A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency

The established causal genes in Alzheimer’s disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease’s initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%–3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD

Leading change: dilemmas, challenges and lessons learned

How can public managers implement organizational change in organizations with very different users? This article presents and illustrates key insights from the change management literature, the literature on employee motivation and user capacity literature and the sociology of professions. The empirical case is a merger between two schools in Denmark. The theory expects public managers to be able to influence whether the changes are seen as transformational or incremental and to choose between proactive and reactive actions. Especially if they act proactively, a shared vision is expected to be important, but it can be challenging to secure ownership of this vision for professional employees with high public service motivation. The theory also expects that the establishment of common rules is challenging, when we are looking at changes involving very different users and in organizations with different cultures. All these theoretical insights are illustrated for a specific merger of two primary and lower secondary Danish schools

Ledelse af forandring: dilemmaer, udfordringer og erfaringer

Hvordan kan offentlige ledere gennemføre forandringsledelse i organisationer med meget forskelligartede brugere? Artiklen belyser dette spørgsmål ved at inddrage og illustrere pointer fra forandringsledelsesteori, handlingskapacitets- og motivationsteori samt professionssociologi i en analyse af en konkret fusion mellem to skoler. Ifølge teorien kan offentlige ledere arbejde med forståelsen af forandringer som enten transformationelle eller inkrementelle, ligesom de kan vælge mellem at handle proaktivt eller reaktivt. Især ved proaktiv handling forventes en fælles vision at være vigtig, selvom det er udfordrende at skabe ejerskab til visionen hos professionelle medarbejdere med høj public service motivation. Teorien forventer også, at etablering af fælles regler med gyldighed for alle er udfordrende for forandringer, der involverer forskelligartede brugere og organisationskulturer

Serum vitamin K1 associated to microangiopathy and/or macroangiopathy in individuals with and without diabetes

ObjectiveVitamin K has proposed beneficial effects on cardiovascular health. We investigated whether serum vitamin K1 was associated with prevalence of microangiopathy and/or macroangiopathy.Research design and methodsSerum vitamin K was quantified in 3239 individuals with and 3808 without diabetes enrolled in Vejle Diabetes Biobank (2007–2010). Each individual was assessed for microangiography and macroangiopathy at enrollment based on registered diagnoses in the Danish National Patient Registry according to the International Classification of Disease 8 (1977–1993) and 10 (since 1994). Using multinomial logistic regression, relative risk ratios (RRRs) were calculated within each group of individuals with and without diabetes. RRRs were estimated for microangiopathic/macroangiopathic status compared with individuals without complications as a function of 1 nmol/L increments in K1. Adjustment for potential confounders was also performed.ResultsVitamin K1 (median) varied 0.86–0.95 nmol/L depending on diabetes, microangiopathic and macroangiopathic status. In individuals with diabetes, the crude RRR for only having microangiopathy was 1.05 (95% CI 0.98 to 1.12) and was found significant when adjusting 1.10 (95% CI 1.01 to 1.19). RRR for having only macroangiopathy was 0.89 (95% CI 0.77 to 1.03) and was again significant when adjusting 0.79 (95% CI 0.66 to 0.96). In individuals without diabetes, adjustments again led to similar estimates that was not significant. The adjusted RRR for having only macroangiopathy was 1.08 (95% CI 0.98 to 1.19).ConclusionsSerum vitamin K1 levels were associated with microangiopathic and macroangiopathic status in individuals with diabetes, but considered of no clinical relevance. The clinical value of other candidate markers for vitamin K status needs to be evaluated in future studies

Standardised Resting Time Prior to Blood Sampling and Diurnal Variation Associated with Risk of Patient Misclassification:Results from Selected Biochemical Components

According to current recommendations, blood samples should be taken in the morning after 15 minutes' resting time. Some components exhibit diurnal variation and in response to pressures to expand opening hours and reduce waiting time, the aims of this study were to investigate the impact of resting time prior to blood sampling and diurnal variation on biochemical components, including albumin, thyrotropin (TSH), total calcium and sodium in plasma.All patients referred to an outpatient clinic for blood sampling were included in the period Nov 2011 until June 2014 (opening hours: 7am-3pm). Each patient's arrival time and time of blood sampling were registered. The impact of resting time and the time of day for all components was analysed using simple linear regression. The "maximum allowable bias" was used as quality indicator for the change in reference interval.Significant diurnal variation was found for albumin (n = 15,544; p<2×10-16), TSH (n = 20,019; p<2×10-16), calcium (n = 13,588; p = 2.8×10-12) and sodium (n = 51,917; p<2×10-16). Further significant influence for resting time was found for albumin (p = 2.6×10-4), TSH (p = 0.004), calcium (p = 8.9×10-7) and sodium (p = 8.7×10-16). Only TSH and albumin were clinically significantly influenced by diurnal variation. Resting time had no clinically significant effect.We found no need for resting 15 minutes prior to blood sampling. However, diurnal variation was found to have a significant and considerable impact on TSH and, to a minor degree, albumin. This has to be taken into account to ensure that reference intervals provided by the laboratory are valid on a 24-hour basis

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency

The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%–3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD