Novel enzyme-linked immunosorbent assay for bivalent ZnT8 autoantibodies

Autoantibodies to zinc transporter 8 (ZnT8A) are a powerful diagnostic or predictive marker in type 1 diabetes. However, the widely used current ZnT8A radioligand binding assay (RBA) has proved to be difficult for many laboratories to implement. The aim of this study was the development and characterization of the performance of a novel fluid-phase ZnT8A enzyme-linked immunosorbent assay (ELISA) in relation to standard RBA in type 1 diabetes. Sera from 114 patients with type 1 diabetes and 140 blinded Islet Autoantibody Standardization Program (IASP2012) samples were studied. The sensitivity of ELISA-ZnT8A is equivalent to or slightly higher than that of conventional RBA with similar specificity. Furthermore, the median SD score using this ELISA was significantly higher than that obtained with RBA (P < 0.0001). Multiple logistic regression analysis revealed that ELISA-ZnT8A positivity was associated with younger age of onset (?20 years; OR 15.91, P = 0.0002), acute-onset form of type 1 diabetes (OR 3.38, P = 0.019), and the presence of IA-2 autoantibodies (OR 3.75, P = 0.014). Furthermore, the levels of ELISA-ZnT8A were associated with the reactivity to ZnT8-325Arg, but not ZnT8-325Trp. We conclude that this nonradioactive bivalent ZnT8A assay has high performance and should facilitate large-scale autoantibody screening. Moreover, these results suggest that the humoral autoimmunity against ZnT8 is related to a high risk of faster development of type 1 diabetes and the ZnT8A levels are associated with the known aa325 variants

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201

Gränslöst arbete eller arbetets nya gränser Delstudie 1

Ten strategically selected individuals, seven men and three women, working with flexible arrangements with regard to time, space and work organisation, were interviewed. The interviews lasted for 1-3 hours and were fully transcribed. The interviews were then analysed in an inductive manner, i.e. without explicit preconceptions, as well as in a deductive manner. The inductive analysis outlines a set of working conditions without many of the regulations that have traditionally defined work, leaving the jobs described more open and unpredictable but also more personcentred. There is also a tendency among the participants to idealise their own working conditions. This suggests an overall shift in the rules and regulations of work: from a more constitutive to a more regulative form. According to the deductive analysis, the participants were characterised by a very high work pace, sustained activation and difficulties to unwind and relax. They also seem to have few safeguards and a limited set of life-roles, which make them vulnerable when difficulties arise. The action strategies of the participants can be described as both purposeful and creative. At the same time they reported cognitive problems handling and integrating the large amount of information generated through such creative strategies.I en studie intervjuades tio strategiskt utvalda personer, sju män och tre kvinnor. Gemensamt för de intervjuade var att de arbetade med modern informationsteknik, och att deras arbetsvillkor till följd av detta kännetecknades av en utpräglad flexibilitet med avseende på tid, rum och arbetsorganisation. Intervjuerna som hade omfattningen av 1-3 timmar dokumenterades i fullständiga bandutskrifter och analyserades därefter dels induktivt, i ett mer förutsättningslöst kategoriserande, och dels deduktivt, utifrån fyra fördefinierade teoretiska teman. Den induktiva analysen beskriver ett arbete utan många av de normer och regler som traditionellt definierat arbetet, ett arbete som därmed är mer öppet och oförutsägbart, men också mer personfixerat än vad som är traditionellt. Det finns också en tendens till idealisering av arbetsvillkoren bland de intervjuade. Detta antyder en generell förskjutning från en yttre och mer objektiv reglering till en inre och mer subjektiv reglering av arbetet. Enligt den deduktiva analysen karakteriseras intervjupersonerna av högt arbetstempo och en hög aktiveringsnivå, samt svårigheter att koppla av och varva ned. Samtidigt verkar de ha få buffertar och en begränsad uppsättning livsroller, vilket gör dem sårbara vid motgångar. På samma sätt kan intervjupersonernas handlingsstrategier beskrivas som mycket målmedvetna och öppna, samtidigt som de beskriver problemen med att hantera och integrera de stora informationsmängderna som en sådan öppenhet medför