122 research outputs found
The effect of age and gender on the genetic regulation of serum 25-hydroxyvitamin D - the FIN-D2D population-based study
The effect of temperature, gradient and load carriage on oxygen consumption, posture and gait characteristics
Purpose The purpose of this experiment was to evaluate the effect of load carriage in a range of temperatures to establish the interaction between cold exposure, the magnitude of change from unloaded to loaded walking and gradient. Methods Eleven participants (19-27 years) provided written informed consent before performing six randomly ordered walking trials in six temperatures (20°C, 10°C, 5°C, 0°C, -5°C and -10°C). Trials involved two unloaded walking bouts before and after loaded walking (18.2 kg) at 4 km.hrâ»Âč, on 0% and 10% gradients in 4 minute bouts. Results The change in absolute oxygen consumption (VÌOâ) from the first unloaded bout to loaded walking was similar across all six temperatures. When repeating the second unloaded bout, VÌOâ at both -5°C and-10°C was greater compared to the first. At -10°C, VÌOâ was increased from 1.60 ± 0.30 L.minâ»Âč to 1.89 ± 0.51 L.minâ»Âč. Regardless of temperature, gradient had a greater effect on VÌOâ and heart rate (HR) than backpack load. HR was unaffected by temperature. Stride length (SL) decreased with decreasing temperature but trunk forward lean was greater during cold exposure. Conclusion Decreased ambient temperature did not influence the magnitude of change in VÌOâ from unloaded to loaded walking. However, in cold temperatures, VÌOâ was significantly higher than in warm conditions. The increased VÌOâ in colder temperatures at the same exercise intensity is predicted to ultimately lead to earlier onset of fatigue and cessation of exercise. These results highlight the need to consider both appropriate clothing and fitness during cold exposure
High prevalence of obesity, central obesity and abnormal glucose tolerance in the middle-aged Finnish population
<p>Abstract</p> <p>Background</p> <p>There is a worldwide increase in the prevalence of obesity and disturbances in glucose metabolism. The aim of this study was to assess the current prevalence of obesity, central obesity and abnormal glucose tolerance in Finnish population, and to investigate the associations between body mass index (BMI), waist circumference and abnormal glucose tolerance.</p> <p>Methods</p> <p>A cross-sectional population-based survey was conducted in Finland during October 2004 and January 2005. A total of 4500 randomly selected individuals aged 45â74 years were invited to a health examination that included an oral glucose tolerance test. The participation rate was 62% in men and 67% in women.</p> <p>Results</p> <p>The prevalence of obesity was 23.5% (95% Confidence Interval (CI) 21.1â25.9) in men, and 28.0% (95% CI 25.5â30.5) in women. The overall prevalence of abnormal glucose tolerance (including type 2 diabetes, impaired glucose tolerance, or impaired fasting glucose) was 42.0% (95% CI 39.2â44.8) in men and 33.4% (95% CI 30.9â36.0) in women. The prevalence of previously unknown, screen-detected type 2 diabetes was 9.3% (95% CI 7.7â11.0) in men and 7.3% (95% CI 5.9â8.7) in women. Central obesity was associated with abnormal glucose tolerance within each of the three BMI categories normal (< 25 kg/m<sup>2</sup>), overweight (25â29 kg/m<sup>2</sup>), and obese (â„ 30 kg/m<sup>2</sup>).</p> <p>Conclusion</p> <p>In a population-based random sample of Finnish population, prevalences of obesity, central obesity and abnormal glucose tolerance were found to be high. A remarkably high number of previously undetected cases of type 2 diabetes was detected. Waist circumference is a predictor of abnormal glucose tolerance in all categories of obesity.</p
Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia
Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.Peer reviewe
Rare and low-frequency coding variants alter human adult height
Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways
New genetic loci link adipose and insulin biology to body fat distribution.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (PÂ <Â 5Â ĂÂ 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms
A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.Academy of Finland (129293, 128315, 129330, 131593, 139635, 139635, 121584, 126925, 124282, 129378, 258753); Action on Hearing Loss (G51); Ahokas Foundation; American Diabetes Association (#7-12-MN-02); Atlantic Canada Opportunities Agency; Augustinus foundation; Becket foundation; Benzon Foundation; Biomedical Research Council; British Heart Foundation (SP/04/002); Canada Foundation for Innovation; Commission of the European Communities, Directorate C-Public Health (2004310); Copenhagen County; Danish Centre for Evaluation and Health Technology Assessment; Danish Council for Independent Research; Danish Heart Foundation (07-10-R61-A1754-B838-22392F); Danish Medical Research Council; Danish Pharmaceutical Association; Emil Aaltonen Foundation; European Research Council Advanced Research Grant; European Union FP7 (EpiMigrant, 279143; FP7/2007-2013; 259749); Finland's Slottery Machine Association; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Foundation of Cardiovascular Research; Finnish Medical Society; Finnish National Public Health Institute; Finska LĂ€karesĂ€llskapet; FolkhĂ€lsan Research Foundation; Foundation for Life and Health in Finland; German Center for Diabetes Research (DZD) ; German Federal Ministry of Education and Research; Health Care Centers in Vasa, NĂ€rpes and Korsholm; Health Insurance Foundation (2012B233) ; Helsinki University Central Hospital Research Foundation; Hospital districts of Pirkanmaa, Southern Ostrobothnia, North Ostrobothnia, Central Finland, and Northern Savo; Ib Henriksen foundation; Juho Vainio Foundation; Korea Centers for Disease Control and Prevention (4845â301); Korea National Institute of Health (2012-N73002-00); Li Ka Shing Foundation; Liv och HĂ€lsa; Lundbeck Foundation; Marie-Curie Fellowship (PIEF-GA-2012-329156); Medical Research Council (G0601261, G0900747-91070, G0601966, G0700931); Ministry of Education in Finland; Ministry of Social Affairs and Health in Finland; MRC-PHE Centre for Environment and Health;Municipal Heath Care Center and Hospital in Jakobstad; NĂ€rpes Health Care Foundation; National Institute for Health Research (RP-PG-0407-10371); National Institutes of Health (U01 DK085526, U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584, U01 DK088389, RC2-DK088389, DK085545, DK098032, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN, R01MH107666 and K12CA139160268201300050C, U01 DK062370, R01 DK066358, U01DK085501, R01HL102830, R01DK073541, PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R01 MH101820, R01MH090937, P30DK020595, R01 DK078616, NIDDK K24 DK080140, 1RC2DK088389, T32GM007753); National Medical Research Council; National Research Foundation of Korea (NRF-2012R1A2A1A03006155); Nordic Center of Excellence in Disease Genetics; Novo Nordisk; Ollqvist Foundation; OrionFarmos Research Foundation; Paavo Nurmi Foundation; PerklĂ©n Foundation; Samfundet FolkhĂ€lsan; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; South East Norway Health Authority (2011060); Swedish Cultural Foundation in Finland; Swedish Heart-Lung Foundation; Swedish Research Council; Swedish Research Council (LinnĂ© and Strategic Research Grant); The American Federation for Aging Research; The Einstein Glenn Center; The European Commission (HEALTH-F4-2007-201413); The Finnish Diabetes Association; The FolkhĂ€lsan Research Foundation; The PĂ„hlssons Foundation; The provinces of Newfoundland and Labrador, Nova Scotia, and New Brunswick; The Sigrid Juselius Foundation; The SkĂ„ne Regional Health Authority; The Swedish Heart-Lung Foundation; Timber Merchant Vilhelm Bangâs Foundation; Turku University Foundation; Uppsala University; Wellcome Trust (064890, 083948, 085475, 086596, 090367, 090532, 092447, 095101/Z/10/Z, 200837/Z/16/Z, 095552, 098017, 098381, 098051, 084723, 072960/2/ 03/2, 086113/Z/08/Z, WT098017, WT064890, WT090532, WT098017, 098051, WT086596/Z/08/A and 086596/Z/08/Z). Detailed acknowledgment of funding sources is provided in the Additional Acknowledgements section of the Supplementary Materials
Digitaalisen taloushallinnon kehittÀminen sidosryhmien kanssa tilitoimiston nÀkökulmasta
Tilitoimistoala on ollut voimakkaassa murroksessa 2000-luvulla sĂ€hköisen taloushallinnon menetelmien tullessa kĂ€yttöön. Digitaalinen taloushallinto kuvaa sĂ€hköistĂ€ taloushallintoa vielĂ€ kehityksellisempiĂ€ menetelmiĂ€, joissa keskeistĂ€ on mutkaton tiedonsiirto yli organisaatiorajapintojen. Tutkimuksen toimeksiantajayrityksen mukaan tilitoimistoilla on vielĂ€ kehitettĂ€vÀÀ digitaalisessa taloushallinnossa etenkin sidosryhmien kanssa. Tavoitteena oli selvittÀÀ kuinka tilitoimistoala voi kehittÀÀ digitaalista taloushallintoa sidosryhmien kanssa. Toisena tavoitteena oli löytÀÀ keskeiset nykyiset innovaatiot, jotka edistĂ€vĂ€t digitaalisen taloushallinnon kĂ€ytĂ€ntöjĂ€ tilitoimiston ja sidosryhmien vĂ€lillĂ€. Tutkimuskysymykseen pyrittiin vastaamaan teoria- ja empiriaosuuksien avulla. Keskeinen kirjallisuus koostui digitaalista taloushallintoa, digitaalisen taloushallinnon menetelmiĂ€, digitaalisen taloushallinnon innovaatioita sekĂ€ avointa innovaatiota kĂ€sittelevĂ€stĂ€ aineistosta. Digitaalisen taloushallinnon osaprosesseista korostui ulkoinen raportointi ja sen kehittĂ€misen merkitys etenkin tilitoimistoille. Tutkimuksen menetelmĂ€nĂ€ oli haastattelututkimus, johon yhdistyivĂ€t havainnointi ja julkaistun materiaalin kĂ€yttö eli kyseessĂ€ oli menetelmĂ€triangulaatio. Tutkimusaineistona olivat tutkimuksen tarkoituksenmukaisuuden ja resurssien ohjaamana keskeiset tilitoimiston keskeiset sidosryhmĂ€t Verohallinto, Patentti- ja rekisterihallitus (PRH) sekĂ€ Taloushallintoliitto. LisĂ€ksi tilitoimistoalan luonteen ymmĂ€rtĂ€miseksi haastateltiin erÀÀn suuren tilitoimiston henkilöitĂ€. Tutkimusaineiston analyysiĂ€ ohjasi aihetta kĂ€sittelevĂ€ teoriaosuus. Tutkimus perustuu abduktiiviseen eli teoriasidonnaiseen analyysiin. Aineistoa kĂ€siteltiin ensin aineistolĂ€htöisesti ja sen jĂ€lkeen siihen liitettiin tueksi havaintoja teoriasta. Aineiston kĂ€sittely perustui sisĂ€llönanalyysiin, jossa kuvailtiin, luokiteltiin ja tulkittiin aineistosta keskeinen sisĂ€ltö. NykyistĂ€ digitaalista taloushallintoa edistĂ€vinĂ€ asioina sekĂ€ kirjallisuudessa ettĂ€ haastatteluissa nĂ€htiin organisaatioiden vĂ€liseen tiedonsiirtoon liittyvĂ€t asiat. Lahden ja Salmisen (2014: 23â24) mukaan digitaalisessa taloushallinnossa hyödyt tulevat tiedon kĂ€sittelyn ja tiedonsiirron automatisoinnista organisaatiorajapintojen vĂ€lillĂ€. Empiirisen osuuden perusteella havainnot ovat samankaltaisia: haastateltujen organisaatioiden edustajat painottivat erilaisia palveluita ja sĂ€hköisen asioinnin kanavia, joissa korostuu tiedonsiirron- ja kĂ€sittelyn automatisointi. Tutkimuksen mukaan tilitoimistoalan digitaalisen taloushallinnon kehittĂ€minen perustuu pitkĂ€lti tiedonsiirron kehittĂ€miseen sidosryhmien kanssa. Esimerkiksi TALTIO-hanke ja Tulorekisteri ovat esimerkkejĂ€ avoimen innovaation tuotoksista, joihin kohdistuu suuria odotuksia digitaalisen taloushallinnon kehittĂ€misen kannalta. KeskeistĂ€ esille tulleissa kehittĂ€mismahdollisuuksissa oli tiedonsiirto, rakenteinen tieto ja avoimet standardoidut rajapinnat eri toimijoiden vĂ€lillĂ€. Tutkimuksen kontribuutio suhteessa aiempaan digitaalisen taloushallinnon tutkimukseen on hyvin tukeva. Tutkimuksen keskeiset havainnot tukevat kirjallisuuden nĂ€kemyksiĂ€ tiedonsiirron kehittĂ€misen merkityksestĂ€ digitaalisen taloushallinnon eri sidosryhmille. Tutkimustulosten yleistettĂ€vyyttĂ€ rajaa pieni havainnointijoukko. Mukana olivat vain keskeisimmĂ€t sidosryhmĂ€t, joten muiden sidosryhmien haastatteleminen lisĂ€isi tutkimustulosten yleistettĂ€vyyttĂ€. Toisaalta Taloushallintoliiton nĂ€kemykset edustavat hyvin koko tilitoimistoalaa, joten tutkimuksesta voi olla hyötyĂ€ useille tilitoimistoille
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