosis, Regenerative Medicine, Societies, Scientific, Reproduction genetics, Reproductive Techniques, Assisted adverse effects, Reproductive Techniques, Assisted ethics, Reproductive Techniques, Assisted legislation & jurisprudence, Reproductive Techniques, Assisted trends
- Abstract
In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005.
- Published
- 2013
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31. Vaccines in development against West Nile virus.
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Brandler S and Tangy F
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- Animals, Disease Models, Animal, Disease Outbreaks, Drug Discovery trends, Europe epidemiology, Humans, Mice, North America epidemiology, Primates, Vaccines, Attenuated adverse effects, Vaccines, Attenuated immunology, Vaccines, Attenuated isolation & purification, Vaccines, Synthetic adverse effects, Vaccines, Synthetic immunology, Vaccines, Synthetic isolation & purification, West Nile Virus Vaccines adverse effects, West Nile Fever epidemiology, West Nile Fever prevention & control, West Nile Virus Vaccines immunology, West Nile Virus Vaccines isolation & purification
- Abstract
West Nile encephalitis emerged in 1999 in the United States, then rapidly spread through the North American continent causing severe disease in human and horses. Since then, outbreaks appeared in Europe, and in 2012, the United States experienced a new severe outbreak reporting a total of 5,387 cases of West Nile virus (WNV) disease in humans, including 243 deaths. So far, no human vaccine is available to control new WNV outbreaks and to avoid worldwide spreading. In this review, we discuss the state-of-the-art of West Nile vaccine development and the potential of a novel safe and effective approach based on recombinant live attenuated measles virus (MV) vaccine. MV vaccine is a live attenuated negative-stranded RNA virus proven as one of the safest, most stable and effective human vaccines. We previously described a vector derived from the Schwarz MV vaccine strain that stably expresses antigens from emerging arboviruses, such as dengue, West Nile or chikungunya viruses, and is strongly immunogenic in animal models, even in the presence of MV pre-existing immunity. A single administration of a recombinant MV vaccine expressing the secreted form of WNV envelope glycoprotein elicited protective immunity in mice and non-human primates as early as two weeks after immunization, indicating its potential as a human vaccine.
- Published
- 2013
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32. Experimental comparison of pathogenic potential of two sibling species Anisakis simplex s.s. and Anisakis pegreffii in Wistar rat.
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del Carmen Romero M, Valero A, Navarro-Moll MC, and Martín-Sánchez J
- Subjects
- Amplified Fragment Length Polymorphism Analysis methods, Animals, Anisakiasis genetics, Anisakis genetics, Anisakis isolation & purification, Atlantic Ocean, Europe, Female, Genotype, Humans, Larva classification, Larva genetics, Larva pathogenicity, Logistic Models, Mediterranean Sea, Rats, Species Specificity, Anisakiasis parasitology, Anisakis pathogenicity, Disease Models, Animal, Gadiformes parasitology, Gastric Mucosa parasitology, Rats, Wistar parasitology
- Abstract
Objectives: There are little data available on the pathology caused by the sibling species Anisakis simplex s.s. and Anisakis pegreffii. The differences shown in their ability to penetrate the muscle of fish may also be manifested in humans. The purpose of this study is to confirm possible differences in pathogenicity between A. simplex s.s. and A. pegreffii using an experimental model which simulates infection in humans., Methods: Female Wistar rats were infected with 190 Anisakis type I L3 larvae from the Iberian coastline. After the animal was sacrificed, these L3 larvae were then recovered and identified via PCR-RFLP of the ITS1-5.8S-ITS2. A logistic regression analysis was performed searching for association between experimental pathogenic potential and species., Results: The distribution of A. simplex s.s. and A. pegreffii between Atlantic and Mediterranean waters of the Iberian Peninsula showed statistically significant differences (P < 0.001) which were not observed in the hybrid genotypes (P > 0.3). 21.6% showed pathogenic potential, interpreted as the capacity of the larvae to cause lesions, stick to the gastrointestinal wall or penetrate it. The species variable showed association with the pathogenic role of the larva (P = 0.008). Taking A. simplex s.s. as our reference, the OR for A. pegreffii is 0.351 (P = 0.028)., Conclusions: Despite this difference, A. pegreffii is also capable of causing anisakiasis, being responsible for 14.3% of the penetrations of the gastric mucosa found in rats, which justifies both species being considered aetiologic agents of this parasitic disorder., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
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33. Latest American and European updates on infantile spasms.
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Lux AL
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- Animals, Consensus, Europe, Humans, Infant, United States, Disease Models, Animal, Neurology standards, Practice Guidelines as Topic, Spasms, Infantile classification, Spasms, Infantile physiopathology, Spasms, Infantile therapy
- Abstract
Infantile spasms remain a challenging condition to study and treat, and although they form the commonest epilepsy syndrome with onset in infancy, the challenge is broadened by the wide range of potential underlying causes. The field of study remains dynamic, with debates relating to case definitions and organising structures for classification of seizures and epilepsies in general, and a newly proposed genetic and biologic classification specifically for infantile spasms. There have been recent consensus statements, a Delphi process eliciting prioritised quality-of-care indicators, systematic reviews of treatment, and a survey of clinical practice in the USA. There is increasing evidence that longer duration of spasms is associated with poorer neurodevelopmental outcomes. It has taken many years to develop an animal model that reasonably represents infantile spasms, but there are now several animal models, and they are leading to innovative and valuable studies that suggest novel treatments.
- Published
- 2013
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34. Notes on the epigenetic origins of childhood cancer.
- Author
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Burgio E
- Subjects
- Adolescent, Age of Onset, Animals, Child, Child, Preschool, Chromosome Aberrations, Cocarcinogenesis, Cohort Studies, DNA Damage, DNA, Neoplasm genetics, Disease Models, Animal, Environmental Pollution adverse effects, Europe epidemiology, Female, Gene Expression Regulation, Developmental, Humans, Incidence, Infant, Infant, Newborn, Italy epidemiology, Male, Models, Genetic, Neoplasms embryology, Neoplasms epidemiology, Pesticides toxicity, Pregnancy, Prenatal Exposure Delayed Effects, Registries, Young Adult, Epigenesis, Genetic, Neoplasms genetics
- Published
- 2013
35. [West Nile virus].
- Subjects
- Animals, Antibodies, Viral blood, Cross-Sectional Studies, Disease Models, Animal, Disease Reservoirs, Disease Vectors, Europe, Germany, Humans, Microscopy, Electron, Population Surveillance, Virion immunology, Virion pathogenicity, Virulence, West Nile Fever diagnosis, West Nile virus classification, West Nile virus immunology, West Nile virus pathogenicity, West Nile virus ultrastructure, Blood-Borne Pathogens, Communicable Diseases, Emerging, National Health Programs, Public Health, West Nile Fever epidemiology, West Nile Fever transmission
- Published
- 2012
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36. Comparative molecular analyses of Borrelia burgdorferi sensu stricto strains B31 and N40D10/E9 and determination of their pathogenicity.
- Author
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Chan K, Awan M, Barthold SW, and Parveen N
- Subjects
- Animals, Bacterial Adhesion, Borrelia burgdorferi classification, Borrelia burgdorferi isolation & purification, Chlorocebus aethiops, Disease Models, Animal, Epithelial Cells microbiology, Europe, Female, Humans, Mice, Mice, Inbred C3H, United States, Vero Cells, Virulence, Borrelia burgdorferi genetics, Borrelia burgdorferi pathogenicity, Lyme Disease microbiology, Lyme Disease pathology, Virulence Factors genetics
- Abstract
Background: Lyme disease in the United States is caused primarily by B. burgdorferi sensu stricto while other species are also prevalent in Europe. Genetic techniques have identified several chromosomal and plasmid-borne regulatory and virulence factors involved in Lyme pathogenesis. B31 and N40 are two widely studied strains of B. burgdorferi, which belong to two different 16 S-23 S rRNA spacer types (RST) and outer surface protein C (OspC) allelic groups. However, the presence of several known virulence factors in N40 has not been investigated. This is the first comprehensive study that compared these two strains both in vitro and using the mouse model of infection., Results: Phylogenetic analyses predict B31 to be more infectious. However, our studies here indicate that N40D10/E9 is more infectious than the B31 strain at lower doses of inoculation in the susceptible C3H mice. Based-upon a careful analyses of known adhesins of these strains, it is predicted that the absence of a known fibronectin-glycosaminoglycan binding adhesin, bbk32, in the N40 strain could at least partially be responsible for reduction in its binding to Vero cells in vitro. Nevertheless, this difference does not affect the infectivity of N40D10/E9 strain. The genes encoding known regulatory and virulence factors critical for pathogenesis were detected in both strains. Differences in the protein profiles of these B. burgdorferi strains in vitro suggest that the novel, differentially expressed molecules may affect infectivity of B. burgdorferi. Further exacerbation of these molecular differences in vivo could affect the pathogenesis of spirochete strains., Conclusion: Based upon the studies here, it can be predicted that N40D10/E9 disseminated infection at lower doses may be enhanced by its lower binding to epithelial cells at the site of inoculation due to the absence of BBK32. We suggest that complete molecular analyses of virulence factors followed by their evaluation using the mouse infection model should form the basis of determining infectivity and pathogenicity of different strains rather than simple phylogenetic group analyses. This study further emphasizes a need to investigate multiple invasive strains of B. burgdorferi to fully appreciate the pathogenic mechanisms that contribute to Lyme disease manifestations.
- Published
- 2012
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37. Initial human experience with the XIENCE side-branch access device.
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Rizik DG, Samuels B, Hatten TR, and Gil RJ
- Subjects
- Angioplasty, Balloon, Coronary methods, Animals, Cattle, Coronary Angiography methods, Coronary Artery Disease diagnosis, Disease Models, Animal, Dogs, Equipment Safety, Europe, Follow-Up Studies, Humans, Male, Treatment Outcome, Ultrasonography, Interventional methods, Angioplasty, Balloon, Coronary instrumentation, Coronary Artery Disease therapy, Drug-Eluting Stents, Imaging, Three-Dimensional, Prosthesis Design, Sirolimus pharmacology
- Abstract
The everolimus-eluting XIENCE side-branch access (SBA) stent has been the focus of numerous recent publications. Most of the information available on this device comes from the preclinical studies performed in ovine models as well as perfused synthetic heart models. It has now become available in Europe as part of a limited test launch. Delivered via a low-profile, dual-lumen, single-tip catheter, a single inflation device deploys the stent in the main branch and expands a portal opening into the ostium of the side branch to allow for scaffolding and entry into the side branch. This case report describes the first-in-man experience with this novel device.
- Published
- 2012
38. Immune therapy of multiple sclerosis--future strategies.
- Author
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Meuth SG, Göbel K, and Wiendl H
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Disease Models, Animal, Drug Approval, Europe, Humans, Immunologic Factors adverse effects, Immunologic Factors pharmacology, Medication Adherence, Multiple Sclerosis immunology, Multiple Sclerosis physiopathology, United States, Drug Design, Immunologic Factors therapeutic use, Multiple Sclerosis drug therapy
- Abstract
Baseline disease-modifying therapies (DMTs) for multiple sclerosis (MS) include three different preparations of interferon-beta (IFN-β) and glatiramer acetate (GA). These substances reduce relapse rates, side-effects are tolerated by most patients and - after more than 15 years of experience - the long-term safety profile for these drugs can be appraised as very good. In 2006, the therapeutic tool kit was augmented by the first monoclonal antibody, natalizumab, approved as monotherapy for treatment-refractory highly active MS. The restriction to these patient groups results from the rare, but fatal risk of JC virus-induced progressive multifocal leukoencephalopathy (PML). The first oral agent (fingolimod) was approved in 2010 for the United States and in 2011 for Europe. As a further option for therapy escalation the chemotherapeutic agent mitoxantrone is approved for non-responding relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS). The use of mitoxantrone is limited by severe cardiotoxicity and the risk of treatment related acute leukemia. However, despite the fact that therapeutic options for MS have significantly been widened over the past decade new treatment options and more convenient modes of application are needed to enhance efficacy and improve adherence to therapy. This article will review recent developments in MS treatments focusing on oral agents (cladribine, fingolimod, BG00012, teriflunomide and laquinimod) and novel monoclonal antibodies (alemtumzumab, daclizumab, ocrelizumab, ofatumumab).
- Published
- 2012
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39. The OBELIX project: early life exposure to endocrine disruptors and obesity.
- Author
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Legler J, Hamers T, van Eck van der Sluijs-van de Bor M, Schoeters G, van der Ven L, Eggesbo M, Koppe J, Feinberg M, and Trnovec T
- Subjects
- Animals, Biomarkers, Child, Child Nutritional Physiological Phenomena, Child, Preschool, Cohort Studies, Disease Models, Animal, Europe, Female, Flame Retardants toxicity, Follow-Up Studies, Food Contamination analysis, Humans, Male, Maternal Exposure, Mice, Milk, Human chemistry, Pesticides toxicity, Risk Assessment, Risk Factors, Endocrine Disruptors toxicity, Environmental Exposure adverse effects, Obesity epidemiology, Obesity etiology, Polychlorinated Biphenyls toxicity
- Abstract
The hypothesis of whether early life exposure (both pre- and early postnatal) to endocrine-disrupting chemicals (EDCs) may be a risk factor for obesity and related metabolic diseases later in life will be tested in the European research project OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life). OBELIX is a 4-y project that started in May 2009 and which has the following 5 main objectives: 1) to assess early life exposure in humans to major classes of EDCs identified as potential inducers of obesity (ie, dioxin-like compounds, non-dioxin-like polychlorinated biphenyls, organochlorine pesticides, brominated flame retardants, phthalates, and perfluorinated compounds) by using mother-child cohorts from 4 European regions with different food-contaminant exposure patterns; 2) to relate early life exposure to EDCs with clinical markers, novel biomarkers, and health-effect data related to obesity; 3) to perform hazard characterization of early life exposure to EDCs for the development of obesity later in life by using a mouse model; 4) to determine mechanisms of action of obesogenic EDCs on developmental programming with in vivo and in vitro genomics and epigenetic analyses; and 5) to perform risk assessments of prenatal exposure to obesogenic EDCs in food by integrating maternal exposure through food-contaminant exposure and health-effect data in children and hazard data in animal studies.
- Published
- 2011
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40. LUPA: a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs.
- Author
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Lequarré AS, Andersson L, André C, Fredholm M, Hitte C, Leeb T, Lohi H, Lindblad-Toh K, and Georges M
- Subjects
- Animals, Chromosome Mapping veterinary, DNA analysis, Dogs, Europe, Humans, International Cooperation, Pedigree, Disease Models, Animal, Dog Diseases genetics, Genome-Wide Association Study veterinary, Polymorphism, Single Nucleotide
- Abstract
The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal model organism for comparative disease genetics. Using newly developed resources, genome-wide association studies in dog breeds are proving to be exceptionally powerful. Towards this aim, veterinarians and geneticists from 12 European countries are collaborating to collect and analyse the DNA from large cohorts of dogs suffering from a range of carefully defined diseases of relevance to human health. This project, named LUPA, has already delivered considerable results. The consortium has collaborated to develop a new high density single nucleotide polymorphism (SNP) array. Mutations for four monogenic diseases have been identified and the information has been utilised to find mutations in human patients. Several complex diseases have been mapped and fine mapping is underway. These findings should ultimately lead to a better understanding of the molecular mechanisms underlying complex diseases in both humans and their best friend., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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41. The protective effect and action mechanism of Vaccinium myrtillus L. on gastric ulcer in mice.
- Author
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Ogawa K, Oyagi A, Tanaka J, Kobayashi S, and Hara H
- Subjects
- Animals, Anthocyanins isolation & purification, Anthocyanins pharmacology, Antioxidants pharmacology, Disease Models, Animal, Europe, Free Radical Scavengers isolation & purification, Free Radical Scavengers pharmacology, Gastric Mucosa metabolism, Hydroxyl Radical metabolism, Lipid Peroxidation drug effects, Male, Medicine, Traditional, Mice, Stomach Ulcer chemically induced, Stomach Ulcer metabolism, Superoxides metabolism, Anti-Ulcer Agents isolation & purification, Anti-Ulcer Agents pharmacology, Gastric Mucosa drug effects, Plant Extracts isolation & purification, Plant Extracts pharmacology, Stomach Ulcer drug therapy, Vaccinium myrtillus chemistry
- Abstract
Vaccinium myrtillus L. anthocyanoside (VMA) is used as a folk medicine to treat diseases related to gastric ulcers in northern Europe. However, the effects of VMA and its detailed mechanism on gastric ulcer have not been investigated sufficiently. Therefore, the aim of the present study was to investigate the protective effects of VMA on gastric mucosal damage in a murine gastric ulcer model. First the effects of VMA on ethanol-induced gastric ulcers in mice were investigated. Then, the levels of lipid peroxide in murine stomach homogenates were measured to investigate the antioxidative effects of VMA. In addition, the free radical scavenging activity of VMA and its main anthocyanidins were evaluated by electron spin resonance measurement. Oral administration of VMA (10, 30 and 100 mg/kg) significantly protected gastric mucosa against HCl/ethanol-induced gastric ulcers. Furthermore, VMA inhibited lipid peroxide levels in a concentration-dependent manner and showed high scavenging activity against the superoxide anion radical (·O(2) (-) ) and the hydroxyl radical (·OH). Anthocyanidins also showed scavenging activity against the ·O(2) (-) , while only delphinidin showed high scavenging activity against the ·OH. These findings indicate that the protective effects of VMA on HCl/ethanol-induced gastric mucosal injury may be partially due to the antiperoxidative effects of anthocyanidins., (Copyright © 2011 John Wiley & Sons, Ltd.)
- Published
- 2011
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42. EuroCareCF: working together to improve patient care and therapy development.
- Author
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Sheppard DN
- Subjects
- Animals, Europe, Humans, Biomedical Research trends, Cooperative Behavior, Cystic Fibrosis therapy, Delivery of Health Care trends, Disease Models, Animal
- Published
- 2011
- Full Text
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43. Critical evaluation of the use of dogs in biomedical research and testing in Europe.
- Author
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Hasiwa N, Bailey J, Clausing P, Daneshian M, Eileraas M, Farkas S, Gyertyán I, Hubrecht R, Kobel W, Krummenacher G, Leist M, Lohi H, Miklósi A, Ohl F, Olejniczak K, Schmitt G, Sinnett-Smith P, Smith D, Wagner K, Yager JD, Zurlo J, and Hartung T
- Subjects
- Animal Rights, Animals, Animals, Laboratory, Biomedical Research ethics, Disease Models, Animal, Dog Diseases chemically induced, Dog Diseases therapy, Drug-Related Side Effects and Adverse Reactions, Europe, Pesticides adverse effects, Pets, Veterinary Medicine methods, Animal Use Alternatives methods, Biomedical Research methods, Dogs physiology
- Abstract
Dogs are sometimes referred to as "man's best friend" and with the increase in urbanization and lifestyle changes, dogs are seen by their owners as family members. Society expresses specific concerns about the experimental use of dogs, as they are sometimes perceived to have a special status for humans. This may appear somewhat conflicting with the idea that the intrinsic value of all animals is the same, and that also several other animal species are used in biomedical research and toxicology. This aspect and many others are discussed in an introductory chapter dealing with ethical considerations on the use of dogs as laboratory animals. The report gives an overview on the use of dogs in biomedical research, safety assessment and the drug developmental process and reflects the discussion on the use of dogs as second (non-rodent)species in toxicity testing. Approximately 20,000 dogs are used in scientific procedures in Europe every year, and their distinct genetic, physiological and behavioral characteristics may support their use as models for e.g. behavioral analysis and genetic research. Advances in the 3Rs (Replacement, Reduction and Refinement of experiments using dogs) are described, potential opportunities are discussed and recommendations for further progress in this area are made.
- Published
- 2011
- Full Text
- View/download PDF
44. Inhaled nitric oxide for premature babies.
- Author
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Gortner L and Reiss I
- Subjects
- Administration, Inhalation, Animals, Bronchopulmonary Dysplasia mortality, Disease Models, Animal, Europe, Fetal Growth Retardation, Humans, Infant, Newborn, Risk Factors, Bronchopulmonary Dysplasia prevention & control, Infant, Premature, Infant, Small for Gestational Age, Nitric Oxide administration & dosage
- Published
- 2010
- Full Text
- View/download PDF
45. Current controversies in spondyloarthritis: SPARTAN.
- Author
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Weisman M, Learch TJ, Baraliakos X, Chandran V, Gladman DD, Raychaudhuri SP, Xu H, Collantes-Estévez E, Vázquez-Mellado J, Mease PJ, Sieper J, Deodhar AA, Colbert RA, and Clegg DO
- Subjects
- Animals, Central America, Disease Models, Animal, Disease Progression, Europe, Humans, Magnetic Resonance Imaging, Mexico, Mice, Mice, SCID, North America, Psoriasis pathology, Psoriasis physiopathology, Spondylarthritis epidemiology, Spondylarthritis pathology, Spondylarthritis therapy, Spondylitis, Ankylosing epidemiology, Spondylitis, Ankylosing pathology, Spondylitis, Ankylosing therapy, Texas, Congresses as Topic, Spondylarthritis physiopathology, Spondylitis, Ankylosing physiopathology
- Abstract
The Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), held its 7th Annual Research and Education Meeting in July 2009 in Houston, Texas. Current controversies in SpA discussed during the meeting included an update on the epidemiology of AS, axial SpA, and inflammatory back pain; the adequacy of the mSASS to assess radiographic involvement; the helpfulness of magnetic resonance imaging in assessing disease progression; the reliability of metrology in assessing damage; and whether biologic agents alter the course of AS. Presentations also were made on psoriasis in the SCID mouse model; the challenges and opportunities of SpA in China; a discussion of the special needs in managing SpA in Ibero-America, and the SPARK Survey in Europe and North America.
- Published
- 2010
- Full Text
- View/download PDF
46. [Acroosteolysis in PVC autoclave cleaners: history of an occupational disease].
- Author
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Zocchetti C, Osculati A, and Colosio C
- Subjects
- Acro-Osteolysis chemically induced, Acro-Osteolysis diagnosis, Acro-Osteolysis epidemiology, Acro-Osteolysis etiology, Acro-Osteolysis physiopathology, Animals, Disease Models, Animal, Disease Susceptibility, Europe epidemiology, Hand Injuries complications, History, 20th Century, Humans, Occupational Diseases chemically induced, Occupational Diseases diagnosis, Occupational Diseases epidemiology, Occupational Diseases etiology, Occupational Diseases physiopathology, United States epidemiology, Acro-Osteolysis history, Occupational Diseases history, Polyvinyl Chloride adverse effects, Sterilization instrumentation
- Abstract
Objectives: This paper examines the history of an occupational disease which has now disappeared: acroosteolysis of manual tank cleaners in the production of polyvinyl chloride (PVC), which is a rare disease characterized by destructive alterations of the distal phalanges of the hands., Methods: All the available literature on this disease was examined. The history of acroosteolysis was studied within the general framework of the history of the discovery of adverse health effects of exposure to vinyl chloride, and this history was studied up to the end of the 1960's., Results: The disease was observed for the first time in mid-1963 in Belgium (Jemeppe) in a chemical plant operated by Solvay, and affected two workers whose job was the manual cleaning of vessels used for the polymerization of vinyl chloride; similar cases occurred in almost all PVC production plants all over the world, but not in the plants where the main activity was the production of vinyl chloride monomer (VCM). Little more than one hundred cases are described in the scientific literature, and this number increases by a few dozen if we consider known but unpublished cases. These figures confirm the rarity of the disease, which peaked at the end of the 1960's and disappeared during the 1970's, probably due to the complete elimination of manual reactor cleaning. Observation of the disease lasted no more than fifteen years and the disease was not replicated in experimental conditions on animals., Discussion: The disease was clinically characterized, had a short latency (from several months to several years), was rare and unequivocally linked to the manual cleaning of PVC polymerization tanks. However many questions still remain open: the period when the disease first appeared (many years after the start of PVC production in the world), the etiology of the disease (the most accredited hypothesis considers three concomitant factors: a chemical factor--one of the many substances used during polymerization, and particularly vinyl chloride monomer, a physical factor--microtraumas of the fingers during manual cleaning, individual susceptibility), the pathogenetic mechanism (in particular: the role of skin, respiratory, or digestive system, as entrance door), a method (or test) to screen subjects potentially predisposed to the disease. In our view acroosteolysis of manual tank cleaners in PVC production is an occupational disease which is distinct from "vinyl chloride disease" as identified by Viola (1974).
- Published
- 2010
47. Transforming growth factor-beta receptor type 1 (TGFBR1) is not associated with non-syndromic cleft lip with or without cleft palate in patients of Central European descent.
- Author
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Reutter H, Birnbaum S, Mende M, de Assis NA, Hoffmann P, Lacava AD, Herms S, Braumann B, Scheer M, Lauster C, Schmidt G, Schiefke F, Dunsche A, Martini M, Knapp M, Kramer FJ, Nöthen MM, and Mangold E
- Subjects
- Abnormalities, Multiple epidemiology, Abnormalities, Multiple surgery, Animals, Animals, Newborn, Cleft Lip epidemiology, Cleft Lip surgery, Cleft Palate epidemiology, Cleft Palate surgery, Cohort Studies, Disease Models, Animal, Europe epidemiology, Female, Gene Expression Regulation, Developmental, Genetics, Population, Humans, Incidence, Infant, Newborn, Male, Mice, Mice, Transgenic, Pedigree, Receptor, Transforming Growth Factor-beta Type I, Risk Assessment, Species Specificity, Syndrome, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease epidemiology, Protein Serine-Threonine Kinases genetics, Receptors, Transforming Growth Factor beta genetics
- Abstract
Objective: Transforming growth factor-beta (TGF-β) type 1 receptor (also known as activin receptor-like kinase 5, ALK5) is expressed in palatal tissue during embryogenesis. Experimental studies in transgenic mice with a genetic deletion of Alk5 showed that TGF-β type 1 receptor is required for upper lip and midline fusion of the hard and soft palate. In humans, association of TGF-β type 1 receptor gene (TGFBR1) and the development of non-syndromic cleft lip with or without cleft palate (NSCL/P) had been observed in a multiethnic sample of Chinese, Philippine, Indian and Turkish families. In order to re-evaluate the relevance of these findings, we carried out a family-based association study among 218 NSCL/P families of Central European descent., Methods: Genomic DNA was obtained from peripheral blood of 218 complete parent-offspring triads with NSCL/P. The sample comprised 14 patients with cleft lip only (CLO) and 204 patients with cleft lip and palate (CLP). Genotyping and transmission disequilibrium test (TDT) were performed on all 218 triads with a total of 17 tagging single-nucleotide polymorphisms (SNPs). We also performed testing for extended haplotypes and a log-linear model by Weinberg was used to screen parent-of-origin effects. Furthermore the use of estimates for the relative risks (RR) of Weinberg's model was obtained., Results: TDT analysis revealed no significant transmission distortion, neither at the level of individual markers nor at the level of haplotypes. Similarly negative results were obtained when we restricted our analysis to the subgroup of patients with CLP (n=204). Relative risk calculations (RR) of the children's and mothers' genotypes obtained negative results, after correction of p-values for multiple testing. Likewise application of Weinberg's log-linear model did not find any evidence for parent-of-origin effects in our sample., Conclusion: Despite the ample evidence supporting the role of TGF-β type 1 receptor as a critically important and widespread morphogenetic regulator of craniofacial development in murine models, our results do not support TGFBR1 as major risk factor for NSCL/P in patients of Central European descent.
- Published
- 2009
- Full Text
- View/download PDF
48. Report and recommendations of the workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity.
- Author
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Stummann TC, Beilmann M, Duker G, Dumotier B, Fredriksson JM, Jones RL, Hasiwa M, Kang YJ, Mandenius CF, Meyer T, Minotti G, Valentin YJ, Zünkler BJ, and Bremer S
- Subjects
- Animal Testing Alternatives trends, Animals, Animals, Laboratory, Arrhythmias, Cardiac chemically induced, Arrhythmias, Cardiac prevention & control, Disease Models, Animal, Education trends, Europe, Humans, Animal Testing Alternatives methods, Cardiotoxins adverse effects, Cardiotoxins toxicity, Drug-Related Side Effects and Adverse Reactions chemically induced, Drug-Related Side Effects and Adverse Reactions prevention & control, Health Planning Guidelines
- Abstract
Cardiotoxicity is among the leading reasons for drug attrition and is therefore a core subject in non-clinical and clinical safety testing of new drugs. European Centre for the Validation of Alternative Methods held in March 2008 a workshop on "Alternative Methods for Drug-Induced Cardiotoxicity" in order to promote acceptance of alternative methods reducing, refining or replacing the use of laboratory animals in this field. This review reports the outcome of the workshop. The participants identified the major clinical manifestations, which are sensitive to conventional drugs, to be arrhythmias, contractility toxicity, ischaemia toxicity, secondary cardiotoxicity and valve toxicity. They gave an overview of the current use of alternative tests in cardiac safety assessments. Moreover, they elaborated on new cardiotoxicological endpoints for which alternative tests can have an impact and provided recommendations on how to cover them.
- Published
- 2009
- Full Text
- View/download PDF
49. Viewpoints on animal models of disease: memory reviews. Editorial.
- Author
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Livingstone C
- Subjects
- Animals, Editorial Policies, Europe, Humans, Peer Review, Research trends, Publishing trends, Allergy and Immunology, Disease Models, Animal, Periodicals as Topic
- Published
- 2009
- Full Text
- View/download PDF
50. Collaborating to bring new therapies to the patient--the TREAT-NMD model.
- Author
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Bushby K, Lynn S, and Straub T
- Subjects
- Animals, Disease Models, Animal, Europe, Humans, Information Services, Neuromuscular Diseases diagnosis, Neuromuscular Diseases genetics, Outcome Assessment, Health Care, Patient Care Management, Registries, Biomedical Research trends, International Cooperation, Models, Organizational, Neuromuscular Diseases therapy
- Published
- 2009
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