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2. Evidence for dissociation of insulin stimulation of blood flow and glucose uptake in human skeletal muscle: studies using [15O]H2O, [18F]fluoro-2-deoxy-D-glucose, and positron emission tomography

Author

Raitakari, M., Nuutila, P., Ruotsalainen, U., Laine, H., Teräs, M., Hidehiro Iida, Mäkimattila, S., Utriainen, T., Oikonen, V., Sipilä, H., Haaparanta, M., Solin, O., Wegelius, U., Knuuti, J., and Yki-Järvinen, H.

Subjects
Endocrinology, Diabetes and Metabolism, Internal Medicine
Published
1996

3. Insulin increases blood volume in human skeletal muscle: studies using [15O]CO and positron emission tomography

Author

Raitakari M, Juhani Knuuti, Ruotsalainen U, Laine H, Mäkeä P, Teräs M, Sipilä H, Niskanen T, Ot, Raitakari, Iida H, Härkönen R, Wegelius U, Yki-Järvinen H, and Nuutila P

Subjects
Adult, Male, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Vasodilation, Blood volume, Oxygen Radioisotopes, Reference Values, Physiology (medical), Internal medicine, medicine, Hyperinsulinemia, Humans, Insulin, Positron emission, Muscle, Skeletal, Carbon Monoxide, Blood Volume, medicine.diagnostic_test, Chemistry, Skeletal muscle, Blood flow, medicine.disease, Endocrinology, medicine.anatomical_structure, Positron emission tomography, Tomography, Emission-Computed
Abstract

High insulin concentrations increase blood flow in the leg, but it is unknown whether this effect is associated with a change in muscle blood volume. In the present study, we used positron emission tomography combined with inhalation of [15O]carbon monoxide to quantitate the effect of insulin on skeletal muscle blood volume in humans. The reproducibility of the method was determined from two consecutive measurements performed in the basal state in five normal subjects. The coefficient of variation of the repeated measurements was 3.0 +/- 1.8%. In 14 normal subjects [age 35 +/- 3 yr, body mass index 24.9 +/- 1.3 (SE) kg/m2], skeletal muscle blood volume was determined in the femoral region in the basal state and during euglycemic hyperinsulinemia (serum insulin 3,200 +/- 190 pmol/l). The mean muscle blood volume was 3.3 +/- 0.1 ml/0.1 kg muscle in the basal state. Insulin increased muscle blood volume by 9 +/- 2% to 3.6 +/- 0.2 ml/0.1 kg muscle (P < 0.01). The rate of whole body glucose uptake was 53 +/- 6 mumol.kg-1.min-1 and correlated with muscle blood volume during insulin stimulation (r = 0.65, P < 0.02). We conclude that high insulin concentrations exert a true vasodilatory effect in human skeletal muscle.

Published
1995

5. T cells in myeloma

Author

Raitakari, M., primary, Brown, R. D., additional, Gibson, J., additional, and Joshua, D. E., additional

Published
2003
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9. Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus.

Author

Utriainen, T, primary, Nuutila, P, additional, Takala, T, additional, Vicini, P, additional, Ruotsalainen, U, additional, Rönnemaa, T, additional, Tolvanen, T, additional, Raitakari, M, additional, Haaparanta, M, additional, Kirvelä, O, additional, Cobelli, C, additional, and Yki-Järvinen, H, additional

Published
1997
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10. Relationship between limb and muscle blood flow in man.

Author

Raitakari, M, primary, Nuutila, P, additional, Ruotsalainen, U, additional, Teräs, M, additional, Eronen, E, additional, Laine, H, additional, Raitakari, O T, additional, Iida, H, additional, Knuuti, M J, additional, and Yki-Järvinen, H, additional

Published
1996
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11. Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography.

Author

Nuutila, P, primary, Raitakari, M, additional, Laine, H, additional, Kirvelä, O, additional, Takala, T, additional, Utriainen, T, additional, Mäkimattila, S, additional, Pitkänen, O P, additional, Ruotsalainen, U, additional, Iida, H, additional, Knuuti, J, additional, and Yki-Järvinen, H, additional

Published
1996
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14. Decreased blood flow but unaltered insulin sensitivity of glucose uptake in skeletal muscle of chronic smokers

Author

Rönnemaa, E.M., Rönnemaa, T., Utriainen, T., Raitakari, M., Laine, H., Takala, T., Pitkänen, O.-P., Kirvelä, O., Knuuti, J., and Nuutila, P.

Abstract

Chronic cigarette smoking is associated with dysfunction of the vascular endothelium. Smokers have also been shown to be insulin-resistant, at least in some studies. Since insulin-induced vasodilation is dependent on endothelial cell nitric oxide (NO) synthesis, we tested the hypothesis that decreased skeletal muscle blood flow causes insulin resistance in smokers. We studied 37 young normotensive normolipidemic nondiabetic men, of which 14 were smokers and 23 lifelong nonsmokers. The groups were similar with respect to age, body mass index (BMI), and maximal oxygen uptake (Vo2max). Basal and insulin-stimulated femoral muscle blood flow was measured using [15O]H2O and insulin-stimulated muscle glucose uptake using [18F]fluoro-2-deoxy-d-glucose ([18F]FDG) and positron emission tomography (PET). Whole-body glucose uptake was measured using the hyperinsulinemic (insulin infusion 5 mU/kg · min)-euglycemic clamp technique. In the basal state, muscle blood flow was 51% lower in smokers (17 ± 3 mL/kg muscle · min) versus nonsmokers (35 ± 17 mL/kg · min, P< .0001). Insulin increased muscle blood flow comparably in both groups; the mean rate of insulin-stimulated blood flow was 30 ± 10 and 55 ± 38 mL/kg · min (P= .049), respectively. Whole-body and skeletal muscle glucose uptake were similar in both groups during insulin infusion. We conclude that muscle blood flow is lower in chronic smokers compared with nonsmokers under both fasting and hyperinsulinemic conditions. The insulin-induced increase in muscle blood flow and insulin-stimulated glucose uptake appear normal, suggesting that the vasodilatory and metabolic effects of insulin are intact in smokers and the reduced muscle blood flow per se does not cause insulin resistance in these subjects.

Published
1999
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15. Quantitative blood flow measurement of skeletal muscle using oxygen-15-water and PET

Author

Ruotsalainen, U., Raitakari, M., Nuutila, P., Oikonen, V., Sipilä, H., Teräs, M., Juhani Knuuti, Bloomfield, P. M., and Iida, H.

Subjects
Adult, Male, Oxygen Radioisotopes, Regional Blood Flow, Autoradiography, Humans, Water, Femur, Models, Theoretical, Muscle, Skeletal, Tomography, Emission-Computed
Abstract

The aim of the present study was to evaluate quantitation of muscle blood flow using [15O]H2O and PET.The autoradiographic (ARG) and the steady-state methods using PET were used to measure femoral muscle blood flow. A simulation study was performed to examine the errors due to contamination of radioactivity in the blood content in muscle tissue, statistical noise and delay and the dispersion of the input curve in the ARG method. Five separate paired muscle blood flow examinations were carried out for comparison of the ARG and the steady-state techniques, including measurement of muscle blood volume in each subject. To obtain the normal range for resting muscle blood flow, additional measurements with the ARG method were performed in 16 normal subjects.When the integration time in ARG was increased to 200-300 sec, the errors due to arterial blood volume, statistical noise, delay and dispersion of the input curve were significantly reduced. Muscle blood flow values in the ARG (200 sec) and the steady-state studies were in good agreement, and each provided an estimated accuracy of 5%. Resting muscle blood flow averaged 3.12 +/- 1.55 ml/min.100 g muscle (range 1.43-6.72 ml/min.100 g muscle, n = 18).The ARG and the steady-state methods provided consistent blood flow values for skeletal muscle when a long tissue integration time (or = 200 sec) was applied in the ARG study. Based on the lower effective radiation dose and the shorter total scan duration, the ARG method is favored over the steady-state method in the measurement of muscle blood flow.

17. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author

Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar

Subjects
Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Published
2023

18. Use of point-of-care testing and early assessment model reduces length of stay for ambulatory patients in an emergency department.

Author

Kankaanpää M, Raitakari M, Muukkonen L, Gustafsson S, Heitto M, Palomäki A, Suojanen K, and Harjola VP

Subjects
Adult, Female, Finland, Follow-Up Studies, Humans, Male, Patient Discharge trends, Prospective Studies, Time Factors, Emergency Service, Hospital statistics & numerical data, Length of Stay trends, Outpatients, Point-of-Care Testing statistics & numerical data
Abstract

Background: To assess whether the use of point-of-care testing (POCT) and early assessment team (EAT) model shortens emergency department (ED) length of stay (LOS)., Methods: This prospective, observational study with comparison between three study periods was performed in three phases in a metropolitan ED with 57,000 annual visits. Data were collected from adult ambulatory patients who were discharged home. Phase 1 served as a control (n = 1559 in one month). In phase 2, a comprehensive POCT panel including complete blood count, sodium, potassium, glucose, C-reactive protein, creatinine, alkaline phosphatase, alanine aminotransferase, bilirubin, amylase, and D-dimer was launched (n = 1442 in one month). In phase 3 (n = 3356 in subsequent two months), POCT approach continued. In addition, the working process was changed by establishing an EAT consisting of an emergency medicine resident and a nurse. The team operated from 12 noon to 10 p.m. was. The primary outcome was LOS (hh:mm) in the ED. Waiting times for patients requiring laboratory testing were analysed also, including time from admission to laboratory blood sampling (A2S interval), time from blood sampling to results ready (S2R interval) and time from results to discharge (R2D interval)., Results: Median LOS of patients requiring laboratory tests in phase 1 was 3:51 (95 % confidence interval 03:38-04:04). During phase 2, introduction of POCT reduced median LOS by 29 min to 03:22 (03:12-03:31, p = 0.000). In phase 3, the EAT model reduced median LOS further by 17 min to 03:05 (02:59-03:12, p = 0.033). Altogether, the process was expedited by 46 min compared with the phase 1. Surprisingly, A2S interval was unaffected by the interventions among all patients needing laboratory testing. In comparison to phase 1, shortening of S2R interval was observed in phase 2 and 3, and that of R2D interval in all patients with laboratory assessments in phase 3., Discussion: The present study included adult ambulatory patients and is the first one to examine the impact of comprehensive POC test panel, first alone and then with additional process change. As a result, LOS was reduced significantly for patients needing laboratory tests. Considerable shortening in LOS came from introduction of POCT, and EAT process decreased the LOS further. We used a comprehensive POC test panel in order to maximise the patient population benefiting from the positive impacts of POC on laboratory turnaround time and length of stay. In EAT, diverse setups exist, and these differences affect the interpretation of results. The process changes in phase 3 were done by rearranging work shifts and no extra resources were added. Regarding to staffing the process improvement was thus cost neutral., Conclusions: The advantage of POCT alone compared with central laboratory seemed to lie in shorter waiting times for results and earlier discharge home. Moreover, POCT and EAT model shorten LOS additively compared with conventional processes. However, a longer time is seemingly needed to adopt a new working process in the ED, and to establish its full benefit.

Published
2016
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19. Population-based audit of fresh-frozen plasma transfusion practices.

Author

Palo R, Capraro L, Hovilehto S, Koivuranta M, Krusius T, Loponen E, Mäntykoski R, Pentti J, Pitkänen O, Raitakari M, Rimpiläinen J, Salmenperä M, Salo H, and Mäki T

Subjects
Finland, Humans, Retrospective Studies, Blood Component Transfusion, Medical Audit, Plasma, Practice Management
Abstract

Background: In contrast to decreasing red blood cell (RBC) consumption in Finland, the use of fresh-frozen plasma (FFP) has been increasing since the 1990s, suggesting that FFP use may not always be optimal. To improve transfusion practices, knowledge of current FFP use and regional, national, and international comparison is necessary., Study Design and Methods: Nine (of 21) Finnish hospital districts participated. Data concerning FFP-transfused patients in the years 2002 and 2003 were collected from existing computerized medical records into a yearly updated database as part of a Finnish benchmarking project on blood component use., Results: Data included 11,590 FFP-transfused patients and 60,240 FFP units (71.2% of Finnish FFP use) delivered to Finnish hospitals during the study period. FFP was transfused most often to surgery patients (62.8% of FFP transfusion hospital visits) with blood circulatory system problems (32.3% of surgically treated and FFP-transfused patients). In only 65.9 percent of FFP-transfused patients were coagulation variables measured at any point in the hospital episode, and FFP was usually transfused in paired doses. Mean FFP use in Finland is comparable to other countries., Conclusion: Although overall FFP use in Finland is similar to that of international figures, it does not ensure best practice. Perioperative staff, being the largest FFP user, should be encouraged to dose FFP based on coagulation variables and body weight. Improvement efforts should be directed to patient groups transfused with large amounts of FFP.

Published
2006
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20. Obesity in youth is not an independent predictor of carotid IMT in adulthood. The Cardiovascular Risk in Young Finns Study.

Author

Juonala M, Raitakari M, S A Viikari J, and Raitakari OT

Subjects
Adolescent, Adult, Body Mass Index, Cardiovascular Diseases etiology, Cardiovascular Diseases pathology, Carotid Arteries diagnostic imaging, Carotid Artery Diseases diagnosis, Child, Child, Preschool, Cohort Studies, Female, Finland, Humans, Longitudinal Studies, Male, Obesity complications, Risk Factors, Ultrasonography, Carotid Arteries pathology, Carotid Artery Diseases etiology, Obesity pathology, Tunica Intima pathology, Tunica Media pathology
Abstract

Being obese in childhood may be associated with increased cardiovascular morbidity and mortality in adulthood. We examined the relationship between obesity and overweight identified in youth and carotid artery intima-media thickness assessed in adulthood. As part of the longitudinal Cardiovascular Risk in Young Finns Study, we assessed tracking of body mass index (BMI) from youth (ages 3-18 years) to young adulthood (ages 24-39 years) in a cohort of 2,260 subjects. BMI measured in youth was significantly associated with BMI measured in adulthood. The risk of being obese in adulthood (BMI > 30 kg/m(2)) was increased by three-fold in subjects who had been overweight or obese (BMI > 80th percentile) in childhood (ages 3-9 years) and by four-fold in subjects who had been overweight or obese in adolescence (ages 12-18 years). Age and sex adjusted adult IMT values were comparable in subjects who had been consistently overweight/obese in youth and adulthood and in subjects who became obese in adulthood, 0.642 mm versus 0.634 mm, respectively. IMT values were lower (overall P < 0.0001) and comparable in subjects who had remained consistently non-obese and those who had been obese in youth but had become non-obese in adulthood, 0.610 mm versus 0.627 mm, respectively. We conclude that being obese in youth is associated with increased carotid IMT in adulthood, but this relationship is explained by significant tracking of body mass from youth to adulthood.

Published
2006
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21. Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose.

Author

Raitakari M, Ilvonen T, Ahotupa M, Lehtimäki T, Harmoinen A, Suominen P, Elo J, Hartiala J, and Raitakari OT

Subjects
Adiponectin, Blood Glucose analysis, C-Reactive Protein analysis, Fasting blood, Female, Food, Formulated, Hemorheology, Hormone Replacement Therapy, Humans, Insulin blood, Lipids blood, Male, Obesity blood, Obesity physiopathology, Postmenopause blood, Proteins analysis, Smoking blood, Treatment Outcome, Vasodilation, Diet, Reducing, Endothelium, Vascular physiopathology, Intercellular Signaling Peptides and Proteins, Obesity diet therapy, Weight Loss
Abstract

Objective: Obesity is associated with endothelial dysfunction that may contribute to the development of atherosclerosis. We studied whether weight reduction improves endothelial function in overweight individuals., Methods and Results: Flow-mediated endothelium-dependent vasodilation of the brachial artery was measured in 67 adults (age: 46+/-7 years, body mass index: 35.2+/-5.4 kg/m2) before and after a 6-week weight reduction program induced by very-low-calorie diet (daily energy: 580 kcal/2.3 MJ). Caloric restriction reduced body weight from 101+/-18 to 90+/-17 kg. Flow-mediated vasodilation increased from 5.5%+/-3.7 to 8.8%+/-3.7% (P<0.0001). Nitrate-mediated vasodilation was not significantly affected. The improvement in flow-mediated dilation was associated with the reduction in plasma glucose concentration (P=0.0003). This relationship was independent of changes in weight, serum lipids, oxidized LDL, C-reactive protein, adiponectin, blood pressure, and insulin., Conclusions: Weight reduction with very-low-calorie diet improves flow-mediated vasodilation in obese individuals. This improvement is related to the reduction in plasma glucose concentration. These observations suggest that changes in glucose metabolism may determine endothelial vasodilatory function in obesity.

Published
2004
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22. Clonal cytotoxic T cells in myeloma.

Author

Sze DM, Brown RD, Yuen E, Gibson J, Ho J, Raitakari M, Basten A, Joshua DE, and Fazekas de St Groth B

Subjects
Bone Marrow pathology, Clone Cells immunology, Clone Cells pathology, Forecasting, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, Humans, Multiple Myeloma genetics, Multiple Myeloma pathology, Phenotype, T-Lymphocytes, Cytotoxic pathology, Multiple Myeloma immunology, Receptors, Antigen, T-Cell genetics, T-Lymphocytes, Cytotoxic immunology
Abstract

Multiple myeloma (MM) is a malignant disease characterized by accumulation of morphologically recognizable plasma cells producing immunoglobulin (Ig) in the bone marrow. The occurrence of clonal T cells in MM, as defined by the presence of rearrangements in the T-cell receptor (TCR)-beta chains detected on Southern blotting, is associated with an improved prognosis. This review aims to describe the various ways in which we have demonstrated the presence of such T cell clones, and to describe the phenotype of these cells. Finally, the specificities of these clinically important CD8+ T cell populations will be discussed in the context of immunotherapy.

Published
2003
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23. Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8(+)CD57(+)CD28(-) compartment.

Author

Sze DM, Giesajtis G, Brown RD, Raitakari M, Gibson J, Ho J, Baxter AG, Fazekas de St Groth B, Basten A, and Joshua DE

Subjects
Adult, Aged, Aged, 80 and over, CD28 Antigens analysis, CD57 Antigens analysis, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Clone Cells immunology, Clone Cells pathology, Complementarity Determining Regions analysis, Female, Humans, Lymphocyte Activation, Male, Matched-Pair Analysis, Middle Aged, Multiple Myeloma immunology, Multiple Myeloma therapy, Receptors, Antigen, T-Cell, alpha-beta, fas Receptor analysis, Multiple Myeloma blood, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic pathology
Abstract

The occurrence of clonal T cells in multiple myeloma (MM), as defined by the presence of rearrangements in the T-cell receptor (TCR)-beta chains detected on Southern blotting, is associated with an improved prognosis. Recently, with the use of specific anti-TCR-variable-beta (anti-TCRV(beta)) antibodies, the presence in MM patients of expanded populations of T cells expressing particular V(beta) regions was reported. The majority of these T-cell expansions have the phenotype of cytotoxic T cells (CD8(+)CD57(+) and perforin positive). Since V(beta) expansions can result from either a true clonal population or a polyclonal response, the clonality of CD8(+)TCRV(beta)(+) T cells was tested by TCRV(beta) complementarity-determining region 3 length analysis and DNA sequencing of the variable region of the TCR. In this report, the CD57(+) and CD57(-) subpopulations within expanded TCRV(beta)(+)CD8(+) cell populations are compared, and it is demonstrated that the CD57(+) subpopulations are generally monoclonal or biclonal, whereas the corresponding CD57(-) cells are frequently polyclonal. The oligoclonality of CD57(+) expanded CD8(+) T cells but not their CD57(-) counterparts was also observed in age-matched controls, in which the T-cell expansions were mainly CD8(-). The CD8(+)CD57(+) clonal T cells had a low rate of turnover and expressed relatively lower levels of the apoptotic marker CD95 than their CD57(-) counterparts. Taken together, these findings demonstrate that MM is associated with CD57(+)CD8(+) T-cell clones, raising the possibility that the expansion and accumulation of activated clonal CD8(+) T cells in MM may be the result of persistent stimulation by tumor-associated antigens, combined with a reduced cellular death rate secondary to reduced expression of the apoptosis-related molecule CD95.

Published
2001
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24. T-cell expansions in patients with multiple myeloma have a phenotype of cytotoxic T cells.

Author

Raitakari M, Brown RD, Sze D, Yuen E, Barrow L, Nelson M, Pope B, Esdale W, Gibson J, and Joshua DE

Subjects
Aged, Analysis of Variance, CD57 Antigens analysis, CD8 Antigens analysis, Female, Flow Cytometry, Humans, Immunophenotyping, Linear Models, Male, Membrane Glycoproteins analysis, Middle Aged, Perforin, Pore Forming Cytotoxic Proteins, Reference Values, Multiple Myeloma immunology, Receptors, Antigen, T-Cell, alpha-beta immunology, T-Lymphocytes, Cytotoxic immunology
Abstract

The presence of T-cell clones in peripheral blood has been previously shown to be associated with a survival advantage in patients with multiple myeloma and suggests that the expanded T-cell populations may be involved in an anti-tumour response. We studied the T-cell receptor (TCR) repertoire of 38 patients with myeloma to identify and characterize the expanded T-cell populations by flow cytometry. T-cell expansions were found in 79% of the patients. The expansions occurred randomly among the 21 variable regions of the TCR beta chain (Vbeta) studied, representing 62% of the V-beta repertoire, and were stable during an 18-month follow-up. The phenotype of the expanded V-beta populations was predominantly CD8+, CD57+, CD28- and perforin+, which differed significantly from the other non-expanded Vbeta populations. The expression of the apoptosis markers Fas (CD95) and bcl-2 were similar between the expanded and non-expanded Vbeta populations. In conclusion, expanded T-cell populations were frequent in patients with myeloma, they remained unchanged during follow-up and had phenotypic characteristics of cytotoxic T cells. These data add further support to the concept that the T-cell expansions may have an immunoregulatory role in myeloma.

Published
2000
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25. Sodium nitroprusside increases human skeletal muscle blood flow, but does not change flow distribution or glucose uptake.

Author

Pitkanen OP, Laine H, Kemppainen J, Eronen E, Alanen A, Raitakari M, Kirvela O, Ruotsalainen U, Knuuti J, Koivisto VA, and Nuutila P

Subjects
Adult, Fluorodeoxyglucose F18, Glucose pharmacokinetics, Humans, Hypoglycemic Agents pharmacology, Insulin pharmacology, Leg blood supply, Male, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Radiopharmaceuticals, Regional Blood Flow drug effects, Tissue Distribution, Tomography, Emission-Computed, Glucose metabolism, Muscle, Skeletal blood supply, Nitroprusside pharmacology, Vasodilator Agents pharmacology
Abstract

1. The role of blood flow as a determinant of skeletal muscle glucose uptake is at present controversial and results of previous studies are confounded by possible direct effects of vasoactive agents on glucose uptake. Since increase in muscle blood flow can be due to increased flow velocity or recruitment of new capillaries, or both, it would be ideal to determine whether the vasoactive agent affects flow distribution or only increases the mean flow. 2. In the present study blood flow, flow distribution and glucose uptake were measured simultaneously in both legs of 10 healthy men (aged 29 +/- 1 years, body mass index 24 +/- 1 kg m-2) using positron emission tomography (PET) combined with [15O]H2O and [18F]fluoro-2-deoxy-D-glucose (FDG). The role of blood flow in muscle glucose uptake was studied by increasing blood flow in one leg with sodium nitroprusside (SNP) and measuring glucose uptake simultaneously in both legs during euglycaemic hyperinsulinaemia (insulin infusion 6 pmol kg-1 min-1). 3. SNP infusion increased skeletal muscle blood flow by 86 % (P < 0.01), but skeletal muscle flow distribution and insulin-stimulated glucose uptake (61.4 +/- 7. 5 vs. 67.0 +/- 7.5 micromol kg-1 min-1, control vs. SNP infused leg, not significant), as well as flow distribution between different tissues of the femoral region, remained unchanged. The effect of SNP infusion on blood flow and distribution were unchanged during infusion of physiological levels of insulin (duration, 150 min). 4. Despite a significant increase in mean blood flow induced by an intra-arterial infusion of SNP, glucose uptake and flow distribution remained unchanged in resting muscles of healthy subjects. These findings suggest that SNP, an endothelium-independent vasodilator, increases non-nutritive, but not nutritive flow or capillary recruitment.

Published
1999
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26. Preserved relative dispersion but blunted stimulation of mean flow, absolute dispersion, and blood volume by insulin in skeletal muscle of patients with essential hypertension.

Author

Laine H, Knuuti MJ, Ruotsalainen U, Utriainen T, Oikonen V, Raitakari M, Luotolahti M, Kirvelä O, Vicini P, Cobelli C, Nuutila P, and Yki-Järvinen H

Subjects
Adult, Glucose metabolism, Humans, Male, Middle Aged, Regional Blood Flow, Blood Volume drug effects, Hypertension physiopathology, Insulin pharmacology, Muscle, Skeletal blood supply
Abstract

Background: We examined the integrity of the effects of insulin on mean muscle blood flow, flow heterogeneity, and blood volume in essential hypertension., Methods and Results: Positron emission tomography, combined with [15O]H2O and [15O]CO as tracers for direct measurement of blood flow and volume in skeletal muscle, and a new bayesian iterative reconstruction algorithm allowing pixel-by-pixel quantitation of blood flow and flow dispersion, were used. Measurements were performed basally after an overnight fast and under normoglycemic hyperinsulinemic conditions in 11 newly diagnosed, untreated mildly hypertensive men (age, 35 +/- 1 years; body mass index, 25.2 +/- 0.4 kg/m2, blood pressure 141 +/- 4/96 +/- 2 mm Hg, mean +/- SE) and 11 matched normotensive men. Insulin-stimulated whole body glucose uptake was significantly decreased in the hypertensive men (41 +/- 4 mumol/kg per minute) compared with the normotensive (59 +/- 4 mumol/kg per minute, P < 0.005) men. Mean blood flow in skeletal muscle was significantly lower in the hypertensive than the normal subjects basally (1.7 +/- 0.2 versus 2.7 +/- 0.4 mL/0.1 kg per minute, P < 0.05) and during hyperinsulinemia (2.3 +/- 0.2 versus 4.2 +/- 0.8, P < 0.05). The flow response to insulin (0.6 +/- 0.2 versus 1.9 +/- 0.5 mL/0.1 kg per minute, hypertensive versus normal subjects, P < 0.05) was also significantly blunted. Muscle blood volume was significantly lower in the hypertensive than in the normal subjects, both basally (3.0 +/- 0.2 versus 3.5 +/- 0.2 mL/0.1 kg, P < 0.05) and during hyperinsulinemia (3.1 +/- 0.2 versus 4.0 +/- 0.2 mL/0.1 kg muscle, P < 0.02). The increase in muscle blood volume by insulin was significant in the normal (P < 0.05) but not the hypertensive subjects. Regional pixel-by-pixel analysis within femoral muscles revealed significant spatial heterogeneity of blood flow. Insulin increased absolute dispersion of blood flow significantly more in the normal subjects than in the hypertensive subjects (P < 0.05)., Conclusions: True flow heterogeneity, as judged from the coefficients of variation (relative dispersion), was comparable between the groups basally and during hyperinsulinemia. We conclude that mean flow, its absolute dispersion, and blood volume exhibit insulin resistance in patients with essential hypertension.

Published
1998
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27. Estimation of blood flow heterogeneity distribution in human skeletal muscle from positron emission tomography data.

Author

Vicini P, Bonadonna RC, Utriainen T, Nuutila P, Raitakari M, Yki-Järvinen H, and Cobelli C

Subjects
Adult, Animals, Biomedical Engineering, Blood Flow Velocity drug effects, Glucose Clamp Technique, Humans, Insulin blood, Insulin pharmacology, Male, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Regional Blood Flow drug effects, Tomography, Emission-Computed, Vasodilation drug effects, Muscle, Skeletal blood supply
Abstract

Regional blood flow distribution in animal skeletal muscle is markedly uneven at rest and during various physiological states (exercise and hyperemia). It has been hypothesized that the vasodilatory properties of insulin may concur with insulin action on the myocite in determining stimulation of muscle glucose metabolism in vivo. In this study, we developed a method to determine noninvasively both bulk flow and regional flow heterogeneity in human skeletal muscle. Positron emission tomography studies with [15O] water were performed in seven normal subjects, both in the basal state and after 1 hr of euglycemic hyperinsulinemia. Hyperinsulinemia almost doubled skeletal muscle blood flow, but apparently did not affect the relative dispersion, the skewness, or the kurtosis of the flow distribution. However, the regression line between basal and insulin-stimulated flow values showed a nonzero intercept, and the relationship between basal flow and its insulin-stimulated fractional change was hyperbolic. These findings suggest that insulin vasodilated proportionally more the areas with the lowest basal perfusion values. These are the first data to demonstrate that in human skeletal muscle: (i) blood flow is heterogeneous; and (ii) insulin, although doubling muscle bulk flow, does not affect the relative dispersion of its distribution. This result implies that regional redistribution of perfusion is not involved in determining the metabolic response of skeletal muscle to insulin. Yet, since insulin vasodilates proportionally more the less perfused areas, it still exerts an optimizing effect on flow distribution in human muscle.

Published
1997
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28. Quantitative blood flow measurement of skeletal muscle using oxygen-15-water and PET.

Author

Ruotsalainen U, Raitakari M, Nuutila P, Oikonen V, Sipilä H, Teräs M, Knuuti MJ, Bloomfield PM, and Iida H

Subjects
Adult, Autoradiography, Femur, Humans, Male, Models, Theoretical, Oxygen Radioisotopes, Regional Blood Flow, Water, Muscle, Skeletal blood supply, Muscle, Skeletal diagnostic imaging, Tomography, Emission-Computed
Abstract

Unlabelled: The aim of the present study was to evaluate quantitation of muscle blood flow using [15O]H2O and PET., Methods: The autoradiographic (ARG) and the steady-state methods using PET were used to measure femoral muscle blood flow. A simulation study was performed to examine the errors due to contamination of radioactivity in the blood content in muscle tissue, statistical noise and delay and the dispersion of the input curve in the ARG method. Five separate paired muscle blood flow examinations were carried out for comparison of the ARG and the steady-state techniques, including measurement of muscle blood volume in each subject. To obtain the normal range for resting muscle blood flow, additional measurements with the ARG method were performed in 16 normal subjects., Results: When the integration time in ARG was increased to 200-300 sec, the errors due to arterial blood volume, statistical noise, delay and dispersion of the input curve were significantly reduced. Muscle blood flow values in the ARG (200 sec) and the steady-state studies were in good agreement, and each provided an estimated accuracy of 5%. Resting muscle blood flow averaged 3.12 +/- 1.55 ml/min.100 g muscle (range 1.43-6.72 ml/min.100 g muscle, n = 18)., Conclusion: The ARG and the steady-state methods provided consistent blood flow values for skeletal muscle when a long tissue integration time (> or = 200 sec) was applied in the ARG study. Based on the lower effective radiation dose and the shorter total scan duration, the ARG method is favored over the steady-state method in the measurement of muscle blood flow.

Published
1997

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