106 results on '"Vidal PM"'
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2. Epidemiological evaluation of dietary intake in the Swiss population: dietary intake in Switzerland : Diet in Switzerland: not only chocolate and cheese
- Author
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Marques-Vidal, PM, Franco Duran, OH (Oscar), Voortman, Trudy, and Epidemiology
- Published
- 2019
3. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma
- Author
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Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE, Coin LJ, Deng G, Gieger C, Heard Costa NL, Hottenga JJ, Kühnel B, Kumar V, Lagou V, Liang L, Luan J, Vidal PM, Mateo Leach I, O'Reilly PF, Peden JF, Rahmioglu N, Soininen P, Speliotes EK, Yuan X, Thorleifsson G, Alizadeh BZ, Atwood LD, Borecki IB, Brown MJ, Charoen P, Cucca F, Das D, de Geus EJ, Dixon AL, Döring A, Ehret G, Eyjolfsson GI, Farrall M, Forouhi NG, Friedrich N, Goessling W, Gudbjartsson DF, Harris TB, Hartikainen AL, Heath S, Hirschfield GM, Hofman A, Homuth G, Hyppönen E, Janssen HL, Johnson T, Kangas AJ, Kema IP, Kühn JP, Lai S, Lathrop M, Lerch MM, Li Y, Liang TJ, Lin JP, Loos RJ, Martin NG, Moffatt MF, Montgomery GW, Munroe PB, Musunuru K, Nakamura Y, O'Donnell CJ, Olafsson I, Penninx BW, Pouta A, Prins BP, Prokopenko I, Puls R, Ruokonen A, Savolainen MJ, Schlessinger D, Schouten JN, Seedorf U, Sen Chowdhry S, Siminovitch KA, Smit JH, Spector TD, Tan W, Teslovich TM, Tukiainen T, Uitterlinden AG, Van der Klauw MM, Vasan RS, Wallace C, Wallaschofski H, Wichmann HE, Willemsen G, Würtz P, Xu C, Yerges Armstrong LM, Alcohol Genome wide Association Consortium, Diabetes Genetics Replication, Meta analyses Study, Genetic Investigation of Anthropometric Traits Consortium, Global Lipids Genetics Consortium, Genetics of Liver Disease Consortium, International Consortium for Blood Pressure, Meta analyses of Glucose, Insulin Related Traits Consortium, Abecasis GR, Ahmadi KR, Boomsma DI, Caulfield M, Cookson WO, van Duijn CM, Froguel P, Matsuda K, McCarthy MI, Meisinger C, Mooser V, Pietiläinen KH, Schumann G, Snieder H, Sternberg MJ, Stolk RP, Thomas HC, Thorsteinsdottir U, Uda M, Waeber G, Wareham NJ, Waterworth DM, Watkins H, Whitfield JB, Witteman JC, Wolffenbuttel BH, Fox CS, Ala Korpela M, Stefansson K, Vollenweider P, Völzke H, Schadt EE, Scott J, Järvelin MR, Elliott P, Kooner JS, PAOLISSO, Giuseppe, Chambers, Jc, Zhang, W, Sehmi, J, Li, X, Wass, Mn, Van der Harst, P, Holm, H, Sanna, S, Kavousi, M, Baumeister, Se, Coin, Lj, Deng, G, Gieger, C, Heard Costa, Nl, Hottenga, Jj, Kühnel, B, Kumar, V, Lagou, V, Liang, L, Luan, J, Vidal, Pm, Mateo Leach, I, O'Reilly, Pf, Peden, Jf, Rahmioglu, N, Soininen, P, Speliotes, Ek, Yuan, X, Thorleifsson, G, Alizadeh, Bz, Atwood, Ld, Borecki, Ib, Brown, Mj, Charoen, P, Cucca, F, Das, D, de Geus, Ej, Dixon, Al, Döring, A, Ehret, G, Eyjolfsson, Gi, Farrall, M, Forouhi, Ng, Friedrich, N, Goessling, W, Gudbjartsson, Df, Harris, Tb, Hartikainen, Al, Heath, S, Hirschfield, Gm, Hofman, A, Homuth, G, Hyppönen, E, Janssen, Hl, Johnson, T, Kangas, Aj, Kema, Ip, Kühn, Jp, Lai, S, Lathrop, M, Lerch, Mm, Li, Y, Liang, Tj, Lin, Jp, Loos, Rj, Martin, Ng, Moffatt, Mf, Montgomery, Gw, Munroe, Pb, Musunuru, K, Nakamura, Y, O'Donnell, Cj, Olafsson, I, Penninx, Bw, Pouta, A, Prins, Bp, Prokopenko, I, Puls, R, Ruokonen, A, Savolainen, Mj, Schlessinger, D, Schouten, Jn, Seedorf, U, Sen Chowdhry, S, Siminovitch, Ka, Smit, Jh, Spector, Td, Tan, W, Teslovich, Tm, Tukiainen, T, Uitterlinden, Ag, Van der Klauw, Mm, Vasan, R, Wallace, C, Wallaschofski, H, Wichmann, He, Willemsen, G, Würtz, P, Xu, C, Yerges Armstrong, Lm, Alcohol Genome wide Association, Consortium, Diabetes Genetics, Replication, Meta analyses, Study, Genetic Investigation of Anthropometric Traits, Consortium, Global Lipids Genetics, Consortium, Genetics of Liver Disease, Consortium, International Consortium for Blood, Pressure, Meta analyses of, Glucose, Insulin Related Traits, Consortium, Abecasis, Gr, Ahmadi, Kr, Boomsma, Di, Caulfield, M, Cookson, Wo, van Duijn, Cm, Froguel, P, Matsuda, K, Mccarthy, Mi, Meisinger, C, Mooser, V, Pietiläinen, Kh, Schumann, G, Snieder, H, Sternberg, Mj, Stolk, Rp, Thomas, Hc, Thorsteinsdottir, U, Uda, M, Waeber, G, Wareham, Nj, Waterworth, Dm, Watkins, H, Whitfield, Jb, Witteman, Jc, Wolffenbuttel, Bh, Fox, C, Ala Korpela, M, Stefansson, K, Vollenweider, P, Völzke, H, Schadt, Ee, Scott, J, Järvelin, Mr, Elliott, P, Kooner, J, and Paolisso, Giuseppe
- Published
- 2011
4. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma
- Author
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Chambers, JC, Zhang, W, Sehmi, J, Li, X, Wass, MN, Van der Harst, P, Holm, H, Sanna, S, Kavousi, M, Baumeister, SE, Coin, LJ, Deng, G, Gieger, C, Heard-Costa, NL, Hottenga, J-J, Kühnel, B, Kumar, V, Lagou, V, Liang, L, Luan, J, Vidal, PM, Leach, IM, O'Reilly, PF, Peden, JF, Rahmioglu, N, Soininen, P, Speliotes, EK, Yuan, X, Thorleifsson, G, Alizadeh, BZ, Atwood, LD, Borecki, IB, Brown, MJ, Charoen, P, Cucca, F, Das, D, de Geus, EJC, Dixon, AL, Döring, A, Ehret, G, Eyjolfsson, GI, Farrall, M, Forouhi, NG, Friedrich, N, Goessling, W, Gudbjartsson, DF, Harris, TB, Hartikainen, A-L, Heath, S, Hirschfield, GM, Hofman, A, Homuth, G, Hyppönen, E, Janssen, HLA, Johnson, T, Kangas, AJ, Kema, IP, Kühn, JP, Lai, S, Lathrop, M, Lerch, MM, Li, Y, Liang, TJ, Lin, J-P, Loos, RJF, Martin, NG, Moffatt, MF, Montgomery, GW, Munroe, PB, Musunuru, K, Nakamura, Y, O'Donnell, CJ, Olafsson, I, Penninx, BW, Pouta, A, Prins, BP, Prokopenko, I, Puls, R, Ruokonen, A, Savolainen, MJ, Schlessinger, D, Schouten, JNL, Seedorf, U, Sen-Chowdhry, S, Siminovitch, KA, Smit, JH, Spector, TD, Tan, W, Teslovich, TM, Tukiainen, T, Uitterlinden, AG, Van der Klauw, MM, Vasan, RS, Wallace, C, Wallaschofski, H, Wichmann, H-E, Willemsen, G, Würtz, P, Xu, C, Yerges-Armstrong, LM, Abecasis, GR, Ahmadi, KR, Boomsma, DI, Caulfield, M, Cookson, WO, van Duijn, CM, Froguel, P, Matsuda, K, McCarthy, MI, Meisinger, C, Mooser, V, Pietiläinen, KH, Schumann, G, Snieder, H, Sternberg, MJE, Stolk, RP, Thomas, HC, Thorsteinsdottir, U, Uda, M, Waeber, G, Wareham, NJ, Waterworth, DM, Watkins, H, Whitfield, JB, Witteman, JCM, Wolffenbuttel, BHR, Fox, CS, Ala-Korpela, M, Stefansson, K, Vollenweider, P, Völzke, H, Schadt, EE, Scott, J, Järvelin, M-R, Elliott, P, and Kooner, JS
- Published
- 2011
5. Body composition using bio-impedance analysis in pediatric patients with inflammatory bowel disease. Corcordance with dual energy X-ray absorptiometry and comparison with healthy controls
- Author
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Callias, C, primary, Chatton, T, additional, Marques-Vidal, PM, additional, and Nydegger, A, additional
- Published
- 2013
- Full Text
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6. DIetary intake of children with inflammatory bowel disease and of healthy controls
- Author
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Chatton, T, primary, Marques-Vidal, PM, additional, and Nydegger, A, additional
- Published
- 2013
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7. Assessment of skinfold thickness equations in estimating body composition in children with inflammatory bowel
- Author
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Callias, C, primary, Chatton, T, additional, Marques-Vidal, PM, additional, and Nydegger, A, additional
- Published
- 2013
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8. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome.
- Author
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Firmann M, Mayor V, Vidal PM, Bochud M, Pécoud A, Hayoz D, Paccaud F, Preisig M, Song KS, Yuan X, Danoff TM, Stirnadel HA, Waterworth D, Mooser V, Waeber G, Vollenweider P, Firmann, Mathieu, Mayor, Vladimir, Vidal, Pedro Marques, and Bochud, Murielle
- Abstract
Background: Cardiovascular diseases and their associated risk factors remain the main cause of mortality in western societies. In order to assess the prevalence of cardiovascular risk factors (CVRFs) in the Caucasian population of Lausanne, Switzerland, we conducted a population-based study (Colaus Study). A secondary aim of the CoLaus study will be to determine new genetic determinants associated with CVRFs.Methods: Single-center, cross-sectional study including a random sample of 6,188 extensively phenotyped Caucasian subjects (3,251 women and 2,937 men) aged 35 to 75 years living in Lausanne, and genotyped using the 500 K Affymetrix chip technology.Results: Obesity (body mass index > or = 30 kg/m2), smoking, hypertension (blood pressure > or = 140/90 mmHg and/or treatment), dyslipidemia (high LDL-cholesterol and/or low HDL-cholesterol and/or high triglyceride levels) and diabetes (fasting plasma glucose > or = 7 mmol/l and/or treatment) were present in 947 (15.7%), 1673 (27.0%), 2268 (36.7%), 2113 (34.2%) and 407 (6.6%) of the participants, respectively, and the prevalence was higher in men than in women. In both genders, the prevalence of obesity, hypertension and diabetes increased with age.Conclusion: The prevalence of major CVRFs is high in the Lausanne population in particular in men. We anticipate that given its size, the depth of the phenotypic analysis and the availability of dense genome-wide genetic data, the CoLaus Study will be a unique resource to investigate not only the epidemiology of isolated, or aggregated CVRFs like the metabolic syndrome, but can also serve as a discovery set, as well as replication set, to identify novel genes associated with these conditions. [ABSTRACT FROM AUTHOR]- Published
- 2008
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9. Regulatory T cells administration reduces anxiety-like behavior in mice submitted to chronic restraint stress.
- Author
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Cepeda Y, Elizondo-Vega R, Garrido C, Tobar C, Araneda M, Oliveros P, Ordenes P, Carril C, Vidal PM, Luz-Crawford P, García-Robles MA, and Oyarce K
- Abstract
Background: Major depression disorder (MDD) and anxiety are common mental disorders that significantly affect the quality of life of those who suffer from them, altering the person's normal functioning. From the biological perspective, the most classical hypothesis explaining their occurrence relies on neurotransmission and hippocampal excitability alterations. However, around 30% of MDD patients do not respond to medication targeting these processes. Over the last decade, the involvement of inflammatory responses in depression and anxiety pathogenesis has been strongly acknowledged, opening the possibility of tackling these disorders from an immunological point of view. In this context, regulatory T cells (Treg cells), which naturally maintain immune homeostasis by suppressing inflammation could be promising candidates for their therapeutic use in mental disorders., Methods: To test this hypothesis, C57BL/6 adult male mice were submitted to classical stress protocols to induce depressive and anxiety-like behavior; chronic restriction stress (CRS), and chronic unpredictable stress (CUS). Some of the stressed mice received a single adoptive transfer of Treg cells during stress protocols. Mouse behavior was analyzed through the open field (OFT) and forced swim test (FST). Blood and spleen samples were collected for T cell analysis using cell cytometry, while brains were collected to study changes in microglia by immunohistochemistry., Results: Mice submitted to CRS and CUS develop anxiety and depressive-like behavior, and only CRS mice exhibit lower frequencies of circulating Treg cells. Adoptive transfer of Treg cells decreased anxiety-like behavior in the OFT only in CRS model, but not depressive behavior in FST in neither of the two models. In CRS mice, Treg cells administration lowered the number of microglia in the hippocampus, which increased due this stress paradigm, and restored its arborization. However, in CUS mice, Treg cells administration increased microglia number with no significant effect on their arborization., Conclusion: Our results for effector CD4
+ T cells in the spleen and microglia number and morphology in the hippocampus add new evidence in favor of the participation of inflammatory responses in the development of depressive and anxiety-like behavior and suggest that the modulation of key immune cells such as Treg cells, could have beneficial effects on these disorders., 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 © 2024 Cepeda, Elizondo-Vega, Garrido, Tobar, Araneda, Oliveros, Ordenes, Carril, Vidal, Luz-Crawford, García-Robles and Oyarce.)- Published
- 2024
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10. Dairy products and hypertension: Cross-sectional and prospective associations.
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Farinha VO, Vaucher J, and Vidal PM
- Abstract
Background: The association between dairy intake and prevalence or incidence of hypertension remains controversial. We aimed to investigate the association between intake of different dairy products and prevalence and incidence of hypertension in a community-dwelling sample., Methods: Three cross-sectional studies (2009-12, 2014-17 and 2018-21) and one prospective study (2009-12 to 2018-21) were conducted in Lausanne, Switzerland. Dietary intake was assessed via a validated food frequency questionnaire. Dairy consumption was compared between participants with and without prevalent or incident hypertension., Results: For the cross-sectional analyses, data from 4437 (2009-12, 54.0% women, 57.7 ± 10.5 years), 2925 (2014-17, 53.4% women, 62.5 ± 10.0 years), and 2144 (2018-21; 53.3% women, 65.5 ± 9.6 years) participants were used. No consistent differences between participants with and without hypertension were found for all dairy products (total dairy, milk, yogurt, cheese, low-fat dairy, and full-fat dairy) although participants with hypertension tended to consume less cheese (51 ± 1 vs. 55 ± 1, p = 0.014, 52 ± 1 vs. 56 ± 1, p = 0.053, and 54 ± 1 vs. 56 ± 1 g/day for 2009-12, 2014-17 and 2018-21, respectively). For the prospective study, data from 2303 participants (60.8% women, 53.9 ± 9.0 years) were used. Irrespective of the dairy product considered, no association was found between quartiles of dairy consumption and development of hypertension. Similar findings were obtained after stratifying on dietary quality., Conclusion: In this population-based study, no association was found between the consumption of different dairy products and the prevalence or incidence of hypertension., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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11. Neuromotor decline is associated with gut dysbiosis following surgical decompression for Degenerative Cervical Myelopathy.
- Author
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Vidal PM, Brockie S, Farkas C, Hong J, Zhou C, and Fehlings MG
- Subjects
- Animals, Mice, Spinal Cord Diseases surgery, Male, Cervical Vertebrae surgery, Spinal Cord Compression surgery, Dysbiosis, Decompression, Surgical methods, Gastrointestinal Microbiome physiology, Mice, Inbred C57BL
- Abstract
Degenerative cervical myelopathy (DCM) describes a spectrum of disorders that cause progressive and chronic cervical spinal cord compression. The clinical presentation can be complex and can include locomotor impairment, hand and upper extremity dysfunction, pain, loss of bladder and bowel function, as well as gastrointestinal dysfunction. Once diagnosed, surgical decompression is the recommended treatment for DCM patients with moderate to severe impairment. Our body is composed of a large community of microorganisms, known as the microbiota. Traumatic and non-traumatic spinal cord injuries (SCIs) can induce changes in the gut microbiota and gut microbiota derived metabolites. These changes have been reported as important disease-modifying factors after injury. However, whether gut dysbiosis is associated with functional neurological recovery after surgical decompression has not been examined to date. Here, DCM was induced in C57BL/6 mice by implanting an aromatic polyether material underneath the C5-6 laminae. The extent of gut dysbiosis was assessed by gas chromatography and 16S rRNA sequencing from fecal samples before and after decompression. Neuromotor activity was assessed using the Catwalk test. Our results show that DCM pre- and post- surgical decompression is associated with gut dysbiosis, without altering short chain fatty acids (SCFAs) levels. Significant differences in Clostridia, Verrumicrobiae, Lachnospiracea, Firmicutes, Bacteroidales, and Clostridiaceae were observed between the DCM group (before decompression) and after surgical decompression (2 and 5 weeks). The changes in gut microbiota composition correlated with locomotor features of the Catwalk. For example, a longer duration of ground contact and dysfunctional swing in the forelimbs, were positively correlated with gut dysbiosis. These results show for the first time an association between gut dysbiosis and locomotor deterioration after delayed surgical decompression. Thus, providing a better understanding of the extent of changes in microbiota composition in the setting of DCM pre- and post- surgical decompression., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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12. Healthy ageing in a multi-ethnic population: A descriptive cross-sectional analysis from the HELIUS study.
- Author
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Menassa M, Franco OH, Galenkamp H, Moll van Charante EP, van den Born BH, Vriend EMC, Vidal PM, and Stronks K
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Chronic Disease ethnology, Cognition, Cross-Sectional Studies, Mental Health ethnology, Netherlands, Quality of Life, Social Support, Surveys and Questionnaires, Ethnicity statistics & numerical data, Healthy Aging ethnology
- Abstract
Objective: We investigated ethnic health disparities in the Healthy Life in an Urban Setting multi-ethnic cohort using the multidimensional Healthy Ageing Score., Study Design: We conducted a cross-sectional analysis of the study baseline data (2011-2015) collected through questionnaires/physical examinations for 17,091 participants (54.8 % women, mean (SD) age = 44.5 (12.8) years) from South-Asian Surinamese (14.8 %), African Surinamese (20.5 %), Dutch (24.3 %), Moroccan (15.5 %), Turkish (14.9 %), and Ghanaian (10.1 %) origins, living in Amsterdam, the Netherlands., Main Outcome Measures: We computed the Healthy Ageing Score developed in the Rotterdam Study, which has seven biopsychosocial domains: chronic diseases, mental health, cognitive function, physical function, pain, social support, and quality of life. That score was used to discern between healthy, moderate, and poor ageing. We explored differences in healthy ageing by ethnicity, sex, and age group using multinomial logistic regression., Results: The Healthy Ageing Score [overall: poor (69.0 %), moderate (24.8 %), and healthy (6.2 %)] differed between ethnicities and was poorer in women and after midlife (cut-off 45 years) across ethnicities (all p < 0.001). In the fully adjusted models in men and women, poor ageing (vs. healthy ageing) was highest in the South-Asian Surinamese [adjusted odds ratios (95 % confidence intervals)] [2.96 (2.24-3.90) and 6.88 (3.29-14.40), respectively] and Turkish [2.80 (2.11-3.73) and 7.10 (3.31-15.24), respectively] vs. Dutch, in the oldest [5.89 (3.62-9.60) and 13.17 (1.77-98.01), respectively] vs. youngest, and in the divorced [1.48 (1.10-2.01) and 2.83 (1.39-5.77), respectively] vs. married. Poor ageing was inversely associated with educational and occupational levels, mainly in men., Conclusions: Compared with those of Dutch ethnic origin, ethnic minorities displayed less healthy ageing, which was more pronounced in women, before and after midlife, and was associated with sociodemographic factors., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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13. Potential Mediating Role of Iron Biomarkers in the Association of Sex With Glucose, Insulin, and Type 2 Diabetes.
- Author
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Khatami F, Lange T, Groothof D, Ahanchi NS, Quezada-Pinedo HG, Raeisi-Dehkordi H, De Borst MH, Vidal PM, Sailesh M, Prabhakaran D, Bano A, Bakker SJL, Muka T, and Eisenga MF
- Abstract
Context: Sex-specific prevalence and incidence of type 2 diabetes (T2D) have been reported, but the underlying mechanisms are uncertain., Objective: In this study, we aimed to investigate whether iron biomarkers mediate the association between biological sex and glucose metabolism and the incidence of T2D., Methods: We used data from the general population enrolled in the prospective Prevention of REnal and Vascular ENd-stage Disease study in Groningen, The Netherlands. We measured ferritin, transferrin saturation (TSAT), hepcidin, soluble transferrin receptor (sTfR), fasting plasma glucose (FPG), fasting plasma insulin (FPI) levels, and incidence of T2D. We used multivariable regression and mediation analyses to investigate our hypothesis. All iron biomarkers, FPG, and FPI were log-transformed., Results: The mean (SD) age of the 5312 (51.3% female) individuals was 52.2 (11.6) years. Compared with males, females had lower FPG (β = -.01; 95% CI -0.02, -0.01) and FPI (β = -.03; 95% CI -0.05, -0.02) levels. Ferritin, hepcidin, and sTfR showed potential mediating effects on the association between sex and FPG, 21%, 5%, and 7.1%, respectively. Furthermore, these variables mediated 48.6%, 5.7%, and 3.1% of the association between sex and FPI, respectively. Alternatively, TSAT had a suppressive mediating role in the association of sex with FPG and FPI. The incidence of T2D was lower in females than in males (hazard ratio 0.58; 95% CI 0.44, 0.77), with 19.2% of this difference being mediated by ferritin., Conclusion: Iron biomarkers may partially mediate the association between sex and glucose homeostasis. Future studies addressing the causality of our findings are needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2024
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14. Identification of master regulator genes controlling pathogenic CD4 + T cell fate in inflammatory bowel disease through transcriptional network analysis.
- Author
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Jiménez JM, Contreras-Riquelme JS, Vidal PM, Prado C, Bastías M, Meneses C, Martín AJM, Perez-Acle T, and Pacheco R
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- Animals, Mice, Disease Models, Animal, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Mice, Inbred C57BL, Mice, Knockout, Gene Expression Regulation, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases metabolism, Inflammatory Bowel Diseases pathology, Gene Regulatory Networks, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism
- Abstract
Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune response. Effector CD4
+ T cells and regulatory CD4+ T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4+ T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4+ T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1-/- mice received the transfer of the whole CD4+ T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4+ T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4+ T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD., (© 2024. The Author(s).)- Published
- 2024
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15. Cross-sectional and longitudinal associations of Iron biomarkers and cardiovascular risk factors in pre- and postmenopausal women: leveraging repeated measurements to address natural variability.
- Author
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Ahanchi NS, Fischer AS, Quezada-Pinedo HG, Khatami F, Eisenga MF, Muka T, and Vidal PM
- Subjects
- Humans, Female, Cross-Sectional Studies, Middle Aged, Longitudinal Studies, Risk Assessment, Adult, Iron blood, Time Factors, Brazil epidemiology, Aged, Blood Glucose metabolism, Reproducibility of Results, Age Factors, Biomarkers blood, Ferritins blood, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases blood, Transferrin metabolism, Transferrin analysis, Heart Disease Risk Factors, Postmenopause blood
- Abstract
Background: The association between iron biomarkers and cardiovascular disease risk factors (CVD-RFs) remains unclear. We aimed to (1) evaluate the cross-sectional and longitudinal associations between iron biomarkers (serum ferritin, transferrin saturation (TSAT), transferrin) and CVD-RFs among women, and (2) explore if these associations were modified by menopausal status., Method: Cross-sectional and longitudinal analyses including 2542 and 1482 women from CoLaus cohort, respectively. Multiple linear regression and multilevel mixed models were used to analyse the associations between Iron biomarkers and CVD-RFs. Variability of outcomes and iron markers between surveys was accessed using intraclass correlation (ICC)., Results: After multivariable adjustment, elevated serum ferritin levels were associated with increased insulin and glucose levels, while higher transferrin levels were linked to elevated glucose, insulin and total cholesterol, and systolic and diastolic blood pressure (p < 0.05). No association was observed between CVD-RFs and TSAT (p > 0.05). Iron biomarkers demonstrated low reliability across reproductive stages but exhibited stronger associations in the perimenopausal group. In longitudinal analysis, we found association only for transferrin with lower glucose levels [β = - 0.59, 95% CI (- 1.10, - 0.08), p = 0.02] and lower diastolic blood pressure [β = - 7.81, 95% CI (- 15.9, - 0.56), p = 0.04]., Conclusion: In cross-sectional analysis, transferrin was associated with several CVD-RFs, and the associations did not change according to menopausal status. Conversely, in the longitudinal analyses, changes in transferrin were associated only with lower glucose and diastolic blood pressure levels. These differences might stem from the substantial longitudinal variation of iron biomarkers, underscoring the need for multiple iron measurements in longitudinal analyses., (© 2024. The Author(s).)
- Published
- 2024
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16. The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes.
- Author
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Ahanchi NS, Khatami F, Llanaj E, Quezada-Pinedo HG, Dizdari H, Bano A, Glisic M, Eisenga MF, Vidal PM, and Muka T
- Subjects
- Humans, Female, Male, Cardiometabolic Risk Factors, Diabetes Mellitus, Type 2, Sex Factors, Menopause, Estrogens metabolism, Cardiovascular Diseases etiology, Iron metabolism
- Abstract
Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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17. Development and external validation of a home-based risk predicTion modEl of natUral onseT of menopAuse -TEUTA.
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Kastrati L, Vidal PM, Dhana K, Bally L, Lambrinoudaki I, Groothof D, Bakker SJL, Eisenga MF, and Muka T
- Abstract
Objective: To develop and externally validate a 10-year risk prediction model of natural onset of menopause using ready-to-use predictors., Design: Population-based prospective cohort study., Participants: Community-dwelling, premenopausal women aged 28 years and older enrolled in the Swiss (CoLaus) and Dutch (PREVEND) study., Main Outcome Measure: Incidence of self-reported natural menopause., Model Development: Based on existing literature, 11 predictors were tested in this study. The CoLaus cohort was used to develop the model by applying the backward-elimination approach and Bayesian Model Averaging. Internal validation was performed by bootstrapping. External validation was performed using data from the PREVEND cohort and recalibrating the baseline survival estimate. C-statistic, calibration slopes, and expected/observed probabilities were calculated as measures of model internal and/or external performances., Results: The final analysis included 750 and 1032 premenopausal women from the CoLaus and the PREVEND cohort, respectively. Among them, 445 (59%) from CoLaus and 387 (38%) from PREVEND experienced menopause over a median follow-up of 10.7 and 9 years, respectively. The final model included age, alcohol consumption, smoking status, education level, and systolic blood pressure. Upon external calibration in the PREVEND cohort, the model exhibited good discrimination, with a C-statistic of 0.888 and an expected/observed probability of 0.82., Conclusions: We present the first internally and externally validated prediction model of natural menopause onset using readily available predictors. Validation of our model to other populations is needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2024
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18. Blood pressure status, trajectories and cardiovascular disease: the CoLaus|PsyCoLaus prospective study.
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Chocron Y, Rousakis M, Vollenweider P, Vaucher J, and Marques-Vidal PM
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- Humans, Blood Pressure physiology, Prospective Studies, Risk Factors, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Hypertension diagnosis, Hypertension drug therapy, Hypertension epidemiology
- Abstract
Background: High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD). Adequate treatment of high BP should reduce the risk of CVD, but this association has seldom been assessed in a general population setting., Methods: Population-based prospective study conducted in Lausanne, Switzerland, with a follow-up between 2003 and 2021. Participants were categorised as normal BP, untreated high BP, treated and uncontrolled BP and treated and controlled BP. Total and CVD mortality as well as any CVD event were assessed., Results: 5341 participants (65% normal, 17.4% untreated, 8.8% treated and uncontrolled and 8.8% treated and controlled) were included. After a median follow-up of 14 years (IQR: 11-15), 575 CVD events occurred. Relative to participants with normal BP, multivariable-adjusted HRs (and 95% CI) for total CVD were 1.38 (1.11 to 1.72) for untreated, 1.35 (1.04 to 1.76) for treated and uncontrolled and 1.50 (1.15 to 1.95) for treated and controlled. The corresponding HRs for CVD mortality (112 events) were 0.94 (0.52 to 1.70), 1.77 (1.00 to 3.12) and 2.52 (1.50 to 4.23), respectively. For total mortality (677 events), the HRs were 1.24 (1.01 to 1.52), 1.26 (0.99 to 1.60) and 1.27 (0.99 to 1.62), respectively. Sensitivity analysis using BP status during a 5-year period and categorising participants as always normal, always treated and uncontrolled, always treated and controlled and other led to similar findings., Conclusion: Over a long follow-up period of 14 years, BP control was not associated with reduction of CVD events, CVD-related or total mortality. This finding should help define further studies on factors affecting CVD and mortality in people treated for hypertension in the general population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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19. Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy.
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Ojeda J, Vergara M, Ávila A, Henríquez JP, Fehlings M, and Vidal PM
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Degenerative Cervical Myelopathy (DCM) is a progressive neurological condition characterized by structural alterations in the cervical spine, resulting in compression of the spinal cord. While clinical manifestations of DCM are well-documented, numerous unanswered questions persist at the molecular and cellular levels. In this study, we sought to investigate the neuromotor axis during DCM. We use a clinically relevant mouse model, where after 3 months of DCM induction, the sensorimotor tests revealed a significant reduction in both locomotor activity and muscle strength compared to the control group. Immunohistochemical analyses showed alterations in the gross anatomy of the cervical spinal cord segment after DCM. These changes were concomitant with the loss of motoneurons and a decrease in the number of excitatory synaptic inputs within the spinal cord. Additionally, the DCM group exhibited a reduction in the endplate surface, which correlated with diminished presynaptic axon endings in the supraspinous muscles. Furthermore, the biceps brachii (BB) muscle exhibited signs of atrophy and impaired regenerative capacity, which inversely correlated with the transversal area of remnants of muscle fibers. Additionally, metabolic assessments in BB muscle indicated an increased proportion of oxidative skeletal muscle fibers. In line with the link between neuromotor disorders and gut alterations, DCM mice displayed smaller mucin granules in the mucosa layer without damage to the epithelial barrier in the colon. Notably, a shift in the abundance of microbiota phylum profiles reveals an elevated Firmicutes-to-Bacteroidetes ratio-a consistent hallmark of dysbiosis that correlates with alterations in gut microbiota-derived metabolites. Additionally, treatment with short-chain fatty acids stimulated the differentiation of the motoneuron-like NSC34 cell line. These findings shed light on the multifaceted nature of DCM, resembling a synaptopathy that disrupts cellular communication within the neuromotor axis while concurrently exerting influence on other systems. Notably, the colon emerges as a focal point, experiencing substantial perturbations in both mucosal barrier integrity and the delicate balance of intestinal microbiota., 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 © 2024 Ojeda, Vergara, Ávila, Henríquez, Fehlings and Vidal.)
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- 2024
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20. Utility of iron biomarkers in differentiating menopausal status: Findings from CoLaus and PREVEND.
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Kastrati L, Groothof D, Quezada-Pinedo HG, Raeisi-Dehkordi H, Bally L, De Borst MH, Bakker SJL, Vidal PM, Eisenga MF, and Muka T
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- Female, Humans, Biomarkers, Cross-Sectional Studies, Ferritins, Menopause, Transferrin analysis, Hepcidins, Iron metabolism
- Abstract
Aim: To examine the association of iron biomarkers with menopausal status and assess whether these biomarkers can help differentiate menopausal status beyond age., Methods: In this cross-sectional study we included 1679 women from the CoLaus and 2133 from the PREVEND cohorts, with CoLaus used as primary cohort and PREVEND for replication. Ferritin, transferrin, iron, and transferrin saturation (TSAT) were used to assess iron status. Hepcidin and soluble transferrin receptor were assessed only in PREVEND. Menopausal status was self-reported and defined as menopausal or non-menopausal. Logistic regressions were used to explore the association of these iron biomarkers with menopause status. Sensitivity, specificity, area under the receiver operating characteristic curves (AUC), positive and negative predictive values as well as cut-off points for the iron biomarkers were calculated. The model with the highest AUC was defined as the best., Results: In the CoLaus and PREVEND cohorts, respectively, 513 (30.6 %) and 988 (46.3 %) women were postmenopausal. Ferritin (OR, 2.20; 95 % CI 1.72-2.90), transferrin (OR, 0.03; 95 % CI 0.01-0.10), and TSAT (OR, 1.28; 95 % CI 1.06-1.54) were significantly associated with menopausal status in CoLaus, with the findings replicated in PREVEND. AUC of age alone was 0.971. The best model resulted from combining age, ferritin, and transferrin, with an AUC of 0.976, and sensitivity and specificity of 87.1 % and 96.5 %, respectively. Adding transferrin and ferritin to a model with age improved menopause classification by up to 7.5 %. In PREVEND, a model with age and hepcidin outperformed a model with age, ferritin, and transferrin., Conclusion: Iron biomarkers were consistently associated with menopausal status in both cohorts, and modestly improved a model with age alone for differentiating menopause status. Our findings on hepcidin need replication., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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21. Degenerative Cervical Myelopathy induces sex-specific dysbiosis in mice.
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Farkas C, Retamal-Fredes E, Ávila A, Fehlings MG, and Vidal PM
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Degenerative Cervical Myelopathy (DCM) is the most common cause of spinal cord impairment in elderly populations. It describes a spectrum of disorders that cause progressive spinal cord compression, neurological impairment, loss of bladder and bowel functions, and gastrointestinal dysfunction. The gut microbiota has been recognized as an environmental factor that can modulate both the function of the central nervous system and the immune response through the microbiota-gut-brain axis. Changes in gut microbiota composition or microbiota-producing factors have been linked to the progression and development of several pathologies. However, little is known about the potential role of the gut microbiota in the pathobiology of DCM. Here, DCM was induced in C57BL/6 mice by implanting an aromatic polyether material underneath the C5-6 laminae. The extent of DCM-induced changes in microbiota composition was assessed by 16S rRNA sequencing of the fecal samples. The immune cell composition was assessed using flow cytometry. To date, several bacterial members have been identified using BLAST against the largest collection of metagenome-derived genomes from the mouse gut. In both, female and males DCM caused gut dysbiosis compared to the sham group. However, dysbiosis was more pronounced in males than in females, and several bacterial members of the families Lachnospiraceae and Muribaculaceae were significantly altered in the DCM group. These changes were also associated with altered microbe-derived metabolic changes in propionate-, butyrate-, and lactate-producing bacterial members. Our results demonstrate that DCM causes dynamic changes over time in the gut microbiota, reducing the abundance of butyrate-producing bacteria, and lactate-producing bacteria to a lesser extent. Genome-scale metabolic modeling using gapseq successfully identified pyruvate-to-butanoate and pyruvate-to-propionate reactions involving genes such as Buk and ACH1, respectively. These results provide a better understanding of the sex-specific molecular effects of changes in the gut microbiota on DCM pathobiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Farkas, Retamal-Fredes, Ávila, Fehlings and Vidal.)
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- 2023
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22. Associations of genetic and infectious risk factors with coronary heart disease.
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Hodel F, Xu ZM, Thorball CW, de La Harpe R, Letang-Mathieu P, Brenner N, Butt J, Bender N, Waterboer T, Marques-Vidal PM, Vollenweider P, Vaucher J, and Fellay J
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- Humans, Prospective Studies, Risk Factors, Incidence, Proportional Hazards Models, Coronary Disease epidemiology, Coronary Disease genetics
- Abstract
Coronary heart disease (CHD) is one of the most pressing health problems of our time and a major cause of preventable death. CHD results from complex interactions between genetic and environmental factors. Using multiplex serological testing for persistent or frequently recurring infections and genome-wide analysis in a prospective population study, we delineate the respective and combined influences of genetic variation, infections, and low-grade inflammation on the risk of incident CHD. Study participants are enrolled in the CoLaus|PsyCoLaus study, a longitudinal, population-based cohort with baseline assessments from 2003 through 2008 and follow-up visits every 5 years. We analyzed a subgroup of 3459 individuals with available genome-wide genotyping data and immunoglobulin G levels for 22 persistent or frequently recurring pathogens. All reported CHD events were evaluated by a panel of specialists. We identified independent associations with incident CHD using univariable and multivariable stepwise Cox proportional hazards regression analyses. Of the 3459 study participants, 210 (6.07%) had at least one CHD event during the 12 years of follow-up. Multivariable stepwise Cox regression analysis, adjusted for known cardiovascular risk factors, socioeconomic status, and statin intake, revealed that high polygenic risk (hazard ratio [HR] 1.31, 95% CI 1.10-1.56, p=2.64 × 10
-3 ) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08-2.45, p=1.99 × 10-2 ) were independently associated with incident CHD. In a prospective, population-based cohort, high polygenic risk and infection with F. nucleatum have a small, yet independent impact on CHD risk., Competing Interests: FH, ZX, CT, Rd, PL, NB, JB, NB, TW, PM, PV, JV, JF No competing interests declared, (© 2023, Hodel et al.)- Published
- 2023
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23. Ten-Year Evolution of Statin Eligibility and Use in a Population-Based Cohort.
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Rochat M, Delabays B, Marques-Vidal PM, Vollenweider P, Mach F, and Vaucher J
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- United States epidemiology, Female, Humans, Cross-Sectional Studies, American Heart Association, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Cardiovascular Diseases epidemiology, Cardiovascular Diseases prevention & control, Dyslipidemias drug therapy, Dyslipidemias epidemiology, Atherosclerosis drug therapy, Atherosclerosis epidemiology, Atherosclerosis prevention & control
- Abstract
Studies showing that the management of dyslipidemia is suboptimal are hampered by their cross-sectional design or short follow-up. Using recent data from a population-based cohort with a 10-year follow-up, we assessed the use of statins, including their intensity. We used data from the CoLaus|PsyColaus study, involving 4,655 participants at baseline (2003 to 2006) and 3,587 at 10-year follow-up (2014 to 2017). We assessed the cardiovascular risk of participants according to established guidelines from the European Society of Cardiology (ESC) and from the American Heart Association/American College of Cardiology and estimated 10-year cardiovascular risk using corresponding risk scores, Systemic Coronary Risk Evaluation risk prediction model and Pooled Cohort Equations. We first determined eligibility for statins and adherence to recommendations at 2 time periods. Additionally, we assessed the prevalence of statin users from 2014 to 2017 in persons without atherosclerotic cardiovascular disease at baseline and who developed it during the follow-up (secondary prevention). A total of 219 participants developed a first atherosclerotic cardiovascular disease during follow-up. Statin use in eligible subjects was 25.9% and 24.0% from 2003 to 2006 and 35.9% and 26.3% from 2014 to 2017, according to ESC and American Heart Association/American College of Cardiology guidelines, respectively. Per ESC guidelines, only 28.2% of treated persons achieved low-density lipoproteins cholesterol target levels from 2014 to 2017 (15.8% from 2003 to 2006), and women less frequently attained goals. Only 18% of subjects used high-intensity statins from 2014 to 2017, with women less often receiving them (14% vs 22%). In secondary prevention, only 74% of eligible subjects were using statins. In conclusion, based on contemporaneous data, management of dyslipidemia is suboptimal, including in secondary prevention, especially in women who are less frequently treated and, if treated, less frequently receive high-intensity treatment., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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24. [Translated article] Necrotising fasciitis: Management experience over the last two decades in our hospital.
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Pérez-Sánchez I, Martínez-Gil L, Piqueras-Vidal PM, Pont-Gutiérez C, Cebrián-Gómez R, and Montoza-Nuñez JM
- Abstract
Background: Necrotising fasciitis is a potentially life-threatening soft tissue infection that mainly affects the fascia and deep planes, with a very high mortality rate and severe related complications., Aim: To evaluate clinical and demographic characteristics of patients with necrotising fasciitis in our hospital and to describe their diagnostic and therapeutic management., Material and Methods: Retrospective review of medical records of 21 patients diagnosed with necrotising fasciitis with limb involvement between January 2003 and February 2021 in our hospital. Demographic data, clinical features and details of management and prognosis were collected for each patient., Results: Of 21 patients included, 15 were male (71.43%), with a mean age at diagnosis of 54.38±19.55 years. The most frequent comorbidities were insulin-dependent diabetes mellitus in seven patients (33.33%) and a history of cancer in five patients (23.81%). Infection was monomicrobial in 14 cases (66.66%), with Streptococcus pyogenes being the most frequent microorganism; multiple pathogens were isolated in 2 patients (9.52%) and no microorganism was identified in 5 patients (23.81%). All patients underwent surgery at our hospital, with a mean of 4.14±3.98 surgeries. Only one patient underwent amputation of the affected limb. The mean hospital stay was 23.14±16.44 days, with an overall mortality of 47.62% (10 cases)., Conclusions: Despite being a rare disease, necrotising fasciitis is a very aggressive pathology, with a high mortality rate, especially in immunocompromised patients. Advanced age and oncological disease are potential factors of worse prognosis in the evolution of this condition., (Copyright © 2022. Publicado por Elsevier España, S.L.U.)
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- 2022
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25. Intuitive Eating Behavior, Diet Quality and Metabolic Health in the Postpartum in Women with Gestational Diabetes.
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Quansah DY, Schenk S, Gilbert L, Arhab A, Gross J, Marques-Vidal PM, Gonzalez Rodriguez E, Hans D, Horsch A, and Puder JJ
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- Female, Humans, Pregnancy, Body Mass Index, Diet psychology, Eating psychology, Feeding Behavior psychology, Postpartum Period psychology, Surveys and Questionnaires, Diabetes, Gestational, Insulin Resistance
- Abstract
Little is known regarding intuitive eating (IE), diet quality and adherence. We investigated the associations between IE, diet quality and metabolic health after gestational diabetes (GDM), who have an increased diabetes risk. Data from 179 women with GDM from MySweetheart trial (NCT02872974) were analyzed. IE was assessed using the eating for physical rather than emotional reasons (EPR) and reliance on hunger and satiety cues (RHSC) subscales of the French Intuitive Eating Scale-2. Metabolic outcomes included weight, central body fat and insulin resistance. Diet quality was calculated using the Alternative Health Eating Index (AHEI) and compliance with national recommendations was evaluated. Both IE subscales were associated with lower BMI and fat mass (BIA) at 1-year postpartum (all p ≤ 0.034). The EPR subscale inversely correlated with fat mass (DXA) and visceral adipose tissue (both p ≤ 0.028), whereas RHSC with higher insulin sensitivity (Matsuda, p = 0.034). RHSC during pregnancy predicted increased AHEI ( p = 0.043) at 1-year postpartum, whilst EPR predicted lower fat mass and insulin resistance (HOMA-IR) (all p ≤ 0.04). In longitudinal analyses, both subscales were associated with increased adherence to dairy and fiber intake recommendations (both p ≤ 0.023). These data suggest IE may be an interesting approach to improve diet quality and metabolic outcomes in women with GDM.
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- 2022
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26. A saturated map of common genetic variants associated with human height.
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Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, Graff M, Eliasen AU, Jiang Y, Raghavan S, Miao J, Arias JD, Graham SE, Mukamel RE, Spracklen CN, Yin X, Chen SH, Ferreira T, Highland HH, Ji Y, Karaderi T, Lin K, Lüll K, Malden DE, Medina-Gomez C, Machado M, Moore A, Rüeger S, Sim X, Vrieze S, Ahluwalia TS, Akiyama M, Allison MA, Alvarez M, Andersen MK, Ani A, Appadurai V, Arbeeva L, Bhaskar S, Bielak LF, Bollepalli S, Bonnycastle LL, Bork-Jensen J, Bradfield JP, Bradford Y, Braund PS, Brody JA, Burgdorf KS, Cade BE, Cai H, Cai Q, Campbell A, Cañadas-Garre M, Catamo E, Chai JF, Chai X, Chang LC, Chang YC, Chen CH, Chesi A, Choi SH, Chung RH, Cocca M, Concas MP, Couture C, Cuellar-Partida G, Danning R, Daw EW, Degenhard F, Delgado GE, Delitala A, Demirkan A, Deng X, Devineni P, Dietl A, Dimitriou M, Dimitrov L, Dorajoo R, Ekici AB, Engmann JE, Fairhurst-Hunter Z, Farmaki AE, Faul JD, Fernandez-Lopez JC, Forer L, Francescatto M, Freitag-Wolf S, Fuchsberger C, Galesloot TE, Gao Y, Gao Z, Geller F, Giannakopoulou O, Giulianini F, Gjesing AP, Goel A, Gordon SD, Gorski M, Grove J, Guo X, Gustafsson S, Haessler J, Hansen TF, Havulinna AS, Haworth SJ, He J, Heard-Costa N, Hebbar P, Hindy G, Ho YA, Hofer E, Holliday E, Horn K, Hornsby WE, Hottenga JJ, Huang H, Huang J, Huerta-Chagoya A, Huffman JE, Hung YJ, Huo S, Hwang MY, Iha H, Ikeda DD, Isono M, Jackson AU, Jäger S, Jansen IE, Johansson I, Jonas JB, Jonsson A, Jørgensen T, Kalafati IP, Kanai M, Kanoni S, Kårhus LL, Kasturiratne A, Katsuya T, Kawaguchi T, Kember RL, Kentistou KA, Kim HN, Kim YJ, Kleber ME, Knol MJ, Kurbasic A, Lauzon M, Le P, Lea R, Lee JY, Leonard HL, Li SA, Li X, Li X, Liang J, Lin H, Lin SY, Liu J, Liu X, Lo KS, Long J, Lores-Motta L, Luan J, Lyssenko V, Lyytikäinen LP, Mahajan A, Mamakou V, Mangino M, Manichaikul A, Marten J, Mattheisen M, Mavarani L, McDaid AF, Meidtner K, Melendez TL, Mercader JM, Milaneschi Y, Miller JE, Millwood IY, Mishra PP, Mitchell RE, Møllehave LT, Morgan A, Mucha S, Munz M, Nakatochi M, Nelson CP, Nethander M, Nho CW, Nielsen AA, Nolte IM, Nongmaithem SS, Noordam R, Ntalla I, Nutile T, Pandit A, Christofidou P, Pärna K, Pauper M, Petersen ERB, Petersen LV, Pitkänen N, Polašek O, Poveda A, Preuss MH, Pyarajan S, Raffield LM, Rakugi H, Ramirez J, Rasheed A, Raven D, Rayner NW, Riveros C, Rohde R, Ruggiero D, Ruotsalainen SE, Ryan KA, Sabater-Lleal M, Saxena R, Scholz M, Sendamarai A, Shen B, Shi J, Shin JH, Sidore C, Sitlani CM, Slieker RC, Smit RAJ, Smith AV, Smith JA, Smyth LJ, Southam L, Steinthorsdottir V, Sun L, Takeuchi F, Tallapragada DSP, Taylor KD, Tayo BO, Tcheandjieu C, Terzikhan N, Tesolin P, Teumer A, Theusch E, Thompson DJ, Thorleifsson G, Timmers PRHJ, Trompet S, Turman C, Vaccargiu S, van der Laan SW, van der Most PJ, van Klinken JB, van Setten J, Verma SS, Verweij N, Veturi Y, Wang CA, Wang C, Wang L, Wang Z, Warren HR, Bin Wei W, Wickremasinghe AR, Wielscher M, Wiggins KL, Winsvold BS, Wong A, Wu Y, Wuttke M, Xia R, Xie T, Yamamoto K, Yang J, Yao J, Young H, Yousri NA, Yu L, Zeng L, Zhang W, Zhang X, Zhao JH, Zhao W, Zhou W, Zimmermann ME, Zoledziewska M, Adair LS, Adams HHH, Aguilar-Salinas CA, Al-Mulla F, Arnett DK, Asselbergs FW, Åsvold BO, Attia J, Banas B, Bandinelli S, Bennett DA, Bergler T, Bharadwaj D, Biino G, Bisgaard H, Boerwinkle E, Böger CA, Bønnelykke K, Boomsma DI, Børglum AD, Borja JB, Bouchard C, Bowden DW, Brandslund I, Brumpton B, Buring JE, Caulfield MJ, Chambers JC, Chandak GR, Chanock SJ, Chaturvedi N, Chen YI, Chen Z, Cheng CY, Christophersen IE, Ciullo M, Cole JW, Collins FS, Cooper RS, Cruz M, Cucca F, Cupples LA, Cutler MJ, Damrauer SM, Dantoft TM, de Borst GJ, de Groot LCPGM, De Jager PL, de Kleijn DPV, Janaka de Silva H, Dedoussis GV, den Hollander AI, Du S, Easton DF, Elders PJM, Eliassen AH, Ellinor PT, Elmståhl S, Erdmann J, Evans MK, Fatkin D, Feenstra B, Feitosa MF, Ferrucci L, Ford I, Fornage M, Franke A, Franks PW, Freedman BI, Gasparini P, Gieger C, Girotto G, Goddard ME, Golightly YM, Gonzalez-Villalpando C, Gordon-Larsen P, Grallert H, Grant SFA, Grarup N, Griffiths L, Gudnason V, Haiman C, Hakonarson H, Hansen T, Hartman CA, Hattersley AT, Hayward C, Heckbert SR, Heng CK, Hengstenberg C, Hewitt AW, Hishigaki H, Hoyng CB, Huang PL, Huang W, Hunt SC, Hveem K, Hyppönen E, Iacono WG, Ichihara S, Ikram MA, Isasi CR, Jackson RD, Jarvelin MR, Jin ZB, Jöckel KH, Joshi PK, Jousilahti P, Jukema JW, Kähönen M, Kamatani Y, Kang KD, Kaprio J, Kardia SLR, Karpe F, Kato N, Kee F, Kessler T, Khera AV, Khor CC, Kiemeney LALM, Kim BJ, Kim EK, Kim HL, Kirchhof P, Kivimaki M, Koh WP, Koistinen HA, Kolovou GD, Kooner JS, Kooperberg C, Köttgen A, Kovacs P, Kraaijeveld A, Kraft P, Krauss RM, Kumari M, Kutalik Z, Laakso M, Lange LA, Langenberg C, Launer LJ, Le Marchand L, Lee H, Lee NR, Lehtimäki T, Li H, Li L, Lieb W, Lin X, Lind L, Linneberg A, Liu CT, Liu J, Loeffler M, London B, Lubitz SA, Lye SJ, Mackey DA, Mägi R, Magnusson PKE, Marcus GM, Vidal PM, Martin NG, März W, Matsuda F, McGarrah RW, McGue M, McKnight AJ, Medland SE, Mellström D, Metspalu A, Mitchell BD, Mitchell P, Mook-Kanamori DO, Morris AD, Mucci LA, Munroe PB, Nalls MA, Nazarian S, Nelson AE, Neville MJ, Newton-Cheh C, Nielsen CS, Nöthen MM, Ohlsson C, Oldehinkel AJ, Orozco L, Pahkala K, Pajukanta P, Palmer CNA, Parra EJ, Pattaro C, Pedersen O, Pennell CE, Penninx BWJH, Perusse L, Peters A, Peyser PA, Porteous DJ, Posthuma D, Power C, Pramstaller PP, Province MA, Qi Q, Qu J, Rader DJ, Raitakari OT, Ralhan S, Rallidis LS, Rao DC, Redline S, Reilly DF, Reiner AP, Rhee SY, Ridker PM, Rienstra M, Ripatti S, Ritchie MD, Roden DM, Rosendaal FR, Rotter JI, Rudan I, Rutters F, Sabanayagam C, Saleheen D, Salomaa V, Samani NJ, Sanghera DK, Sattar N, Schmidt B, Schmidt H, Schmidt R, Schulze MB, Schunkert H, Scott LJ, Scott RJ, Sever P, Shiroma EJ, Shoemaker MB, Shu XO, Simonsick EM, Sims M, Singh JR, Singleton AB, Sinner MF, Smith JG, Snieder H, Spector TD, Stampfer MJ, Stark KJ, Strachan DP, 't Hart LM, Tabara Y, Tang H, Tardif JC, Thanaraj TA, Timpson NJ, Tönjes A, Tremblay A, Tuomi T, Tuomilehto J, Tusié-Luna MT, Uitterlinden AG, van Dam RM, van der Harst P, Van der Velde N, van Duijn CM, van Schoor NM, Vitart V, Völker U, Vollenweider P, Völzke H, Wacher-Rodarte NH, Walker M, Wang YX, Wareham NJ, Watanabe RM, Watkins H, Weir DR, Werge TM, Widen E, Wilkens LR, Willemsen G, Willett WC, Wilson JF, Wong TY, Woo JT, Wright AF, Wu JY, Xu H, Yajnik CS, Yokota M, Yuan JM, Zeggini E, Zemel BS, Zheng W, Zhu X, Zmuda JM, Zonderman AB, Zwart JA, Chasman DI, Cho YS, Heid IM, McCarthy MI, Ng MCY, O'Donnell CJ, Rivadeneira F, Thorsteinsdottir U, Sun YV, Tai ES, Boehnke M, Deloukas P, Justice AE, Lindgren CM, Loos RJF, Mohlke KL, North KE, Stefansson K, Walters RG, Winkler TW, Young KL, Loh PR, Yang J, Esko T, Assimes TL, Auton A, Abecasis GR, Willer CJ, Locke AE, Berndt SI, Lettre G, Frayling TM, Okada Y, Wood AR, Visscher PM, and Hirschhorn JN
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- Humans, Gene Frequency genetics, Genome, Human genetics, Genome-Wide Association Study, Haplotypes genetics, Linkage Disequilibrium genetics, Europe ethnology, Sample Size, Phenotype, Body Height genetics, Polymorphism, Single Nucleotide genetics, Chromosome Mapping
- Abstract
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes
1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)- Published
- 2022
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27. Acute Systemic White Blood Cell Changes following Degenerative Cervical Myelopathy (DCM) in a Mouse Model.
- Author
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Ulndreaj A, Ávila A, Hong J, Zhou C, Fehlings MG, and Vidal PM
- Subjects
- Animals, Cervical Vertebrae, Cytokines, Disease Models, Animal, Leukocytes pathology, Mice, Spinal Cord Compression diagnosis, Spinal Cord Compression etiology, Spinal Cord Compression pathology, Spinal Cord Diseases pathology
- Abstract
Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood cell composition. If so, these changes can be used for diagnosis complementing established imaging approaches and for the development of treatment strategies, since peripheral immunity affects the progression of DCM. Gradual compression of the spinal cord was induced in C57B/L mice at the C5-6 level. The composition of circulating white blood cells was analyzed longitudinally at four time points after induction of DCM using flow cytometry. At 12 weeks, serum cytokine levels were measured using a Luminex x-MAP assay. Neurological impairment in the mouse model was also assessed using the ladder walk test and CatWalk. Stepping function (* p < 0.05) and overground locomotion (*** p < 0.001) were impaired in the DCM group. Importantly, circulating monocytes and T cells were affected primarily at 3 weeks following DCM. T cells were two-fold lower in the DCM group (*** p < 0.0006), whereas monocytes were four-fold increased (*** p < 0.0006) in the DCM compared with the sham group. Our data suggest that changes in white blood cell populations are modest, which is unique to other spinal cord pathologies, and precede the development of neurobehavioral symptoms.
- Published
- 2022
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28. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.
- Author
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Wang Z, Emmerich A, Pillon NJ, Moore T, Hemerich D, Cornelis MC, Mazzaferro E, Broos S, Ahluwalia TS, Bartz TM, Bentley AR, Bielak LF, Chong M, Chu AY, Berry D, Dorajoo R, Dueker ND, Kasbohm E, Feenstra B, Feitosa MF, Gieger C, Graff M, Hall LM, Haller T, Hartwig FP, Hillis DA, Huikari V, Heard-Costa N, Holzapfel C, Jackson AU, Johansson Å, Jørgensen AM, Kaakinen MA, Karlsson R, Kerr KF, Kim B, Koolhaas CM, Kutalik Z, Lagou V, Lind PA, Lorentzon M, Lyytikäinen LP, Mangino M, Metzendorf C, Monroe KR, Pacolet A, Pérusse L, Pool R, Richmond RC, Rivera NV, Robiou-du-Pont S, Schraut KE, Schulz CA, Stringham HM, Tanaka T, Teumer A, Turman C, van der Most PJ, Vanmunster M, van Rooij FJA, van Vliet-Ostaptchouk JV, Zhang X, Zhao JH, Zhao W, Balkhiyarova Z, Balslev-Harder MN, Baumeister SE, Beilby J, Blangero J, Boomsma DI, Brage S, Braund PS, Brody JA, Bruinenberg M, Ekelund U, Liu CT, Cole JW, Collins FS, Cupples LA, Esko T, Enroth S, Faul JD, Fernandez-Rhodes L, Fohner AE, Franco OH, Galesloot TE, Gordon SD, Grarup N, Hartman CA, Heiss G, Hui J, Illig T, Jago R, James A, Joshi PK, Jung T, Kähönen M, Kilpeläinen TO, Koh WP, Kolcic I, Kraft PP, Kuusisto J, Launer LJ, Li A, Linneberg A, Luan J, Vidal PM, Medland SE, Milaneschi Y, Moscati A, Musk B, Nelson CP, Nolte IM, Pedersen NL, Peters A, Peyser PA, Power C, Raitakari OT, Reedik M, Reiner AP, Ridker PM, Rudan I, Ryan K, Sarzynski MA, Scott LJ, Scott RA, Sidney S, Siggeirsdottir K, Smith AV, Smith JA, Sonestedt E, Strøm M, Tai ES, Teo KK, Thorand B, Tönjes A, Tremblay A, Uitterlinden AG, Vangipurapu J, van Schoor N, Völker U, Willemsen G, Williams K, Wong Q, Xu H, Young KL, Yuan JM, Zillikens MC, Zonderman AB, Ameur A, Bandinelli S, Bis JC, Boehnke M, Bouchard C, Chasman DI, Smith GD, de Geus EJC, Deldicque L, Dörr M, Evans MK, Ferrucci L, Fornage M, Fox C, Garland T Jr, Gudnason V, Gyllensten U, Hansen T, Hayward C, Horta BL, Hyppönen E, Jarvelin MR, Johnson WC, Kardia SLR, Kiemeney LA, Laakso M, Langenberg C, Lehtimäki T, Marchand LL, Magnusson PKE, Martin NG, Melbye M, Metspalu A, Meyre D, North KE, Ohlsson C, Oldehinkel AJ, Orho-Melander M, Pare G, Park T, Pedersen O, Penninx BWJH, Pers TH, Polasek O, Prokopenko I, Rotimi CN, Samani NJ, Sim X, Snieder H, Sørensen TIA, Spector TD, Timpson NJ, van Dam RM, van der Velde N, van Duijn CM, Vollenweider P, Völzke H, Voortman T, Waeber G, Wareham NJ, Weir DR, Wichmann HE, Wilson JF, Hevener AL, Krook A, Zierath JR, Thomis MAI, Loos RJF, and Hoed MD
- Subjects
- Actinin genetics, Cross-Sectional Studies, Exercise physiology, Humans, Leisure Activities, Genome-Wide Association Study, Sedentary Behavior
- Abstract
Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II
A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention., (© 2022. The Author(s).)- Published
- 2022
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29. Macrophage-based delivery of interleukin-13 improves functional and histopathological outcomes following spinal cord injury.
- Author
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Van Broeckhoven J, Erens C, Sommer D, Scheijen E, Sanchez S, Vidal PM, Dooley D, Van Breedam E, Quarta A, Ponsaerts P, Hendrix S, and Lemmens S
- Subjects
- Animals, Female, Humans, Interleukin-13 therapeutic use, Macrophages metabolism, Mice, Neuroblastoma, Neuroprotective Agents therapeutic use, Spinal Cord Injuries pathology
- Abstract
Background: Spinal cord injury (SCI) elicits a robust neuroinflammatory reaction which, in turn, exacerbates the initial mechanical damage. Pivotal players orchestrating this response are macrophages (Mφs) and microglia. After SCI, the inflammatory environment is dominated by pro-inflammatory Mφs/microglia, which contribute to secondary cell death and prevent regeneration. Therefore, reprogramming Mφ/microglia towards a more anti-inflammatory and potentially neuroprotective phenotype has gained substantial therapeutic interest in recent years. Interleukin-13 (IL-13) is a potent inducer of such an anti-inflammatory phenotype. In this study, we used genetically modified Mφs as carriers to continuously secrete IL-13 (IL-13 Mφs) at the lesion site., Methods: Mφs were genetically modified to secrete IL-13 (IL-13 Mφs) and were phenotypically characterized using qPCR, western blot, and ELISA. To analyze the therapeutic potential, the IL-13 Mφs were intraspinally injected at the perilesional area after hemisection SCI in female mice. Functional recovery and histopathological improvements were evaluated using the Basso Mouse Scale score and immunohistochemistry. Neuroprotective effects of IL-13 were investigated using different cell viability assays in murine and human neuroblastoma cell lines, human neurospheroids, as well as murine organotypic brain slice cultures., Results: In contrast to Mφs prestimulated with recombinant IL-13, perilesional transplantation of IL-13 Mφs promoted functional recovery following SCI in mice. This improvement was accompanied by reduced lesion size and demyelinated area. The local anti-inflammatory shift induced by IL-13 Mφs resulted in reduced neuronal death and fewer contacts between dystrophic axons and Mφs/microglia, suggesting suppression of axonal dieback. Using IL-4Rα-deficient mice, we show that IL-13 signaling is required for these beneficial effects. Whereas direct neuroprotective effects of IL-13 on murine and human neuroblastoma cell lines or human neurospheroid cultures were absent, IL-13 rescued murine organotypic brain slices from cell death, probably by indirectly modulating the Mφ/microglia responses., Conclusions: Collectively, our data suggest that the IL-13-induced anti-inflammatory Mφ/microglia phenotype can preserve neuronal tissue and ameliorate axonal dieback, thereby promoting recovery after SCI., (© 2022. The Author(s).)
- Published
- 2022
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30. Gut Microbiota-Brain Axis as a Potential Modulator of Psychological Stress after Spinal Cord Injury.
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Musleh-Vega S, Ojeda J, and Vidal PM
- Abstract
A growing body of evidence from preclinical and clinical studies has associated alterations of the gut microbiota-brain axis with the progression and development of a number of pathological conditions that also affect cognitive functions. Spinal cord injuries (SCIs) can be produced from traumatic and non-traumatic causes. It has been reported that SCIs are commonly associated with anxiety and depression-like symptoms, showing an incidence range between 11 and 30% after the injury. These psychological stress-related symptoms are associated with worse prognoses in SCIs and have been attributed to psychosocial stressors and losses of independence. Nevertheless, emotional and mental modifications after SCI could be related to changes in the volume of specific brain areas associated with information processing and emotions. Additionally, physiological modifications have been recognized as a predisposing factor for mental health depletion, including the development of gut dysbiosis. This condition of imbalance in microbiota composition has been shown to be associated with depression in clinical and pre-clinical models. Therefore, the understanding of the mechanisms underlying the relationship between SCIs, gut dysbiosis and psychological stress could contribute to the development of novel therapeutic strategies to improve SCI patients' quality of life.
- Published
- 2022
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31. Global urban environmental change drives adaptation in white clover.
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Santangelo JS, Ness RW, Cohan B, Fitzpatrick CR, Innes SG, Koch S, Miles LS, Munim S, Peres-Neto PR, Prashad C, Tong AT, Aguirre WE, Akinwole PO, Alberti M, Álvarez J, Anderson JT, Anderson JJ, Ando Y, Andrew NR, Angeoletto F, Anstett DN, Anstett J, Aoki-Gonçalves F, Arietta AZA, Arroyo MTK, Austen EJ, Baena-Díaz F, Barker CA, Baylis HA, Beliz JM, Benitez-Mora A, Bickford D, Biedebach G, Blackburn GS, Boehm MMA, Bonser SP, Bonte D, Bragger JR, Branquinho C, Brans KI, Bresciano JC, Brom PD, Bucharova A, Burt B, Cahill JF, Campbell KD, Carlen EJ, Carmona D, Castellanos MC, Centenaro G, Chalen I, Chaves JA, Chávez-Pesqueira M, Chen XY, Chilton AM, Chomiak KM, Cisneros-Heredia DF, Cisse IK, Classen AT, Comerford MS, Fradinger CC, Corney H, Crawford AJ, Crawford KM, Dahirel M, David S, De Haan R, Deacon NJ, Dean C, Del-Val E, Deligiannis EK, Denney D, Dettlaff MA, DiLeo MF, Ding YY, Domínguez-López ME, Dominoni DM, Draud SL, Dyson K, Ellers J, Espinosa CI, Essi L, Falahati-Anbaran M, Falcão JCF, Fargo HT, Fellowes MDE, Fitzpatrick RM, Flaherty LE, Flood PJ, Flores MF, Fornoni J, Foster AG, Frost CJ, Fuentes TL, Fulkerson JR, Gagnon E, Garbsch F, Garroway CJ, Gerstein AC, Giasson MM, Girdler EB, Gkelis S, Godsoe W, Golemiec AM, Golemiec M, González-Lagos C, Gorton AJ, Gotanda KM, Granath G, Greiner S, Griffiths JS, Grilo F, Gundel PE, Hamilton B, Hardin JM, He T, Heard SB, Henriques AF, Hernández-Poveda M, Hetherington-Rauth MC, Hill SJ, Hochuli DF, Hodgins KA, Hood GR, Hopkins GR, Hovanes KA, Howard AR, Hubbard SC, Ibarra-Cerdeña CN, Iñiguez-Armijos C, Jara-Arancio P, Jarrett BJM, Jeannot M, Jiménez-Lobato V, Johnson M, Johnson O, Johnson PP, Johnson R, Josephson MP, Jung MC, Just MG, Kahilainen A, Kailing OS, Kariñho-Betancourt E, Karousou R, Kirn LA, Kirschbaum A, Laine AL, LaMontagne JM, Lampei C, Lara C, Larson EL, Lázaro-Lobo A, Le JH, Leandro DS, Lee C, Lei Y, León CA, Lequerica Tamara ME, Levesque DC, Liao WJ, Ljubotina M, Locke H, Lockett MT, Longo TC, Lundholm JT, MacGillavry T, Mackin CR, Mahmoud AR, Manju IA, Mariën J, Martínez DN, Martínez-Bartolomé M, Meineke EK, Mendoza-Arroyo W, Merritt TJS, Merritt LEL, Migiani G, Minor ES, Mitchell N, Mohammadi Bazargani M, Moles AT, Monk JD, Moore CM, Morales-Morales PA, Moyers BT, Muñoz-Rojas M, Munshi-South J, Murphy SM, Murúa MM, Neila M, Nikolaidis O, Njunjić I, Nosko P, Núñez-Farfán J, Ohgushi T, Olsen KM, Opedal ØH, Ornelas C, Parachnowitsch AL, Paratore AS, Parody-Merino AM, Paule J, Paulo OS, Pena JC, Pfeiffer VW, Pinho P, Piot A, Porth IM, Poulos N, Puentes A, Qu J, Quintero-Vallejo E, Raciti SM, Raeymaekers JAM, Raveala KM, Rennison DJ, Ribeiro MC, Richardson JL, Rivas-Torres G, Rivera BJ, Roddy AB, Rodriguez-Muñoz E, Román JR, Rossi LS, Rowntree JK, Ryan TJ, Salinas S, Sanders NJ, Santiago-Rosario LY, Savage AM, Scheepens JF, Schilthuizen M, Schneider AC, Scholier T, Scott JL, Shaheed SA, Shefferson RP, Shepard CA, Shykoff JA, Silveira G, Smith AD, Solis-Gabriel L, Soro A, Spellman KV, Whitney KS, Starke-Ottich I, Stephan JG, Stephens JD, Szulc J, Szulkin M, Tack AJM, Tamburrino Í, Tate TD, Tergemina E, Theodorou P, Thompson KA, Threlfall CG, Tinghitella RM, Toledo-Chelala L, Tong X, Uroy L, Utsumi S, Vandegehuchte ML, VanWallendael A, Vidal PM, Wadgymar SM, Wang AY, Wang N, Warbrick ML, Whitney KD, Wiesmeier M, Wiles JT, Wu J, Xirocostas ZA, Yan Z, Yao J, Yoder JB, Yoshida O, Zhang J, Zhao Z, Ziter CD, Zuellig MP, Zufall RA, Zurita JE, Zytynska SE, and Johnson MTJ
- Subjects
- Cities, Genes, Plant, Genome, Plant, Hydrogen Cyanide metabolism, Rural Population, Trifolium genetics, Adaptation, Physiological, Biological Evolution, Ecosystem, Trifolium physiology, Urbanization
- Abstract
Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
- Published
- 2022
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32. IgM Immunoglobulin Influences Recovery after Cervical Spinal Cord Injury by Modulating the IgG Autoantibody Response.
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Ulndreaj A, Vidal PM, Forgione N, Hong J, and Fehlings MG
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- Animals, Autoantibodies, Immunoglobulin G, Immunoglobulin M, Mice, Recovery of Function, Spinal Cord, Cervical Cord, Spinal Cord Injuries
- Abstract
Spinal cord injury (SCI) results in the development of detrimental autoantibodies against the lesioned spinal cord. IgM immunoglobulin maintains homeostasis against IgG-autoantibody responses, but its effect on SCI recovery remains unknown. In the present study we investigated the role of IgM immunoglobulin in influencing recovery after SCI. To this end, we induced cervical SCI at the C6/C7 level in mice that lacked secreted IgM immunoglobulin [IgM-knock-out (KO)] and their wild-type (WT) littermate controls. Overall, the absence of secretory IgM resulted in worse outcomes as compared with WT mice with SCI. At two weeks after injury, IgM-KO mice had significantly more IgG antibodies, which fixed the complement system, in the injured spinal cord parenchyma. In addition to these findings, IgM-KO mice had more parenchymal T-lymphocytes as well as CD11b+ microglia/macrophages, which co-localized with myelin. At 10 weeks after injury, IgM-KO mice showed significant impairment in neurobehavioral recovery, such as deteriorated coordination, reduced hindlimb swing speed and print area. These neurobehavioral detriments were coupled with increased lesional tissue and myelin loss. Taken together, this study provides the first evidence for the importance of IgM immunoglobulin in modulating recovery after SCI and suggests that modulating IgM could be a novel therapeutic approach to enhance recovery after SCI., (Copyright © 2021 Ulndreaj et al.)
- Published
- 2021
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33. Gut Microbiota Interaction with the Central Nervous System throughout Life.
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Ojeda J, Ávila A, and Vidal PM
- Abstract
During the last years, accumulating evidence has suggested that the gut microbiota plays a key role in the pathogenesis of neurodevelopmental and neurodegenerative diseases via the gut-brain axis. Moreover, current research has helped to elucidate different communication pathways between the gut microbiota and neural tissues (e.g., the vagus nerve, tryptophan production, extrinsic enteric-associated neurons, and short chain fatty acids). On the other hand, altering the composition of gut microbiota promotes a state known as dysbiosis, where the balance between helpful and pathogenic bacteria is disrupted, usually stimulating the last ones. Herein, we summarize selected findings of the recent literature concerning the gut microbiome on the onset and progression of neurodevelopmental and degenerative disorders, and the strategies to modulate its composition in the search for therapeutical approaches, focusing mainly on animal models studies. Readers are advised that this is a young field, based on early studies, that is rapidly growing and being updated as the field advances.
- Published
- 2021
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34. Mir21 modulates inflammation and sensorimotor deficits in cervical myelopathy: data from humans and animal models.
- Author
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Laliberte AM, Karadimas SK, Vidal PM, Satkunendrarajah K, and Fehlings MG
- Abstract
Degenerative cervical myelopathy is a common condition resulting from chronic compression of the spinal cord by degenerating structures of the spine. Degenerative cervical myelopathy present a wide range of outcomes, and the biological factors underlying this variability are poorly understood. Previous studies have found elevated MIR21-5p in the sub-acute and chronic neuroinflammatory environment after spinal cord injury. As chronic spinal cord neuroinflammation is a major feature of degenerative cervical myelopathy, we hypothesized that MIR21-5p may be particularly relevant to disease pathobiology, and could serve as a potential biomarker. A prospective cohort study of 69 human degenerative cervical myelopathy patients (36 male:33 female) between the ages of 30 and 78 years was performed to identify the relationship between MIR21-5p expression, symptom severity and treatment outcomes. Results from this study identified a positive correlation between elevated plasma MIR21-5p expression, initial symptom severity and poor treatment outcomes. Subsequent validation of these relationships using a mouse model of degenerative cervical myelopathy identified a similar elevation of MIR21-5p expression at 6 and 12 weeks after onset, corresponding to moderate to severe neurological deficits. To further determine how MIR21-5p affects cervical myelopathy pathobiology, this mouse model was applied to a Mir21 knockout mouse line. Deletion of the Mir21 gene preserved locomotor function on rotarod and forced swim tests, but also resulted in increased nociception based on tail flick, Von Frey filament and electrophysiological testing. Critically, Mir21 knockout mice also had reduced spinal cord inflammation, demonstrated by the reduction of Iba1+ microglia by ∼50% relative to wild-type controls. In vitro experiments using primary microglial cultures confirmed that MIR21-5p expression was greatly increased after exposure to lipopolysaccharide (pro-inflammatory), Il4 (anti-inflammatory) and hypoxia. Mir21 knockout did not appear to alter the ability of microglia to respond to these stimuli, as expression of key pro- and anti-inflammatory response genes was not significantly altered. However, target prediction algorithms identified the IL6/STAT3 pathway as a potential downstream target of MIR21-5p, and subsequent in vitro testing found that expression of components of the IL6 receptor complex, Il6ra and Il6st, were significantly higher in Mir21 knockout microglia. In aggregate, these data show that Mir21 plays a role in the progression of motor deficits and neuroinflammatory modulation in degenerative cervical myelopathy. Given this role in neuroinflammation, and its association with poor patient outcomes, MIR21-5p represents a potential therapeutic target and a new marker for prognostication., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2021
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35. Amygdala inhibitory neurons as loci for translation in emotional memories.
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Shrestha P, Shan Z, Mamcarz M, Ruiz KSA, Zerihoun AT, Juan CY, Herrero-Vidal PM, Pelletier J, Heintz N, and Klann E
- Subjects
- Animals, Conditioning, Psychological, Cues, Eukaryotic Initiation Factor-2 metabolism, Eukaryotic Initiation Factor-4E metabolism, Fear physiology, Female, Heterotrimeric GTP-Binding Proteins metabolism, Male, Mice, Protein Biosynthesis, RNA Caps genetics, RNA Caps metabolism, Signal Transduction, Somatostatin metabolism, Amygdala cytology, Amygdala physiology, Emotions, Memory physiology, Neural Inhibition, Neurons physiology
- Abstract
To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger
1 . Survival also depends on suppressing the threat-response during a stimulus that predicts the absence of threat (safety)2-5 . An understanding of the biological substrates of emotional memories during a task in which animals learn to flexibly execute defensive responses to a threat-predictive cue and a safety cue is critical for developing treatments for memory disorders such as post-traumatic stress disorder5 . The centrolateral amygdala is an important node in the neuronal circuit that mediates defensive responses6-9 , and a key brain area for processing and storing threat memories. Here we applied intersectional chemogenetic strategies to inhibitory neurons in the centrolateral amygdala of mice to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). We show that de novo translation in somatostatin-expressing inhibitory neurons in the centrolateral amygdala is necessary for the long-term storage of conditioned-threat responses, whereas de novo translation in protein kinase Cδ-expressing inhibitory neurons in the centrolateral amygdala is necessary for the inhibition of a conditioned response to a safety cue. Our results provide insight into the role of de novo protein synthesis in distinct inhibitory neuron populations in the centrolateral amygdala during the consolidation of long-term memories.- Published
- 2020
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36. Computed Tomography Angiography in Peripheral Arterial Disease: Comparison of Three Image Acquisition Techniques to Optimize Vascular Enhancement-Randomized Controlled Trial.
- Author
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Rotzinger DC, Lu TL, Kawkabani A, Marques-Vidal PM, Fetz G, and Qanadli SD
- Abstract
Objectives: To prospectively compare three image acquisition techniques in lower extremity CT angiography: the "standard" anterograde technique (SA), the adaptive anterograde technique (AA), and the retrograde acquisition technique (RA). Materials and Methods: Sixty consecutive patients were prospectively enrolled and randomized into three acquisition groups: 20 patients were evaluated with SA, 20 with AA as described by Qanadli et al., and 20 with caudocranial acquisition from the feet to the abdominal aorta (RA). Quantitative image quality was assessed by measuring the intraluminal attenuation at different levels of interest, with a total of 536 levels. Qualitative image quality was assessed by two radiologists in consensus using a Likert scale to rate the arterial enhancement and venous return. For each patient and limb, the presence of occlusive or aneurysmal disease was documented. Results: In quantitative analysis, RA showed lower attenuation values than SA and AA ( p < 0.01). AA showed the highest and most homogeneous attenuation along the arterial tree. In qualitative analysis, AA had the lowest rate of non-diagnostic vascular segments (3.9%) compared to SA and RA (4.7 and 13.1%, respectively, p < 0.01). The influence of venous return was significantly different among the different techniques; venous contamination was particularly prevalent at the aortic level with RA (9.4% of patients, 0% with SA and AA, p < 0.01). The presence of stenosis or occlusion had no significant influence on the attenuation values across all levels and acquisition techniques. Conversely, the presence of aneurysmal disease had a significant effect on the luminal attenuation in AA (higher attenuation) and RA (lower attenuation) at the iliac ( p = 0.03 and 0.04, respectively) and femoral levels ( p = 0.02 and <0.01, respectively). Conclusion: Considering both quantitative and qualitative analysis, AA performed better than SA and RA, providing the highest percentage of optimal vascular enhancement. AA should be recommended as the technique of choice, specifically in the presence of aneurysmal disease. Alternatively, SA can be useful in case of renal failure, as the test bolus is unnecessary. Finally, the increasing availability of fast CT systems will likely overcome the limitations of RA., (Copyright © 2020 Rotzinger, Lu, Kawkabani, Marques-Vidal, Fetz and Qanadli.)
- Published
- 2020
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37. The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia.
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Vidal PM and Pacheco R
- Abstract
Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported in the prefrontal cortex of schizophrenic patients. Consequently, schizophrenia is associated with several cognitive and behavioral alterations. Of note, the immune system has been found to collaborate with the central nervous system in a number of cognitive and behavioral functions, which are dysregulated in schizophrenia. Moreover, emerging evidence has associated schizophrenia and inflammation. Importantly, different lines of evidence have shown dopamine as a major regulator of inflammation. In this regard, dopamine might exert strong regulation in the activity, migration, differentiation, and proliferation of immune cells that have been shown to contribute to cognitive functions, including T-cells, microglial cells, and peripheral monocytes. Thereby, alterations in dopamine levels associated to schizophrenia might affect inflammatory response of immune cells and consequently some behavioral functions, including reference memory, learning, social behavior, and stress resilience. Altogether these findings support the involvement of an active cross-talk between the dopaminergic and immune systems in the physiopathology of schizophrenia. In this review we summarize, integrate, and discuss the current evidence indicating the involvement of an altered dopaminergic regulation of immunity in schizophrenia., (Copyright © 2020 Vidal and Pacheco.)
- Published
- 2020
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38. Targeting the Dopaminergic System in Autoimmunity.
- Author
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Vidal PM and Pacheco R
- Subjects
- Animals, Autoimmune Diseases immunology, Autoimmunity physiology, Dopamine immunology, Dopamine metabolism, Humans, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases metabolism, Multiple Sclerosis drug therapy, Multiple Sclerosis immunology, Multiple Sclerosis metabolism, Parkinson Disease drug therapy, Parkinson Disease immunology, Parkinson Disease metabolism, Receptors, Dopamine immunology, Receptors, Dopamine metabolism, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Autoimmune Diseases drug therapy, Autoimmune Diseases metabolism, Autoimmunity drug effects, Dopamine Agents administration & dosage, Dopamine Agents metabolism, Drug Delivery Systems trends
- Abstract
Dopamine has emerged as a fundamental regulator of inflammation. In this regard, it has been shown that dopaminergic signalling pathways are key players promoting homeostasis between the central nervous system and the immune system. Dysregulation in the dopaminergic system affects both innate and adaptive immunity, contributing to the development of numerous autoimmune and inflammatory pathologies. This makes dopamine receptors interesting therapeutic targets for either the development of new treatments or repurposing of already available pharmacological drugs. Dopamine receptors are broadly expressed on different immune cells with multifunctional effects depending on the dopamine concentration available and the pattern of expression of five dopamine receptors displaying different affinities for dopamine. Thus, impaired dopaminergic signalling through different dopamine receptors may result in altered behaviour of immunity, contributing to the development and progression of autoimmune pathologies. In this review we discuss the current evidence involving the dopaminergic system in inflammatory bowel disease, multiple sclerosis and Parkinson's disease. In addition, we summarise and analyse the therapeutic approaches designed to attenuate disease development and progression by targeting the dopaminergic system. Graphical Abstract Targetting the dopaminergic system in autoimmunity. Effector T-cells (Teff) orchestrate inflamamtion involved in autoimmunity, whilst regulatory T-cells (Tregs) suppress Teff activity promoting tolerance to self-constituents. Dopamine has emerged as a key regulator of Teff and Tregs function, thereby dopamine receptors have becoming important therapeutic targets in autoimmune disorders, especially in those affecting the brain and the gut, where dopamine levels strongly change with inflammation.
- Published
- 2020
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39. The changes in systemic monocytes in humans undergoing surgical decompression for degenerative cervical myelopathy may influence clinical neurological recovery.
- Author
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Vidal PM, Ulndreaj A, Tetreault L, Hong J, and Fehlings MG
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Decompression, Surgical adverse effects, Female, Humans, Locomotion physiology, Male, Mice, Mice, Inbred C57BL, Middle Aged, Postoperative Complications blood, Postoperative Complications etiology, Prospective Studies, Random Allocation, Retrospective Studies, Cervical Vertebrae surgery, Decompression, Surgical trends, Monocytes metabolism, Recovery of Function physiology, Spinal Cord Diseases blood, Spinal Cord Diseases surgery
- Abstract
Background: Degenerative cervical myelopathy (DCM) is the most common cause of non-traumatic spinal cord injury worldwide. Surgical decompression is recommended as the preferred treatment strategy for DCM as it halts disease progression and improves neurologic symptoms. We previously demonstrated that neuroinflammation, including monocytes, plays a critical role in the pathobiology of DCM and in ischemic-reperfusion injury (IRI) following surgical decompression. Monocytes are able to enter the spinal cord and brain tissues due to damage to the blood spinal cord and blood brain barrier following injury. Studies have demonstrated that stroke patients and individuals undergoing hip replacement surgery have increased systemic levels of monocytes. Additionally, changes in the signalling responses of monocytes are associated with post-surgical recovery or with ischemic neural tissue damage. Herein, we investigated the role of systemic monocytes as a predictive biomarker for clinical recovery following decompressive surgery for DCM., Findings: There was a 2-fold increase in the number of monocytes in DCM patients at 24 h following decompression as compared to baseline levels, which was associated with a significant improvement in the modified Japanese Orthopedic Association scale (mJOA) at 6-months after surgery (p < .0001). In a mouse model of DCM, depleting acute monocytes reduced the non-classical (Ly6C
low ) subset from circulation (p < .05) and resulted in a 1.8-fold increase in CD11b expression in the spinal cord at 5 weeks following decompression. Acute monocyte depletion was accompanied by a modest decline in long-term overground locomotion, as evidenced by significantly reduced hindlimb swing speed., Conclusions: This work demonstrated that decompressive surgery leads to an acute increase in peripheral monocytes in human DCM patients, which is modestly associated with clinical recovery. We anticipate that this work could contribute to the implementation of routine measurements of blood monocyte subsets, their activation state, and production of cytokines following decompressive surgery. This information could help to select perioperative anti-inflammatory treatments that can enhance the beneficial effects of decompressive surgery and reduce the incidence of post-operative complications, while avoiding a reduction in systemic monocytes., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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40. Preoperative Clinical Factors Associated with Short-Stay Laparoscopic Appendectomy.
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Vuagniaux A, Gié O, Butti F, Marques-Vidal PM, Demartines N, and Mantziari S
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- Adolescent, Adult, Aged, Aged, 80 and over, Appendicitis surgery, Female, Humans, Logistic Models, Male, Middle Aged, Retrospective Studies, Young Adult, Appendectomy methods, Laparoscopy methods, Length of Stay
- Abstract
Background: Outpatient appendectomy for acute appendicitis is a feasible, yet not widely performed procedure, as there are no universally accepted criteria for patient selection. The aim of this study was to assess preoperative clinical factors associated with successful short-stay appendectomy (SSA) and establish a predictive score to help with patient selection., Methods: All consecutive laparoscopic appendectomies performed in our institution between January 2013 and June 2015 were retrospectively analyzed. Several preoperative clinical and biological variables were compared between patients with SSA, defined as a postoperative stay <24 h, and those needing inpatient care. Logistic regression analysis was used to identify variables independently associated with SSA, and these variables were then used to create a predictive score., Results: A total of 578 patients were included, 303 (53%) in the SSA group and 275 (48%) in the long-stay appendectomy (LSA) group. In multivariate analysis, male gender (OR 1.61, 95% CI 1.12-2.31, p = 0.010), ASA class I-II (OR 9.52, 95% CI 1.65-180.69, p = 0.037), absence of generalized guarding (OR 3.55, 95% CI 1.30-11.41, p = 0.019), C-reactive protein <100 mg/dl (OR 3.09, 95% CI 1.81-5.42, p < 0.001) and leukocyte count <20 g/l (OR 2.06, 95% CI 1.02-4.30, p = 0.046) were independently associated with SSA. These five parameters were used to construct a predictive score, whereby ≥17 (range 0-21) was defined as the optimal threshold to predict SSA with a high sensitivity (95.6%) and negative predictive value (82.2%)., Conclusions: A purely clinical predictive score based on five widely used preoperative parameters can be used to identify eligible patients for short-stay appendectomy.
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- 2019
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41. ADAM17-deficiency on microglia but not on macrophages promotes phagocytosis and functional recovery after spinal cord injury.
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Sommer D, Corstjens I, Sanchez S, Dooley D, Lemmens S, Van Broeckhoven J, Bogie J, Vanmierlo T, Vidal PM, Rose-John S, Gou-Fabregas M, and Hendrix S
- Subjects
- Animals, Disease Models, Animal, Female, Inflammation metabolism, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Phagocytosis immunology, Phagocytosis physiology, Recovery of Function physiology, ADAM17 Protein metabolism, Microglia metabolism, Spinal Cord Injuries metabolism
- Abstract
A disintegrin and metalloproteinase 17 (ADAM17) is the major sheddase involved in the cleavage of a plethora of cytokines, cytokine receptors and growth factors, thereby playing a substantial role in inflammatory and regenerative processes after central nervous system trauma. By making use of a hypomorphic ADAM17 knockin mouse model as well as pharmacological ADAM10/ADAM17 inhibitors, we showed that ADAM17-deficiency or inhibition significantly increases clearance of apoptotic cells, promotes axon growth and improves functional recovery after spinal cord injury (SCI) in mice. Microglia-specific ADAM17-knockout (ADAM17flox
+/+ -Cx3Cr1 Cre+/- ) mice also showed improved functional recovery similar to hypomorphic ADAM17 mice. In contrast, endothelial-specific (ADAM17flox+/+ -Cdh5Pacs Cre+/- ) and macrophage-specific (ADAM17flox+/+ -LysM Cre+/- ) ADAM17-knockout mice or bone marrow chimera with transplanted ADAM17-deficient macrophages, displayed no functional improvement compared to wild type mice. These data indicate that ADAM17 expression on microglia cells (and not on macrophages or endothelial cells) plays a detrimental role in inflammation and functional recovery after SCI., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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42. Endogenous Interleukin-10 Deficiency Exacerbates Vascular Pathology in Traumatic Cervical Spinal Cord Injury.
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Badner A, Vidal PM, Hong J, Hacker J, and Fehlings MG
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- Animals, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Spinal Cord Injuries diagnostic imaging, Vascular Diseases diagnostic imaging, Cervical Cord injuries, Interleukin-10 blood, Interleukin-10 deficiency, Spinal Cord Injuries blood, Vascular Diseases blood
- Abstract
Although the majority of traumatic spinal cord injuries (SCIs) take place at the cervical level, pre-clinical studies have been disproportionally focused on thoracic insults. With differences in anatomy, physiology, and immune response between spinal cord levels, there is evidence that injury pathophysiology may vary, requiring tailored treatment paradigms. Further, as only a few therapies have been successfully translated to the clinic, cervical models are increasingly recognized as essential for the characterization of trauma and therapy. Using a novel and clinically relevant cervical contusion-compression mouse model of bilateral incomplete injury, this study aimed to assess the role of interleukin10 (IL-10), a potent cytokine with broad anti-inflammatory effects, in SCI vascular pathology. While the effects of IL-10 loss have been previously evaluated, the vascular changes are poorly characterized. Here, using in vivo high-resolution ultrasound imaging, we demonstrate that IL-10 deficiency is associated with increased acute vascular damage. Importantly, the loss of endogenous IL-10 led to significant differences in the acute systemic response to SCI, specifically the circulating levels of IL-12 (p70), LIX (CXCL5), IL-1β, tumor necrosis factor (TNF)-α, and IL-6 relative to genotype sham controls. These effects also fostered modest impairments in long-term functional recovery, assessed by the Basso Mouse Scale, as well as histological outcomes.
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- 2019
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43. A step beyond the hygiene hypothesis-immune-mediated classes determined in a population-based study.
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Ajdacic-Gross V, Mutsch M, Rodgers S, Tesic A, Müller M, Seifritz E, Wagner EN, von Känel R, Landolt MA, Steinemann N, von Wyl V, Castelao E, Strippoli MF, Glaus J, Vandeleur C, Marques-Vidal PM, Vollenweider P, and Preisig M
- Subjects
- Adult, Aged, Aged, 80 and over, Asthma epidemiology, Asthma immunology, Child, Comorbidity, Female, Humans, Inflammation complications, Inflammation epidemiology, Inflammation immunology, Male, Middle Aged, Multiple Chronic Conditions epidemiology, Prevalence, Surveys and Questionnaires, Communicable Diseases epidemiology, Communicable Diseases immunology, Hygiene Hypothesis, Immune System Phenomena physiology, Latent Class Analysis
- Abstract
Background: Comorbidity patterns of childhood infections, atopic diseases, and adverse childhood experiences (ACE) are related to immune system programming conditions. The aim of this study was to make a step beyond the hygiene hypothesis and to comprehensively classify these patterns with latent class analysis (LCA). A second aim was to characterize the classes by associations with immunological, clinical, and sociodemographic variables., Methods: LCA was applied to data from the CoLaus|PsyCoLaus study (N = 4874, age range 35-82 years) separately for men and women. It was based on survey information on chickenpox, measles, mumps, rubella, herpes simplex, pertussis, scarlet fever, hay fever, asthma, eczema, urticaria, drug allergy, interparental violence, parental maltreatment, and trauma in early childhood. Subsequently, we examined how immune-mediated classes were reflected in leukocyte counts, inflammatory markers (IL-1β, IL-6, TNF-α, hsCRP), chronic inflammatory diseases, and mental disorders, and how they differed across social classes and birth cohorts., Results: LCA results with five classes were selected for further analysis. Latent classes were similar in both sexes and were labeled according to their associations as neutral, resilient, atopic, mixed (comprising infectious and atopic diseases), and ACE class. They came across with specific differences in biomarker levels. Mental disorders typically displayed increased lifetime prevalence rates in the atopic, the mixed, and the ACE classes, and decreased rates in the resilient class. The same patterns were apparent in chronic inflammatory diseases, except that the ACE class was relevant specifically in women but not in men., Conclusions: This is the first study to systematically determine immune-mediated classes that evolve early in life. They display characteristic associations with biomarker levels and somatic and psychiatric diseases occurring later in life. Moreover, they show different distributions across social classes and allow to better understand the mechanisms beyond the changes in the prevalence of chronic somatic and psychiatric diseases.
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- 2019
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44. Influence of Acute Physical Activity on Stress Reactivity in Obese and Normal Weight Children: A Randomized Controlled Trial.
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Messerli-Bürgy N, Horsch A, Schindler C, Boichat A, Kriemler S, Munsch S, Crottet B, Marquez-Vidal PM, Borghini A, and Puder JJ
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- Body Mass Index, Body Weight, Child, Exercise Therapy, Female, Humans, Hydrocortisone analysis, Male, Overweight complications, Overweight physiopathology, Overweight psychology, Pediatric Obesity complications, Pediatric Obesity physiopathology, Pediatric Obesity psychology, Saliva chemistry, Saliva metabolism, Stress, Psychological complications, Stress, Psychological physiopathology, Time Factors, Exercise physiology, Hydrocortisone metabolism, Ideal Body Weight physiology, Overweight metabolism, Pediatric Obesity metabolism, Stress, Psychological metabolism
- Abstract
Objective: Physical activity (PA) may influence acute stress reactivity in children differently depending on their weight. This randomized controlled trial investigated the impact of acute PA and of BMI status (overweight/obese (OB/OW) and normal weight (NW) on stress reactivity., Method: 50 prepubertal children (24 OW/OB and 26 NW) were randomly assigned to the PA or sedentary arm (SED) for 30 min followed by a stress task. Salivary cortisol, blood pressure (BP), and heart rate (HR) were measured., Results: An interaction effect between the randomization arms and weight status on salivary cortisol was found after the stress task (p = 0.04). Cortisol increased in the SED, but not in the PA arm (p = 0.004 for differences in time course) of NW children. Time course did not differ between both arms in OW/OB children (p = 0.7). OW/OB SED children had a flat cortisol course, and levels were reduced compared to the NW SED or the OW/OB PA children (p ≤ 0.03). Systolic BP increased only in the SED arm (p = 0.01). HR was higher in the PA than in the SED arm during stress (p < 0.001) and showed different time courses (p = 0.006)., Conclusion: PA impacted on acute stress reactivity and influenced stress reactivity differently in NW and OW/OB children., (© 2019 The Author(s) Published by S. Karger AG, Basel.)
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- 2019
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45. GLI 2012 equations define few spirometric anomalies in the general population: the PneumoLaus study.
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Lenoir A, Fitting JW, Marques-Vidal PM, Vollenweider P, and Nicod LP
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- Aged, Cohort Studies, Female, Follow-Up Studies, Forced Expiratory Volume physiology, Humans, Lung Diseases, Obstructive diagnosis, Male, Middle Aged, Prospective Studies, Reference Values, Spirometry standards, Switzerland epidemiology, Tidal Volume physiology, Vital Capacity, Lung physiology, Lung Diseases, Obstructive epidemiology, Lung Diseases, Obstructive physiopathology, Population Surveillance methods, Spirometry methods
- Abstract
Background: Reduced lung function predicts increased mortality, but its prevalence may vary depending on definition considered, use of bronchodilation and applied reference values. We aimed to assess lung function abnormalities in Lausanne, Switzerland, and their association with clinical history., Methods: In a general population sample, spirometry was performed and bronchodilation applied if the ratio forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC) or the FVC was below the lower limit of normal (LLN) according to Global Lung Function Initiative 2012 references. Results for FEV1/FVC according to the LLN were compared to the 0.7 fixed ratio. Respiratory risk factors, symptoms and self-reported respiratory diagnoses were recorded through a questionnaire., Results: Out of the 3342 included subjects, 3.8% had chronic obstruction and 2.5% reversible obstruction when using the LLN; possible lung restriction alone was present in 1.8%, and associated with chronic obstruction in 0.4%. Ever smokers had a higher prevalence of abnormal spirometry, chronic obstruction and reversible obstruction; there was no difference with regard to possible restriction. Overall, chronic airway obstruction was found in 8.9% of current smokers, 4.6% of former smokers and 1.5% of never smokers. Only one third of participants with chronic obstruction were aware of a respiratory disease., Conclusion: Prevalence of abnormal lung function in the population of Lausanne is low. This may be due to a low rate of ever-smokers, the application of a full bronchodilation dose, but also to inherent characteristics of this population.
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- 2018
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46. Methylprednisolone treatment enhances early recovery following surgical decompression for degenerative cervical myelopathy without compromise to the systemic immune system.
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Vidal PM, Ulndreaj A, Badner A, Hong J, and Fehlings MG
- Subjects
- Analysis of Variance, Animals, Blood Cells drug effects, Cytokines metabolism, Disease Models, Animal, Female, Flow Cytometry, Gait Disorders, Neurologic etiology, Gait Disorders, Neurologic therapy, Laser-Doppler Flowmetry, Leukocytes drug effects, Mice, Mice, Inbred C57BL, Neuroglia drug effects, Neuroglia pathology, Spinal Cord metabolism, Spinal Cord Compression complications, Time Factors, Anti-Inflammatory Agents therapeutic use, Decompression, Surgical methods, Methylprednisolone therapeutic use, Recovery of Function drug effects, Spinal Cord Compression drug therapy, Spinal Cord Compression surgery
- Abstract
Background: Degenerative cervical myelopathy (DCM) is caused by degenerative or congenital changes to the discs and soft tissues of the cervical spine, which leads to chronic compression of the spinal cord. The current treatment for moderate to severe DCM consists of surgical decompression, which, while effective in most cases, can result in neuroinflammation and spinal cord reperfusion injury, leading to perioperative neurological complications and suboptimal neurological recovery. The primary objective of this study was to assess, in a translationally relevant animal model of DCM, the efficacy of perioperative methylprednisolone (MP) in enhancing neurological recovery and to evaluate its effect on the inflammatory response following decompression., Methods: DCM was induced in C57BL/6 mice. Briefly, an aromatic polyether material was implanted underneath the C5-C6 laminae to cause progressive compression of the cervical spinal cord due to focal ossification. Decompressive surgery was undertaken at 12 weeks post initial biomaterial implantation. Animals received one dose of MP (30 mg/kg) or vehicle 30 min before decompression and at 2 weeks after decompression. Acute analysis of secreted cytokines and spinal cord microvasculature was complemented with immunohistochemistry for glial and neuronal cell markers. Locomotor outcomes were measured using the CatWalk system. The composition of circulating white blood cells was analyzed by flow cytometry., Results: A single dose of MP before decompression significantly sped locomotor recovery (*p < 0.05) and reduced the incidence of perioperative motor complications, without affecting the composition of circulating white blood cells. Histological assessment of the spinal cord showed significant neuronal preservation and a modest reduction in parenchymal inflammation., Conclusions: Our data suggest that MP reduces perioperative neurological complications following decompressive surgery for DCM by protecting neurons from inflammation, without compromising the composition of circulating immune cells. We propose that MP, which is commonly used for neurological disorders including spinal cord injury, be considered as a perioperative adjunct to decompressive surgery to attenuate neurological complications.
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- 2018
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47. Cysteine-rich angiogenic inducer 61 (Cyr61): a novel soluble biomarker of acute myocardial injury improves risk stratification after acute coronary syndromes.
- Author
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Klingenberg R, Aghlmandi S, Liebetrau C, Räber L, Gencer B, Nanchen D, Carballo D, Akhmedov A, Montecucco F, Zoller S, Brokopp C, Heg D, Jüni P, Marti Soler H, Marques-Vidal PM, Vollenweider P, Dörr O, Rodondi N, Mach F, Windecker S, Landmesser U, von Eckardstein A, Hamm CW, Matter CM, and Lüscher TF
- Subjects
- Biomarkers metabolism, Case-Control Studies, Coronary Thrombosis diagnosis, Female, Humans, Male, Middle Aged, Myocardial Infarction diagnosis, Prognosis, Prospective Studies, Risk Assessment methods, Acute Coronary Syndrome diagnosis, Coronary Artery Disease diagnosis, Cysteine-Rich Protein 61 metabolism
- Abstract
Aims: We aimed to identify a novel biomarker involved in the early events leading to an acute coronary syndrome (ACS) and evaluate its role in diagnosis and risk stratification., Methods and Results: Biomarker identification was based on gene expression profiling. In coronary thrombi of ACS patients, cysteine-rich angiogenic inducer 61 (Cyr61, CCN1) gene transcripts were highly up-regulated compared with peripheral mononuclear cells. In a murine ischaemia-reperfusion model (I/R), myocardial Cyr61 expression was markedly increased compared with the controls. Cyr61 levels were determined in human serum using an enzyme-linked immunosorbent assay. Cohorts of ACS (n = 2168) referred for coronary angiography, stable coronary artery disease (CAD) (n = 53), and hypertrophic obstructive cardiomyopathy (HOCM) patients (n = 15) served to identify and evaluate the diagnostic and prognostic performance of the biomarker. Cyr61 was markedly elevated in ST-elevation myocardial infarction patients compared with non-ST-elevation myocardial infarction/unstable angina or stable CAD patients, irrespective of whether coronary thrombi were present. Cyr61 was rapidly released after occlusion of a septal branch in HOCM patients undergoing transcoronary ablation of septal hypertrophy. Cyr61 improved risk stratification for all-cause mortality when added to the reference GRACE risk score at 30 days (C-statistic 0.88 to 0.89, P = 0.001) and 1 year (C-statistic 0.77 to 0.80, P < 0.001) comparable to high-sensitivity troponin T (30 days: 0.88 to 0.89, P < 0.001; 1 year: 0.77 to 0.79, P < 0.001). Similar results were obtained for the composite endpoint of all-cause mortality or myocardial infarction. Conversely, in a population-based case-control cohort (n = 362), Cyr61 was not associated with adverse outcome., Conclusion: Cyr61 is a novel early biomarker reflecting myocardial injury that improves risk stratification in ACS patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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48. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.
- Author
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Graff M, Scott RA, Justice AE, Young KL, Feitosa MF, Barata L, Winkler TW, Chu AY, Mahajan A, Hadley D, Xue L, Workalemahu T, Heard-Costa NL, den Hoed M, Ahluwalia TS, Qi Q, Ngwa JS, Renström F, Quaye L, Eicher JD, Hayes JE, Cornelis M, Kutalik Z, Lim E, Luan J, Huffman JE, Zhang W, Zhao W, Griffin PJ, Haller T, Ahmad S, Marques-Vidal PM, Bien S, Yengo L, Teumer A, Smith AV, Kumari M, Harder MN, Justesen JM, Kleber ME, Hollensted M, Lohman K, Rivera NV, Whitfield JB, Zhao JH, Stringham HM, Lyytikäinen LP, Huppertz C, Willemsen G, Peyrot WJ, Wu Y, Kristiansson K, Demirkan A, Fornage M, Hassinen M, Bielak LF, Cadby G, Tanaka T, Mägi R, van der Most PJ, Jackson AU, Bragg-Gresham JL, Vitart V, Marten J, Navarro P, Bellis C, Pasko D, Johansson Å, Snitker S, Cheng YC, Eriksson J, Lim U, Aadahl M, Adair LS, Amin N, Balkau B, Auvinen J, Beilby J, Bergman RN, Bergmann S, Bertoni AG, Blangero J, Bonnefond A, Bonnycastle LL, Borja JB, Brage S, Busonero F, Buyske S, Campbell H, Chines PS, Collins FS, Corre T, Smith GD, Delgado GE, Dueker N, Dörr M, Ebeling T, Eiriksdottir G, Esko T, Faul JD, Fu M, Færch K, Gieger C, Gläser S, Gong J, Gordon-Larsen P, Grallert H, Grammer TB, Grarup N, van Grootheest G, Harald K, Hastie ND, Havulinna AS, Hernandez D, Hindorff L, Hocking LJ, Holmens OL, Holzapfel C, Hottenga JJ, Huang J, Huang T, Hui J, Huth C, Hutri-Kähönen N, James AL, Jansson JO, Jhun MA, Juonala M, Kinnunen L, Koistinen HA, Kolcic I, Komulainen P, Kuusisto J, Kvaløy K, Kähönen M, Lakka TA, Launer LJ, Lehne B, Lindgren CM, Lorentzon M, Luben R, Marre M, Milaneschi Y, Monda KL, Montgomery GW, De Moor MHM, Mulas A, Müller-Nurasyid M, Musk AW, Männikkö R, Männistö S, Narisu N, Nauck M, Nettleton JA, Nolte IM, Oldehinkel AJ, Olden M, Ong KK, Padmanabhan S, Paternoster L, Perez J, Perola M, Peters A, Peters U, Peyser PA, Prokopenko I, Puolijoki H, Raitakari OT, Rankinen T, Rasmussen-Torvik LJ, Rawal R, Ridker PM, Rose LM, Rudan I, Sarti C, Sarzynski MA, Savonen K, Scott WR, Sanna S, Shuldiner AR, Sidney S, Silbernagel G, Smith BH, Smith JA, Snieder H, Stančáková A, Sternfeld B, Swift AJ, Tammelin T, Tan ST, Thorand B, Thuillier D, Vandenput L, Vestergaard H, van Vliet-Ostaptchouk JV, Vohl MC, Völker U, Waeber G, Walker M, Wild S, Wong A, Wright AF, Zillikens MC, Zubair N, Haiman CA, Lemarchand L, Gyllensten U, Ohlsson C, Hofman A, Rivadeneira F, Uitterlinden AG, Pérusse L, Wilson JF, Hayward C, Polasek O, Cucca F, Hveem K, Hartman CA, Tönjes A, Bandinelli S, Palmer LJ, Kardia SLR, Rauramaa R, Sørensen TIA, Tuomilehto J, Salomaa V, Penninx BWJH, de Geus EJC, Boomsma DI, Lehtimäki T, Mangino M, Laakso M, Bouchard C, Martin NG, Kuh D, Liu Y, Linneberg A, März W, Strauch K, Kivimäki M, Harris TB, Gudnason V, Völzke H, Qi L, Järvelin MR, Chambers JC, Kooner JS, Froguel P, Kooperberg C, Vollenweider P, Hallmans G, Hansen T, Pedersen O, Metspalu A, Wareham NJ, Langenberg C, Weir DR, Porteous DJ, Boerwinkle E, Chasman DI, Abecasis GR, Barroso I, McCarthy MI, Frayling TM, O'Connell JR, van Duijn CM, Boehnke M, Heid IM, Mohlke KL, Strachan DP, Fox CS, Liu CT, Hirschhorn JN, Klein RJ, Johnson AD, Borecki IB, Franks PW, North KE, Cupples LA, Loos RJF, and Kilpeläinen TO
- Abstract
[This corrects the article DOI: 10.1371/journal.pgen.1006528.].
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- 2017
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49. Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy.
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Vidal PM, Karadimas SK, Ulndreaj A, Laliberte AM, Tetreault L, Forner S, Wang J, Foltz WD, and Fehlings MG
- Abstract
Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.
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- 2017
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50. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.
- Author
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Graff M, Scott RA, Justice AE, Young KL, Feitosa MF, Barata L, Winkler TW, Chu AY, Mahajan A, Hadley D, Xue L, Workalemahu T, Heard-Costa NL, den Hoed M, Ahluwalia TS, Qi Q, Ngwa JS, Renström F, Quaye L, Eicher JD, Hayes JE, Cornelis M, Kutalik Z, Lim E, Luan J, Huffman JE, Zhang W, Zhao W, Griffin PJ, Haller T, Ahmad S, Marques-Vidal PM, Bien S, Yengo L, Teumer A, Smith AV, Kumari M, Harder MN, Justesen JM, Kleber ME, Hollensted M, Lohman K, Rivera NV, Whitfield JB, Zhao JH, Stringham HM, Lyytikäinen LP, Huppertz C, Willemsen G, Peyrot WJ, Wu Y, Kristiansson K, Demirkan A, Fornage M, Hassinen M, Bielak LF, Cadby G, Tanaka T, Mägi R, van der Most PJ, Jackson AU, Bragg-Gresham JL, Vitart V, Marten J, Navarro P, Bellis C, Pasko D, Johansson Å, Snitker S, Cheng YC, Eriksson J, Lim U, Aadahl M, Adair LS, Amin N, Balkau B, Auvinen J, Beilby J, Bergman RN, Bergmann S, Bertoni AG, Blangero J, Bonnefond A, Bonnycastle LL, Borja JB, Brage S, Busonero F, Buyske S, Campbell H, Chines PS, Collins FS, Corre T, Smith GD, Delgado GE, Dueker N, Dörr M, Ebeling T, Eiriksdottir G, Esko T, Faul JD, Fu M, Færch K, Gieger C, Gläser S, Gong J, Gordon-Larsen P, Grallert H, Grammer TB, Grarup N, van Grootheest G, Harald K, Hastie ND, Havulinna AS, Hernandez D, Hindorff L, Hocking LJ, Holmens OL, Holzapfel C, Hottenga JJ, Huang J, Huang T, Hui J, Huth C, Hutri-Kähönen N, James AL, Jansson JO, Jhun MA, Juonala M, Kinnunen L, Koistinen HA, Kolcic I, Komulainen P, Kuusisto J, Kvaløy K, Kähönen M, Lakka TA, Launer LJ, Lehne B, Lindgren CM, Lorentzon M, Luben R, Marre M, Milaneschi Y, Monda KL, Montgomery GW, De Moor MHM, Mulas A, Müller-Nurasyid M, Musk AW, Männikkö R, Männistö S, Narisu N, Nauck M, Nettleton JA, Nolte IM, Oldehinkel AJ, Olden M, Ong KK, Padmanabhan S, Paternoster L, Perez J, Perola M, Peters A, Peters U, Peyser PA, Prokopenko I, Puolijoki H, Raitakari OT, Rankinen T, Rasmussen-Torvik LJ, Rawal R, Ridker PM, Rose LM, Rudan I, Sarti C, Sarzynski MA, Savonen K, Scott WR, Sanna S, Shuldiner AR, Sidney S, Silbernagel G, Smith BH, Smith JA, Snieder H, Stančáková A, Sternfeld B, Swift AJ, Tammelin T, Tan ST, Thorand B, Thuillier D, Vandenput L, Vestergaard H, van Vliet-Ostaptchouk JV, Vohl MC, Völker U, Waeber G, Walker M, Wild S, Wong A, Wright AF, Zillikens MC, Zubair N, Haiman CA, Lemarchand L, Gyllensten U, Ohlsson C, Hofman A, Rivadeneira F, Uitterlinden AG, Pérusse L, Wilson JF, Hayward C, Polasek O, Cucca F, Hveem K, Hartman CA, Tönjes A, Bandinelli S, Palmer LJ, Kardia SLR, Rauramaa R, Sørensen TIA, Tuomilehto J, Salomaa V, Penninx BWJH, de Geus EJC, Boomsma DI, Lehtimäki T, Mangino M, Laakso M, Bouchard C, Martin NG, Kuh D, Liu Y, Linneberg A, März W, Strauch K, Kivimäki M, Harris TB, Gudnason V, Völzke H, Qi L, Järvelin MR, Chambers JC, Kooner JS, Froguel P, Kooperberg C, Vollenweider P, Hallmans G, Hansen T, Pedersen O, Metspalu A, Wareham NJ, Langenberg C, Weir DR, Porteous DJ, Boerwinkle E, Chasman DI, Abecasis GR, Barroso I, McCarthy MI, Frayling TM, O'Connell JR, van Duijn CM, Boehnke M, Heid IM, Mohlke KL, Strachan DP, Fox CS, Liu CT, Hirschhorn JN, Klein RJ, Johnson AD, Borecki IB, Franks PW, North KE, Cupples LA, Loos RJF, and Kilpeläinen TO
- Subjects
- Adiposity physiology, Body Mass Index, Epigenomics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Obesity physiopathology, Waist Circumference, Waist-Hip Ratio, Adiposity genetics, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Exercise, Obesity genetics
- Abstract
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
- Published
- 2017
- Full Text
- View/download PDF
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