110 results on '"Dall M"'
Search Results
2. Predictors of Early Language Outcomes in Children with Connexin 26 Hearing Loss across Three Countries
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Holzinger, D, Dall, M, Kiblbock, S, Dirks, E, Carew, P, Smith, L, Downie, L, Shepherd, DA, Sung, V, Holzinger, D, Dall, M, Kiblbock, S, Dirks, E, Carew, P, Smith, L, Downie, L, Shepherd, DA, and Sung, V
- Abstract
GJB2-associated hearing loss (GJB2-HL) is the most common genetic cause of hearing loss in children. However, little is known about the clinical characteristics and early language outcomes in population-oriented samples including children with different degrees of hearing loss. Insight into these characteristics are relevant for the counselling of parents. Our sample consisted of 66 children at approximately 2 years of age (17-32 months) with bilateral hearing loss due to GJB2 from three population-based cohorts in Austria, Australia and the Netherlands. Predictors of early vocabulary, including demographic, audiological, genetic and intervention variables and the role of medical comorbidities and nonverbal cognition were examined. The vocabulary scores of children with GJB2-HL were approximately 0.7 standard deviations (SDs) below the norms of children with typical hearing. Age at access to family-centered early intervention and first-born position among siblings predicted language outcomes, whereas the degree of hearing loss and genetic subtype were not significantly correlated with expressive vocabulary. In children with GJB2-HL, early access to family-centered early intervention significantly affected language outcomes at the age of two.
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- 2022
3. P720 Use of proton pump inhibitors associated with a markedly increased risk of microscopic colitis
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Bonderup, O., Lauge Nielsen, G., Dall, M., Pottegård, A., and Hallas, J.
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- 2017
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4. Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis
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Winther-Sorensen, M., Galsgaard, K., Santos, A., Trammell, S., Sulek, K., Kuhre, R., Pedersen, J., Andersen, D., Hassing, A., Dall, M., Treebak, J., Gillum, M., Torekov, S., Windelov, J., Hunt, J., Kjeldsen, S., Jepsen, S., Vasilopoulou, C., Knop, F., Orskov, C., Werge, M., Bisgaard, H., Eriksen, P., Vilstrup, H., Gluud, L., Holst, J., and Albrechtsen, N.
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hormones, hormone substitutes, and hormone antagonists - Abstract
Objective: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear. Methods: We assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD). Results: Amino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis). Conclusions: Glucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism. (C) 2020 The Author(s). Published by Elsevier GmbH.
- Published
- 2020
5. Next generation diabetes scientists shape global research culture:A reflective proposal from postdoctoral researchers in diabetes research
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Broadley, M.M., Gonzalez‐Franquesa, A., Jonsson, A., Christiansen, C.B., Carrasquilla, G.D., Mamidi, A., Ghiasi, S.M., Juel, H.B., Falk, S., Isidor, M.S., Aldiss, P., Gillberg, L., Santos, K. Carolo dos, Sabaratnam, R., Huang, L.O., Quist, J.S., Knudsen, J.R., Poulsen, S., Quaranta, R., Tozzi, M., Mikkelsen, R.B., Andersen, M.K., Dall, M., Møller, A.B., Drag, M.H., Panahi, S., Lyons, C.L., Small, L., Altıntaş, A., Poursharifi, P., Osborne, B., Sarvari, A.K., Johnston, L.W., Solheim, M.H., Modvig, I.M., Husted, A.S., Jespersen, N.Z., Brown, E.L., Bak, E., Peluso, A., Finger, F., Grunddal, K.V., Rupar, K., Vistisen, H.T., Henningsen, J.B., Ma, T., Pedersen, M. Hauge, Plucinska, K., Jepsen, S. L., and Repasky, G.
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Physiology ,Diabetes mellitus ,medicine ,Engineering ethics ,medicine.disease ,Psychology - Abstract
The annual Winter School of the Danish Diabetes Academy (DDA) in November 2019 challenged postdoctoral researchers with tough questions regarding research culture that scientists around the world are discussing. The complexity and competitiveness of modern research makes it increasingly difficult for junior researchers to navigate in the science community. This editorial reflects the voices of nearly 200 international researchers ranging from early-career scientists to professors and medical doctors discussing five challenges of modern research culture - and proposes innovative solutions to overcome them.
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- 2020
6. Hepatic steatosis and glucagon resistance develope in parallel resulting in hyperglucagonaemia and hyperaminoacidaemia
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Winther-Sorensen, M., Galsgaard, K. D., Santos, A., Pedersen, J., Hassing, A. S., Dall, M., Treebak, J. T., Kjeldsen, S. A. S., Knop, F. K., Werge, M. P., Eriksen, P. L., Vilstrup, H., Gluud, L., Holst, J. J., Albrechtsen, N. J. Wewer, Winther-Sorensen, M., Galsgaard, K. D., Santos, A., Pedersen, J., Hassing, A. S., Dall, M., Treebak, J. T., Kjeldsen, S. A. S., Knop, F. K., Werge, M. P., Eriksen, P. L., Vilstrup, H., Gluud, L., Holst, J. J., and Albrechtsen, N. J. Wewer
- Published
- 2020
7. THE ASSOCIATION BETWEEN USE OF SEROTONERGIC ANTIDEPRESSANTS AND PERIOPERATIVE BLEEDING DURING HIP REPLACEMENT - A RETROSPECTIVE FOLLOW-UP STUDY: EHS2012_006
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Primdahl, A., Damborg, F., Dall, M., and Hallas, J.
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- 2012
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8. Re-prescribing of causative drugs in persons discharged after serious drug-induced upper gastrointestinal bleeding
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Dall, M., dePont Christensen, R., Schaffalitzky de Muckadell, O. B., Lassen, A. T., and Hallas, J.
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- 2012
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9. There is an association between selective serotonin reuptake inhibitor use and uncomplicated peptic ulcers: a population-based case-control study
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Dall, M., Schaffalitzky de Muckadell, O. B., Lassen, A. T., and Hallas, J.
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- 2010
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10. DO STATINS PROTECT AGAINST UPPER GASTROINTESTINAL BLEEDING?: O57
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Gulmez, S. E., Lassen, A. T., Aalykke, C., Dall, M., Andries, A., Andersen, B. S., Hansen, J. M., Andersen, M., and Hallas, J.
- Published
- 2009
11. USE OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND UPPER GI BLEEDING: O43
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Dall, M., de Muckadell, Schaffalitzky O. B., Lassen, Touborg A., Hansen, Møller J., and Hallas, J.
- Published
- 2009
12. The 3-phosphoglycerate kinase gene of the yeastYarrowia lipolytica de-represses on gluconeogenic substrates
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Le Dall, M. -T., Nicaud, J. -M., Tréton, B. Y., and Gaillardin, C. M.
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- 1996
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13. Complementation of Saccharomyces cerevisiae acid phosphatase mutation by a genomic sequence from the yeast Yarrowia lipolytica identifies a new phosphatase
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Tréton, B. Y., Le Dall, M. -T., and Gaillardin, C. M.
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- 1992
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14. Overcoming ABCB1-mediated olaparib resistance in advanced prostate cancer
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Gao, A., primary, Lombard, A., additional, Liu, C., additional, Lou, W., additional, Armstrong, C., additional, Dall, M., additional, and Evans, C., additional
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- 2019
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15. HSP70/STUB1 complex regulates androgen receptor variants through proteostasis and confers enzalutamide and abiraterone resistance in lethal prostate cancer
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Gao, A., primary, Liu, C., additional, Lou, W., additional, Yang, J., additional, Liu, L., additional, Armstrong, C., additional, Lombard, A., additional, Zhao, R., additional, Noel, O., additional, Tepper, C., additional, Chen, H., additional, Dall, M., additional, and Evans, C., additional
- Published
- 2019
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16. 861 - Overcoming ABCB1-mediated olaparib resistance in advanced prostate cancer
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Gao, A., Lombard, A., Liu, C., Lou, W., Armstrong, C., Dall, M., and Evans, C.
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- 2019
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17. There is an association between selective serotonin reuptake inhibitor use and uncomplicated peptic ulcers:a population-based case–control study
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Dall, M, Schaffalitzky de Muckadell, O B, Lassen, A T, and Hallas, J
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mental disorders ,digestive, oral, and skin physiology ,behavioral disciplines and activities - Abstract
Persons who use serotonin reuptake inhibitors (SSRIs) seem to be at increased risk of having serious upper gastrointestinal bleeding. In vitro studies have shown that SSRIs inhibit platelet aggregation. It remains unknown if SSRIs have a direct ulcerogenic effect.
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- 2010
18. UV-induced curing of the double-stranded RNA virus of the yeast Yarrowia lipolytica
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Tréton, B. Y., Le Dall, M. T., and Heslot, H.
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- 1987
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19. Cloning and characterization of the peroxisomal acyl CoA oxidase ACO3 gene from the alkane-utilizing yeast Yarrowia lipolytica
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Wang, H., Le Clainche, A., Le Dall, M. T., Waché, Yves, Pagot, Y., Belin, J. M., Gaillardin, C., Nicaud, J. M., Microbiologie et Génétique Moléculaire (MGM), Institut National de la Recherche Agronomique (INRA)-Institut National Agronomique Paris-Grignon (INA P-G)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Microbiologie, UMR INRA 1082, AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Génie des Procédés Microbiologiques et Alimentaires (GPMA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de Microbioologie, Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Collection de Levures d'Intérêt Biotechnologique et Laboratoire de Génétique Moléculaire et Cellulaire, Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Microbiologie et Génétique Moléculaire ( MGM ), Institut National de la Recherche Agronomique ( INRA ) -Institut National Agronomique Paris-Grignon ( INA P-G ) -Centre National de la Recherche Scientifique ( CNRS ), Génie des Procédés Microbiologiques et Alimentaires ( GPMA ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de Microbioologie, UMR INRA 1283 Ecole Nationale Supérieure de Biologie Appliquée à la. Nutrition et à l'Alimentation, Institut National de la Recherche Agronomique ( INRA ), and Institut National de la Recherche Agronomique ( INRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS )
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MESH : Restriction Mapping ,MESH : Escherichia coli ,MESH: Sequence Analysis, DNA ,MESH : Molecular Sequence Data ,Restriction Mapping ,MESH: Microbodies ,MESH : Gene Deletion ,MESH: Amino Acid Sequence ,MESH: Base Sequence ,Microbodies ,Polymerase Chain Reaction ,MESH : Microbodies ,Cloning, Molecular ,[INFO.INFO-BT]Computer Science [cs]/Biotechnology ,MESH : Polymerase Chain Reaction ,ComputingMilieux_MISCELLANEOUS ,MESH: Restriction Mapping ,MESH: Escherichia coli ,MESH : Amino Acid Sequence ,MESH: Acyl-CoA Oxidase ,PROTEASE ALKALINE ,MESH : Oxidoreductases ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Fungal ,MESH : Acyl-CoA Oxidase ,Oxidoreductases ,Sequence Analysis ,[ INFO.INFO-BT ] Computer Science [cs]/Biotechnology ,MESH : Cloning, Molecular ,Genes, Fungal ,Molecular Sequence Data ,Alkanes ,Escherichia coli ,MESH: Cloning, Molecular ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Amino Acid Sequence ,MESH: Oxidoreductases ,MESH: Saccharomycetales ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH : Alkanes ,MESH: Molecular Sequence Data ,Base Sequence ,Molecular ,MESH: Polymerase Chain Reaction ,MESH : Saccharomycetales ,DNA ,Sequence Analysis, DNA ,MESH: Alkanes ,Genes ,MESH: Gene Deletion ,Saccharomycetales ,CLONAGE DE GENE ,MESH : Base Sequence ,MESH : Genes, Fungal ,Acyl-CoA Oxidase ,ACYL COA OXYDASE ,MESH: Genes, Fungal ,Gene Deletion ,MESH : Sequence Analysis, DNA ,Cloning - Abstract
International audience; The ACO3 gene, which encodes one of the acyl-CoA oxidase isoenzymes, was isolated from the alkane-utilizing yeast Yarrowia lipolytica as a 10 kb genomic fragment. It was sequenced and found to encode a 701-amino acid protein very similar to other ACOs, 67.5% identical to Y. lipolytica Aco1p and about 40% identical to S. cerevisiae Pox1p. Haploid strains with a disrupted allele were able to grow on fatty acids. The levels of acyl-CoA oxidase activity in the ACO3 deleted strain, in an ACO1 deleted strain and in the wild-type strain, suggested that ACO3 encodes a short chain acyl-CoA oxidase isoenzyme. This narrow substrate spectrum was confirmed by expression of Aco3p in E. coli.
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- 1998
20. Identification and characterisation of LIP7 and LIP8 genes encoding two extracellular triacylglycerol lipases in the yeast Yarrowia lipolytica.
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Fickers, Patrick, Fudalej, F, Le Dall, M T, Casaregola, S, Gaillardin, C, Thonart, Philippe, Nicaud, J M, Fickers, Patrick, Fudalej, F, Le Dall, M T, Casaregola, S, Gaillardin, C, Thonart, Philippe, and Nicaud, J M
- Abstract
In the lipolytic yeast Yarrowia lipolytica, the LIP2 gene was previously reported to encode an extracellular lipase. The growth of a Deltalip2 strain on triglycerides as sole carbon source suggest an alternative pathway for triglycerides utilisation in this yeast. Here, we describe the isolation and the characterisation of the LIP7 and LIP8 genes which were found to encode a 366 and a 371-amino acid precursor protein, respectively. These proteins which belong to the triacylglycerol hydrolase family (EC 3.1.1.3) presented a high homology with the extracellular lipase CdLIP2 and CdLIP3 from Candida deformans. The physiological function of the lipase isoenzymes was investigated by creating single and multi-disrupted strains. Lip7p and Lip8p were found to correspond to active secreted lipases. The lack of lipase production in a Deltalip2 Deltalip7 Deltalip8 strain suggest that no additional extracellular lipase remains to be discovered in Y. lipolytica. The substrate specificity towards synthetic ester molecules indicates that Lip7p presented a maximum activity centred on caproate (C6) while that of Lip8p is in caprate (C10)., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published
- Published
- 2005
21. New disruption cassettes for rapid gene disruption and marker rescue in the yeast Yarrowia lipolytica.
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Fickers, Patrick, Le Dall, M T, Gaillardin, C, Thonart, Philippe, Nicaud, J M, Fickers, Patrick, Le Dall, M T, Gaillardin, C, Thonart, Philippe, and Nicaud, J M
- Abstract
Yarrowia lipolytica is one of the most extensively studied nonconventional yeasts. Unfortunately, few methods for gene disruption have been reported for this yeast, and all of them are time-consuming and laborious. The functional analysis of unknown genes requires powerful disruption methods. Here, we describe such a new method for rapid gene disruption in Y. lipolytica. This knockout system combines SEP method and the Cre-lox recombination system, facilitating efficient marker rescue. Versatility was increased by using both auxotrophic markers like ylURA3 and ylLEU2, as well as the antibiotic resistance marker hph. The hph marker, which confers resistance to hygromycin-B, allows gene disruption in a strain lacking any conventional auxothrophic marker. The disruption cassette was shown to integrate at the correct locus at an average frequency of 45%. Upon expression of Cre recombinase, the marker was excised at a frequency of 98%, by recombination between the two lox sites. This new method for gene disruption is an ideal tool for the functional analysis of gene families, or for creating large-scale mutant collections in general., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published
- Published
- 2003
22. Characterization of Yarrowia lipolytica mutants affected in hydrophobic substrate utilization
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Thevenieau, F., primary, Le Dall, M.-T., additional, Nthangeni, B., additional, Mauersberger, S., additional, Marchal, R., additional, and Nicaud, J.-M., additional
- Published
- 2007
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23. The 3-phosphoglycerate kinase gene of the yeast Yarrowia lipolytica de-represses on gluconeogenic substrates
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Dall, M.-T. Le, primary
- Published
- 1996
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24. Yarrowia lipolytica, a yeast model for the genetic studies of hydroxy fatty acids biotransformation into lactones
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Nicaud, J.-M., Clainche, A. Le, Dall, M.-T. Le, Wang, H., and Gaillardin, C.
- Published
- 1998
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25. 47 - HSP70/STUB1 complex regulates androgen receptor variants through proteostasis and confers enzalutamide and abiraterone resistance in lethal prostate cancer.
- Author
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Gao, A., Liu, C., Lou, W., Yang, J., Liu, L., Armstrong, C., Lombard, A., Zhao, R., Noel, O., Tepper, C., Chen, H., Dall, M., and Evans, C.
- Subjects
- *
ANDROGEN receptors , *PROSTATE cancer , *RNA sequencing , *UBIQUITIN ligases - Published
- 2019
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26. Preschool Children with Hearing Loss: Social Communication and Parenting Stress.
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Dall M, Weber C, Holzinger D, Binder D, Hofer J, Horvarth S, Müllegger D, Rosenthaler C, Zöhrer R, and Fellinger J
- Abstract
Studies on parenting stress (PS) in parents of children with hearing loss (HL) have found relationships between child behavior, language skills and parenting stress. The role of early social communication skills has not been researched before. The aim of this cross-sectional study was to investigate the relationship between child behavior, social communication and PS. The study was performed in a subgroup of a total population sample from the AChild (Austrian Children with Hearing Impairment-Longitudinal Databank) study. Preschool children (n = 81) with all degrees of HL and average cognitive functioning and their families were included, and the Parenting Stress Index (PSI) was used. Through factor component analysis, compound scores for externalizing/internalizing problem behavior and hyperactivity were analyzed. Although mean PS was not elevated, the proportion of those with elevated scores was higher compared with the norm population. There was a strong correlation between child behavior problems and PS (strongest correlation: externalizing problem behavior r = 0.643; p < 0.001). All three problem behaviors accounted for 49.7% of the variance in PS. An indirect effect of social communication on PS was almost completely mediated by problem behavior (especially hyperactivity). The importance of social communication development with respect to problem behavior and PS is highlighted.
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- 2023
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27. ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging.
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Snieckute G, Ryder L, Vind AC, Wu Z, Arendrup FS, Stoneley M, Chamois S, Martinez-Val A, Leleu M, Dreos R, Russell A, Gay DM, Genzor AV, Choi BS, Basse AL, Sass F, Dall M, Dollet LCM, Blasius M, Willis AE, Lund AH, Treebak JT, Olsen JV, Poulsen SS, Pownall ME, Jensen BAH, Clemmensen C, Gerhart-Hines Z, Gatfield D, and Bekker-Jensen S
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- Animals, Mice, Protein Biosynthesis, Zebrafish, Mice, Knockout, Aging metabolism, MAP Kinase Kinase Kinase 3 genetics, MAP Kinase Kinase Kinase 3 metabolism, Obesity metabolism, Reactive Oxygen Species metabolism, Ribosomes metabolism, Stress, Physiological
- Abstract
The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.
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- 2023
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28. Seasonal light hours modulate peripheral clocks and energy metabolism in mice.
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Small L, Lundell LS, Iversen J, Ehrlich AM, Dall M, Basse AL, Dalbram E, Hansen AN, Treebak JT, Barrès R, and Zierath JR
- Abstract
Except for latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to the light duration at the equator. We hypothesized that altering the seasonal photoperiod affects both the rhythmicity of peripheral tissue clocks and energy homeostasis. Mice were housed at photoperiods representing either light hours in summer, winter, or the equinox. Mice housed at a winter photoperiod exhibited an increase in the amplitude of rhythmic lipid metabolism and a modest reduction in fat mass and liver triglyceride content. Comparing melatonin-proficient and -deficient mice, the effect of seasonal light on energy metabolism was largely driven by differences in the rhythmicity of food intake and not melatonin. Together, these data indicate that seasonal light impacts energy metabolism by modulating the timing of eating., Competing Interests: Declaration of interests J.R.Z. is an Advisory Board member for Cell and Cell Metabolism., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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29. Denmark's big tent includes postdocs.
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Dall M and Pedersen MH
- Published
- 2023
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30. NAMPT-dependent NAD + biosynthesis controls circadian metabolism in a tissue-specific manner.
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Basse AL, Nielsen KN, Karavaeva I, Ingerslev LR, Ma T, Havelund JF, Nielsen TS, Frost M, Peics J, Dalbram E, Dall M, Zierath JR, Barrès R, Færgeman NJ, Treebak JT, and Gerhart-Hines Z
- Subjects
- Animals, Circadian Rhythm physiology, Adipose Tissue, Brown metabolism, Obesity metabolism, Cytokines metabolism, NAD metabolism, Nicotinamide Phosphoribosyltransferase genetics, Nicotinamide Phosphoribosyltransferase metabolism
- Abstract
Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD
+ , which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis, and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not in WAT, and loss of NAD+ abolishes these oscillations similarly to high-fat diet-induced circadian disruption. Moreover, adipose NAMPT depletion improved the ability of animals to defend body temperature during cold stress but in a time-of-day-independent manner. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.- Published
- 2023
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31. MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives.
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Hochreuter MY, Dall M, Treebak JT, and Barrès R
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- Biomarkers metabolism, Humans, Liver Cirrhosis, MicroRNAs genetics, MicroRNAs metabolism, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease ranging from simple hepatic steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) which may progress to cirrhosis and liver cancer. NAFLD is rapidly becoming a global health challenge, and there is a need for improved diagnostic- and prognostic tools and for effective pharmacotherapies to treat NASH. The molecular mechanisms of NAFLD development and progression remain incompletely understood, though ample evidence supports a role of microRNAs (miRNAs) - small non-coding RNAs regulating gene expression - in the progression of metabolic liver disease., Scope of Review: In this review, we summarise the currently available liver miRNA profiling studies in people with various stages of NAFLD. We further describe the mechanistic role of three of the most extensively studied miRNA species, miR-34a, miR-122 and miR-21, and highlight selected findings on novel NAFLD-linked miRNAs. We also examine the literature on exosomal microRNAs (exomiRs) as inter-hepatocellular or -organ messengers in NAFLD. Furthermore, we address the status for utilizing circulating NAFLD-associated miRNAs as minimally invasive tools for disease diagnosis, staging and prognosis as well as their potential use as NASH pharmacotherapeutic targets. Finally, we reflect on future directions for research in the miRNA field., Major Conclusions: NAFLD is associated with changes in hepatic miRNA expression patterns at early, intermediate and late stages, and specific miRNA species appear to be involved in steatosis development and NAFL progression to NASH and cirrhosis. These miRNAs act either within or between hepatocytes and other liver cell types such as hepatic stellate cells and Kupffer cells or as circulating inter-organ messengers carrying signals between the liver and extra-hepatic metabolic tissues, including the adipose tissues and the cardiovascular system. Among circulating miRNAs linked to NAFLD, miR-34a, miR-122 and miR-192 are the best candidates as biomarkers for NAFLD diagnosis and staging. To date, no miRNA-targeting pharmacotherapy has been approved for the treatment of NASH, and no such therapy is currently under clinical development. Further research should be conducted to translate the contribution of miRNAs in NAFLD into innovative therapeutic strategies., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2022
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32. The link between social communication and mental health from childhood to young adulthood: A systematic review.
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Dall M, Fellinger J, and Holzinger D
- Abstract
This systematic review investigates the current state of the literature on the association between social communication (SC) skills and mental health outcomes in children and young adults. We ran searches using terms describing SC and mental health in the following databases: PubMed, the Psychology and Behavioral Sciences Collection, APA PsychInfo, the Education Resource Information Center (ERIC) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We included studies that both measured SC before age 21 years and assessed a mental health component, such as behavior/conduct problems, anxiety, depression, or emotional problems, before age 30. Only peer-reviewed articles published in or after 2000 were retained. In total, 27 studies were included in the narrative synthesis. Overall, the methodological quality was good. A longitudinal design was used in 12 studies, seven of which sourced data from the Avon Longitudinal Study of Parents and Children. Most studies investigated the broad concept of pragmatic language and its influence on internalizing, externalizing, and peer-relationship problems. The analyzed publications included population-based studies and studies investigating special populations with existing mental health problems or at increased risk of developing them. The population-based cross-sectional studies showed significantly higher rates of SC problems in children with mental health problems while those with a longitudinal design found earlier onset and more persistent mental health problems in children who had the most severe SC difficulties. Studies with special populations confirmed more SC problems as compared to typically developing children and worse mental health outcomes in children with additional SC difficulties. The available literature thus shows consistently significant, mostly moderate associations between SC skills and mental health outcomes. SC difficulties earlier in life can predict mental health problems and impact their trajectories., Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=286598], identifier [CRD42022286598]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dall, Fellinger and Holzinger.)
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- 2022
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33. Intellectual Disability Profiles, Quality of Life and Maladaptive Behavior in Deaf Adults: An Exploratory Study.
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Eisinger J, Dall M, Fogler J, Holzinger D, and Fellinger J
- Subjects
- Adaptation, Psychological, Adult, Cognition, Female, Humans, Male, Quality of Life, Social Adjustment, Intellectual Disability psychology
- Abstract
Individuals who are prelingually deaf and have intellectual disabilities experience great challenges in their language, cognitive and social development, leading to heterogeneous profiles of intellectual and adaptive functioning. The present study describes these profiles, paying particular attention to domain discrepancies, and explores their associations with quality of life and maladaptive behavior. Twenty-nine adults with prelingual deafness (31% female) and mild intellectual functioning deficits (mean IQ = 67.3, SD = 6.5) were administered the Vineland Adaptive Behavior Scales-II (VABS-II) and an adapted sign language version of a quality of life scale (EUROHIS-QOL 8). Intellectual disability domain discrepancies were characterized as at least one standard deviation difference between the social domain and IQ and the practical domain and IQ, and a significant difference, according to the VABS-II manual, between the social and practical domains. Domain discrepancies were found between intellectual functioning and both the practical (58.6%) and social domain (65.5%). A discrepancy between intellectual and social functioning was significantly associated with a higher level of internalizing maladaptive behavior (T = 1.89, p < 0.05). The heterogeneous profiles highlight the importance of comprehensive assessments for adequate service provision.
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- 2022
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34. Communicative deficits associated with maladaptive behavior in individuals with deafness and special needs.
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Fellinger J, Dall M, Weber C, and Holzinger D
- Abstract
Background: At least one in three individuals who are prelingually deaf has special needs, most commonly due to intellectual disabilities. The scant literature on challenging behavior in this population, however, suggests high rates of prevalence and an important need to better understand the contributing factors., Aim: We sought to analyze the prevalence of maladaptive behavior and its association with intellectual functioning, adaptive skills, language skills, and social communication in a population of adults with deafness and special needs., Methods: Participants were 61 individuals from three therapeutic living communities established for people with deafness and special needs. The participants had a mean age of 54.7 years, 64% were male. Intellectual functioning was measured with two versions of the Snijders-Oomen Non-verbal Intelligence Scale. The Vineland-II Scales were used to assess adaptive and maladaptive behavior. Language skills were measured with instruments specifically adapted for this population, including the Reynell Developmental Language Comprehension Scale, the comprehension scale of the Child Development Inventory, and the Profile of Multiple Language Proficiencies. Due to high correlations between instruments, a composite language score was used. A specific questionnaire to measure social communication in adults with intellectual disabilities was also utilized., Results: The mean nonverbal developmental reference age was 6.5 years, whereas the equivalent for the language measures was about 3.5 years. The prevalence rate of elevated maladaptive behavior was 41% (v-scale score ≥18) and 18% of the participants had a clinically significant score (v-scale score ≥21). Regression analyses showed that only language and social communication skills were significantly associated with maladaptive behavior, while intellectual functioning and adaptive skills were not., Conclusion: These findings emphasize the importance of the constant promotion of communicative skills, as those people with better language and social communication skills demonstrate lower levels of maladaptive behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fellinger, Dall, Weber and Holzinger.)
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- 2022
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35. Predictors of Early Language Outcomes in Children with Connexin 26 Hearing Loss across Three Countries.
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Holzinger D, Dall M, Kiblböck S, Dirks E, Carew P, Smith L, Downie L, Shepherd DA, and Sung V
- Abstract
GJB2-associated hearing loss (GJB2-HL) is the most common genetic cause of hearing loss in children. However, little is known about the clinical characteristics and early language outcomes in population-oriented samples including children with different degrees of hearing loss. Insight into these characteristics are relevant for the counselling of parents. Our sample consisted of 66 children at approximately 2 years of age (17-32 months) with bilateral hearing loss due to GJB2 from three population-based cohorts in Austria, Australia and the Netherlands. Predictors of early vocabulary, including demographic, audiological, genetic and intervention variables and the role of medical comorbidities and nonverbal cognition were examined. The vocabulary scores of children with GJB2-HL were approximately 0.7 standard deviations (SDs) below the norms of children with typical hearing. Age at access to family-centered early intervention and first-born position among siblings predicted language outcomes, whereas the degree of hearing loss and genetic subtype were not significantly correlated with expressive vocabulary. In children with GJB2-HL, early access to family-centered early intervention significantly affected language outcomes at the age of two.
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- 2022
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36. Dietary Protein Restriction Improves Metabolic Dysfunction in Patients with Metabolic Syndrome in a Randomized, Controlled Trial.
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Ferraz-Bannitz R, Beraldo RA, Peluso AA, Dall M, Babaei P, Foglietti RC, Martins LM, Gomes PM, Marchini JS, Suen VMM, de Freitas LCC, Navegantes LC, Pretti MAM, Boroni M, Treebak JT, Mori MA, Foss MC, and Foss-Freitas MC
- Subjects
- Caloric Restriction, Diet, Protein-Restricted, Dietary Proteins, Humans, Obesity, Prospective Studies, Metabolic Syndrome
- Abstract
Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of metabolic syndrome. Nonetheless, it remains elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. This study was conducted to determine whether isocaloric dietary protein restriction is sufficient to confer the beneficial effects of dietary restriction in patients with metabolic syndrome. We performed a prospective, randomized controlled dietary intervention under constant nutritional and medical supervision. Twenty-one individuals diagnosed with metabolic syndrome were randomly assigned for caloric restriction (CR; n = 11, diet of 5941 ± 686 KJ per day) or isocaloric dietary protein restriction (PR; n = 10, diet of 8409 ± 2360 KJ per day) and followed for 27 days. Like CR, PR promoted weight loss due to a reduction in adiposity, which was associated with reductions in blood glucose, lipid levels, and blood pressure. More strikingly, both CR and PR improved insulin sensitivity by 62.3% and 93.2%, respectively, after treatment. Fecal microbiome diversity was not affected by the interventions. Adipose tissue bulk RNA-Seq data revealed minor changes elicited by the interventions. After PR, terms related to leukocyte proliferation were enriched among the upregulated genes. Protein restriction is sufficient to confer almost the same clinical outcomes as calorie restriction without the need for a reduction in calorie intake. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has more significant potential to be used as adjuvant therapy for people with metabolic syndrome.
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- 2022
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37. Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2.
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Holm S, Husted AS, Skov LJ, Morville TH, Hagemann CA, Jorsal T, Dall M, Jakobsen A, Klein AB, Treebak JT, Knop FK, Schwartz TW, Clemmensen C, and Holst B
- Subjects
- 3-Hydroxybutyric Acid metabolism, Animals, Ghrelin metabolism, Liver metabolism, Mice, Obesity metabolism, Antimicrobial Cationic Peptides metabolism, Diet, Ketogenic, Receptors, Ghrelin metabolism
- Abstract
Introduction: Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body beta-hydroxybutyrate (BHB) is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB., Methods: Hepatic and intestinal Leap2 expression were determined in 3 groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet, and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human individuals following endurance exercise, and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB., Results: We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated with increased plasma levels of BHB levels and decreased LEAP2 levels in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for 3 weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased Leap2 expression levels and circulating LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes., Conclusion: From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the ketone body, BHB, which is highly upregulated during fasting metabolism, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor-induced hunger signaling during energy deprivation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2022
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38. Multidimensional Family-Centred Early Intervention in Children with Hearing Loss: A Conceptual Model.
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Holzinger D, Hofer J, Dall M, and Fellinger J
- Abstract
At least two per thousand newborns are affected by hearing loss, with up to 40% with an additional disability. Early identification by universal newborn hearing screening and early intervention services are available in many countries around the world, with limited data on their effectiveness and a lack of knowledge about specific intervention-related determinants of child and family outcomes. This concept paper aimed to better understand the mechanisms by which multi-dimensional family-centred early intervention influences child outcomes, through parent behaviour, targeted by intervention by a review of the literature, primarily in the field of childhood hearing loss, supplemented by research findings on physiological and atypical child development. We present a conceptual model of influences of multi-disciplinary family-centred early intervention on family coping/functioning and parent-child interaction, with effects on child psycho-social and cognitive outcomes. Social communication and language skills are postulated as mediators between parent-child interaction and non-verbal child outcomes. Multi-disciplinary networks of professionals trained in family-centred practice and the evaluation of existing services, with respect to best practice guidelines for family-centred early intervention, are recommended. There is a need for longitudinal epidemiological studies, including specific intervention measures, family behaviours and multidimensional child outcomes.
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- 2022
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39. Understanding the Impact of Child, Intervention, and Family Factors on Developmental Trajectories of Children with Hearing Loss at Preschool Age: Design of the AChild Study.
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Dall M, Kiblböck S, Müllegger D, Fellinger J, Hofer J, Kapplmüller R, Breitwieser S, Schossleitner K, Weber C, Zöhrer R, and Holzinger D
- Abstract
Children with hearing loss and their families represent a large variety with regard to their auditory, medical, psychological, and family resource characteristics. Despite recent advances, developmental outcomes are still below average, with a significant proportion of variety remaining unexplained. Furthermore, there is a lack of studies including the whole diversity of children with hearing loss. The AChild study (Austrian Children with Hearing Impairment-Longitudinal Databank) uses an epidemiological longitudinal design including all children living in Upper and Lower Austria with a permanent uni- or bilateral hearing loss below the age of 6 years, irrespective of additional disabilities, family language, and family resources. The demographic characteristics of the first 126 children enrolled in the study showed that about half of the children are either children with additional disabilities (31%) and/or children not growing up with the majority language (31.7%) that are usually excluded from comprehensive longitudinal studies. AChild aims for a characterization of the total population of young children with hearing loss including developmental outcomes. Another goal is the identification of early predictors of developmental trajectories and family outcomes. In addition to child-related predictors the examination of family-child transactions malleable by family-centred early intervention is of particular interest. The study is designed as participatory including parent representation atall stages. Measures have been chosen, following other large population-based studies in order to gain comparability and to ensure international data pooling.
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- 2022
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40. NAD + and NAFLD - caution, causality and careful optimism.
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Dall M, Hassing AS, and Treebak JT
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- Animals, Dietary Supplements, Humans, Mice, Mice, Inbred C57BL, NAD metabolism, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, and new treatments are sorely needed. Nicotinamide adenine dinucleotide (NAD
+ ) has been proposed as a potential target to prevent and reverse NAFLD. NAD+ is an important redox factor for energy metabolism and is used as a substrate by a range of enzymes, including sirtuins (SIRT), which regulates histone acetylation, transcription factor activity and mitochondrial function. NAD+ is also a precursor for reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is an important component of the antioxidant defense system. NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are available as over-the-counter dietary supplements, and oral supplementation with these precursors increases hepatic NAD+ levels and prevents hepatic lipid accumulation in pre-clinical models of NAFLD. NAD+ precursors have also been found to improve hepatic mitochondrial function and decrease oxidative stress in pre-clinical NAFLD models. NAD+ repletion also prevents NAFLD progression to non-alcoholic steatohepatitis (NASH), as NAD+ precursor supplementation is associated with decreased hepatic stellate cell activation, and decreased fibrosis. However, initial clinical trials have only shown modest effects when NAD+ precursors were administrated to people with obesity. We review the available pre-clinical investigations of NAD+ supplementation for targeting NAFLD, and discuss how data from the first clinical trials can be reconciled with observations from preclinical research., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)- Published
- 2022
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41. Hepatocyte-specific perturbation of NAD + biosynthetic pathways in mice induces reversible nonalcoholic steatohepatitis-like phenotypes.
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Dall M, Hassing AS, Niu L, Nielsen TS, Ingerslev LR, Sulek K, Trammell SAJ, Gillum MP, Barrès R, Larsen S, Poulsen SS, Mann M, Ørskov C, and Treebak JT
- Subjects
- Animals, Cytokines deficiency, Cytokines metabolism, Mice, Mice, Knockout, Mitochondria, Liver genetics, NAD genetics, Nicotinamide Phosphoribosyltransferase deficiency, Nicotinamide Phosphoribosyltransferase metabolism, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease pathology, Oxidative Phosphorylation, Phenotype, Hepatocytes metabolism, Mitochondria, Liver metabolism, NAD metabolism, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide to NAD
+ . As low hepatic NAD+ levels have been linked to the development of nonalcoholic fatty liver disease, we hypothesized that ablation of hepatic Nampt would affect susceptibility to liver injury in response to diet-induced metabolic stress. Following 3 weeks on a low-methionine and choline-free 60% high-fat diet, hepatocyte-specific Nampt knockout (HNKO) mice accumulated less triglyceride than WT littermates but had increased histological scores for liver inflammation, necrosis, and fibrosis. Surprisingly, liver injury was also observed in HNKO mice on the purified control diet. This HNKO phenotype was associated with decreased abundance of mitochondrial proteins, especially proteins involved in oxidoreductase activity. High-resolution respirometry revealed lower respiratory capacity in purified control diet-fed HNKO liver. In addition, fibrotic area in HNKO liver sections correlated negatively with hepatic NAD+ , and liver injury was prevented by supplementation with NAD+ precursors nicotinamide riboside and nicotinic acid. MS-based proteomic analysis revealed that nicotinamide riboside supplementation rescued hepatic levels of oxidoreductase and OXPHOS proteins. Finally, single-nucleus RNA-Seq showed that transcriptional changes in the HNKO liver mainly occurred in hepatocytes, and changes in the hepatocyte transcriptome were associated with liver necrosis. In conclusion, HNKO livers have reduced respiratory capacity, decreased abundance of mitochondrial proteins, and are susceptible to fibrosis because of low NAD+ levels. Our data suggest a critical threshold level of hepatic NAD+ that determines the predisposition to liver injury and supports that NAD+ precursor supplementation can prevent liver injury and nonalcoholic fatty liver disease progression., Competing Interests: Conflict of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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42. Nampt controls skeletal muscle development by maintaining Ca 2+ homeostasis and mitochondrial integrity.
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Basse AL, Agerholm M, Farup J, Dalbram E, Nielsen J, Ørtenblad N, Altıntaş A, Ehrlich AM, Krag T, Bruzzone S, Dall M, de Guia RM, Jensen JB, Møller AB, Karlsen A, Kjær M, Barrès R, Vissing J, Larsen S, Jessen N, and Treebak JT
- Subjects
- Animals, Cells, Cultured, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle Development, Calcium metabolism, Cytokines metabolism, Homeostasis, Mitochondria metabolism, Muscle, Skeletal metabolism, Nicotinamide Phosphoribosyltransferase metabolism
- Abstract
Objective: NAD
+ is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD+ synthesis, and in skeletal muscle, NAD+ is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD+ synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD+ biosynthesis in skeletal muscle development and function., Methods: To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates., Results: SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca2+ -stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival., Conclusions: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca2+ homeostasis and skeletal muscle development, which is vital for juvenile survival., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)- Published
- 2021
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43. Is it feasible to assess self-reported quality of life in individuals who are deaf and have intellectual disabilities?
- Author
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Fellinger J, Dall M, Gerich J, Fellinger M, Schossleitner K, Barbaresi WJ, and Holzinger D
- Subjects
- Adult, Child, Child, Preschool, Humans, Reproducibility of Results, Self Report, Surveys and Questionnaires, Intellectual Disability, Quality of Life
- Abstract
Purpose: There is consensus that Quality of Life (QOL) should be obtained through self-reports from people with intellectual Disability (ID). Thus far, there have been no attempts to collect self-reported QOL from people who are deaf and have ID., Methods: Based on an established short measure for QOL (EUROHIS-QOL), an adapted easy-to-understand sign language interview was developed and applied in a population (n = 61) with severe-to-profound hearing loss and mild-to-profound ID. Self-reports were conducted at two time points (t
1 and t2 ), 6 months apart. The Stark QOL, an established picture-based questionnaire, was also obtained at t2 and three Proxy ratings of QOL (from caregivers) were conducted for each participant at t1 ., Results: Self-reported QOL was successfully administered at both time points for 44 individuals with mild and moderate ID (IQ reference age between 3.3 and 11.8 years). The self-reports showed sufficient test-retest reliability and significant correlations with the Stark QOL. As anticipated, self-reported QOL was higher than proxy-reported QOL. Test-retest reliability and internal consistency were good for self-reported QOL., Conclusion: Reliable and valid self-reports of QOL can be obtained from deaf adults with mild-moderate ID using standard inventories adapted to the linguistic and cognitive level of these individuals., (© 2020. The Author(s).)- Published
- 2021
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44. Therapeutic living communities for adults who are deaf and have intellectual disabilities: A conceptual model linking social communication and mental health.
- Author
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Fellinger J, Dall M, and Holzinger D
- Abstract
As a consequence of long-lasting experiences of communicative and social deprivation and exclusion, adults who are deaf and have intellectual disabilities must be considered a high-risk group for the development of mental health problems. A therapeutic living community model with special emphasis on social communication development that has been implemented at three different sites in Austria is described. Through the development of the therapeutic living communities and subsequent observations, an approach is suggested to understand the mediating role of signed language and social communication skills in mental health outcomes for those with such mental health risk factors. The model requires further empirical verification., Competing Interests: The authors report no conflict of interest, (© The British Society of Developmental Disabilities 2021.)
- Published
- 2021
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45. Deaf Residents With Intellectual Disabilities During the First Covid-19 Associated Lockdown.
- Author
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Salzner J, Dall M, Weber C, Holzinger D, and Fellinger J
- Subjects
- Adult, Aged, Female, Follow-Up Studies, Humans, Intellectual Disability rehabilitation, Male, Middle Aged, Retrospective Studies, SARS-CoV-2, COVID-19 epidemiology, Communicable Disease Control methods, Intellectual Disability epidemiology, Pandemics, Persons With Hearing Impairments rehabilitation
- Abstract
Two indicators for stress (mood and aggressive behavior) were evaluated in order to investigate the effect of the restrictions taken against the spread of the coronavirus on people who are deaf and hard of hearing (DHH) and have intellectual disabilities (ID). In three therapeutic living communities, specifically designed for the visual communication needs of people who are DHH and have ID, the mood of the residents is routinely assessed by staff members and every aggressive incident is recorded with the Staff Observation of Aggressions Scale-Revised (SOAS-R). For the 38 residents who were present 8 weeks before the first lockdown (t1) and the following 8 weeks (t2), mood ratings and ratings of aggressive behavior were compared between the two time periods. In contrast to our hypothesis the mood ratings of the residents had a slight significant improvement, whereas the incidents and severity of aggressive behavior did not change significantly. These results suggest that with proper communicative support, individuals who are DHH and have ID can cope effectively with significant restrictions imposed by a pandemic-caused lockdown., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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46. Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965.
- Author
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Ahwazi D, Neopane K, Markby GR, Kopietz F, Ovens AJ, Dall M, Hassing AS, Gräsle P, Alshuweishi Y, Treebak JT, Salt IP, Göransson O, Zeqiraj E, Scott JW, and Sakamoto K
- Subjects
- 3T3-L1 Cells, AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Adipocytes drug effects, Adipocytes metabolism, Animals, Autophagy-Related Protein-1 Homolog genetics, Autophagy-Related Protein-1 Homolog metabolism, Benzamides metabolism, Cell Line, Cell Line, Tumor, Cells, Cultured, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Molecular Docking Simulation, Mutation, Missense, Protein Binding drug effects, Protein Multimerization, Pyrimidines metabolism, Rats, Sprague-Dawley, Recombinant Proteins chemistry, Recombinant Proteins genetics, Rats, AMP-Activated Protein Kinases antagonists & inhibitors, Autophagy-Related Protein-1 Homolog antagonists & inhibitors, Benzamides pharmacology, Pyrimidines pharmacology, Recombinant Proteins metabolism
- Abstract
SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMP-activated protein kinase (AMPK) inhibitor relative to the widely used, but promiscuous inhibitor Compound C/Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥25 μM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965., (© 2021 The Author(s).)
- Published
- 2021
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47. Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis.
- Author
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Winther-Sørensen M, Galsgaard KD, Santos A, Trammell SAJ, Sulek K, Kuhre RE, Pedersen J, Andersen DB, Hassing AS, Dall M, Treebak JT, Gillum MP, Torekov SS, Windeløv JA, Hunt JE, Kjeldsen SAS, Jepsen SL, Vasilopoulou CG, Knop FK, Ørskov C, Werge MP, Bisgaard HC, Eriksen PL, Vilstrup H, Gluud LL, Holst JJ, and Wewer Albrechtsen NJ
- Subjects
- Adult, Animals, Blood Glucose metabolism, Fatty Liver metabolism, Female, Glucagon physiology, Glucagon-Secreting Cells metabolism, Glucose metabolism, Hepatocytes metabolism, Humans, Insulin metabolism, Insulin Resistance physiology, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Middle Aged, Non-alcoholic Fatty Liver Disease metabolism, Rats, Rats, Wistar, Receptors, Glucagon antagonists & inhibitors, Receptors, Glucagon metabolism, Urea metabolism, Amino Acids metabolism, Fatty Liver physiopathology, Glucagon metabolism
- Abstract
Objective: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear., Methods: We assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD)., Results: Amino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis)., Conclusions: Glucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2020
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48. The Impact of Family Environment on Language Development of Children With Cochlear Implants: A Systematic Review and Meta-Analysis.
- Author
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Holzinger D, Dall M, Sanduvete-Chaves S, Saldaña D, Chacón-Moscoso S, and Fellinger J
- Subjects
- Adult, Child, Child, Preschool, Cross-Sectional Studies, Humans, Language Development, Parents, Young Adult, Cochlear Implantation, Cochlear Implants
- Abstract
Objectives: The authors conducted a systematic review of the literature and meta-analyses to assess the influence of family environment on language development in children with cochlear implants., Design: The Pubmed, excerpta medica dataBASE (EMBASE), Education Research Information Center, cumulative index to nursing and allied health literature (CINAHL), Healthcare Literature Information Network, PubPsych, and Social SciSearch databases were searched. The search strategy included terms describing family environment, child characteristics, and language development. Studies were included that (a) assessed distal family variables (such as parental income level, parental education, family size, and parental stress) with child language outcomes, and/or more proximal correlates that directly affect the child (such as family engagement and participation in intervention, parenting style, and more specifically, the quantity and quality of parental linguistic input) on child language; (b) included children implanted before the age of 5 years; (c) measured child language before the age of 21 years with standardized instruments; (d) were published between 1995 and February 2018; and (e) were published as peer-reviewed articles. The methodological quality was assessed with an adaptation of a previously validated checklist. Meta-analyses were conducted assuming a random-effects model., Results: A total of 22 study populations reported in 27 publications were included. Methodological quality was highly variable. Ten studies had a longitudinal design. Three meta-analyses on the correlations between family variables and child language development could be performed. A strong effect of the quality and quantity of parental linguistic input in the first 4½ years postimplantation on the child's language was found, r = 0.564, p ≤ 0.001, 95% confidence interval (CI) = 0.449 to 0.660, accounting for 31.7% of the variance in child language outcomes. Results demonstrated high homogeneity, Q(3) = 1.823, p = 0.61, I = 0. Higher-level facilitative language techniques, such as parental expansions of the child's utterances or the use of open-ended questions, predicted child language skills. Risk of publication bias was not detected. The results on the impact of family involvement/participation in intervention on child language development were more heterogeneous. The meta-analysis included mainly cross-sectional studies and identified low to moderate benefits, r = 0.380, p ≤ 0.052, 95% CI = -0.004 to 0.667, that almost attained significance level. Socioeconomic status, mainly operationalized by parental level of education, showed a positive correlation with child language development in most studies. The meta-analysis confirmed an overall low and nonsignificant average correlation coefficient, r = 0.117, p = 0.262, 95% CI = -0.087 to 0.312. A limitation of the study was the lack of some potentially relevant variables, such as multilingualism or family screen time., Conclusions: These data support the hypothesis that parental linguistic input during the first years after cochlear implantation strongly predicts later child language outcomes. Effects of parental involvement in intervention and parental education are comparatively weaker and more heterogeneous. These findings underscore the need for early-intervention programs for children with cochlear implants focusing on providing support to parents for them to increase their children's exposure to high-quality conversation.
- Published
- 2020
- Full Text
- View/download PDF
49. Development of Deaf Adults with Intellectual Disability in a Therapeutic Living Community.
- Author
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Fellinger J, Linzner D, Holzinger D, Dall M, Fellinger M, and Fogler J
- Subjects
- Deafness psychology, Deafness rehabilitation, Humans, Intellectual Disability psychology, Intellectual Disability rehabilitation, Communication, Deafness complications, Intellectual Disability etiology, Interpersonal Relations
- Abstract
People with intellectual disabilities who are deaf face obstacles participating in social environments that do not take into account their need for accessible visual communication. In the present case series, we describe the development of the adaptive skills profiles of eight participants in a fully inclusive therapeutic living community, designed specifically for people with developmental disabilities who are deaf and focused on supporting communication, social relationships, conflict resolution, and work satisfaction. Adaptive skills ratings collected at enrollment and twelve years later suggest increases in social awareness and community living, whereas personal care and homemaking showed relatively little change., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
50. A model to predict the risk of aspirin/non-steroidal anti-inflammatory drugs-related upper gastrointestinal bleeding for the individual patient.
- Author
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Petersen J, Møller Hansen J, de Muckadell OBS, Dall M, and Hallas J
- Subjects
- Aged, Aged, 80 and over, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Aspirin administration & dosage, Case-Control Studies, Female, Gastrointestinal Hemorrhage epidemiology, Humans, Incidence, Male, Middle Aged, Models, Statistical, Risk Assessment, Risk Factors, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Aspirin adverse effects, Gastrointestinal Hemorrhage chemically induced
- Abstract
Upper gastrointestinal bleeding is a feared complication of using non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin. Studies predicting the incidence rate for individuals with a given set of characteristics are lacking. The aim of this study was to develop a risk model to predict the incidence rate of upper gastrointestinal bleeding (UGIB) in users of aspirin/NSAID based on presence of well-defined risk factors for the individual patient., Methods: The model was developed from data from a case-control study, sampled from a well-defined source population, residents of the Funen County 1995-2006. All cases and controls were characterized in terms of factors known to affect the risk of UGIB. By using census data, we rescaled the control group, so their composition accurately reflected age and sex distribution of the source population. Only persons using NSAIDs or/and aspirin and no PPI were included in the analysis. As reference group, we chose 80- to 89-year-old women with no ulcer history, using NSAID, but neither aspirin, other platelet inhibitors, vitamin K antagonists, selective serotonin reuptake inhibitors nor corticosteroids., Results: We identified 1388 cases among non-users of PPIs. We found a modelled baseline incidence rate of 10.7 per 1000 person-years for the reference group. The strongest associations were found for ADP inhibitors (OR 5.80), followed by anticoagulants treatment (OR 2.62) and prior ulcer (OR 2.68). The model performed well in terms of calibration and discriminatory power., Conclusion: This study is the first to describe a model, which estimates the incidence rate of UGIB for patients using aspirin/NSAID, based on the specific combination of risk factors. Risk of upper gastrointestinal bleeding for a given patient can be accurately estimated using this model., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)
- Published
- 2020
- Full Text
- View/download PDF
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