TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described... Show moreTET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3's direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease. Show less
After the Fourth Anglo-Dutch War (1780–1784), which ended disastrously for the Dutch East India Company (VOC), the need to reform was strongly felt. The Board of Directors (Heren XVII) asked for... Show moreAfter the Fourth Anglo-Dutch War (1780–1784), which ended disastrously for the Dutch East India Company (VOC), the need to reform was strongly felt. The Board of Directors (Heren XVII) asked for state support. This resulted in the formation of an independent Military Commission, with the mandate ofreporting on the (military) state of affairs in the East, surveying the settlements and making plans for their improvement. The Prussian-born Carl Friedrich Reimer was employed as the main surveyor and military engineer. He had already been in the VOC’s service for two decades before he was given this important task and became a confidant of Governor-General Arnold Willem Alting. The Governor-General wasvery skeptical towards the activities of the Military Commission, which operated fully outside the Company’s established chain of command. By maneuvering Reimer into the Commission, Alting had eyes and ears in its affairs. Next to observing, surveying, drawing plans and writing recommendations, Reimer wouldalso inform Alting about the journeys. Every major Dutch settlement from South Africa to the Moluccas was visited by the Military Commission, forming a unique view on the (military) state of affairs of the Dutch presence in Asia in around 1790. Together with the various recommendations that were accompanied by the excellent military maps by Reimer, the Dutch could make a fresh start in their imperial ambitions. However, when the Commission Fleet returned to the Republic in 1793 and all the reports and maps were transferred, the political constellation no longer had an eye for the overseas troubles of the VOC. The young and revolutionary French Republic just declared war. As such, the cartographic legacy of CF Reimerwas ‘dead on arrival’. Show less
The Fourth Dutch-Anglo War (1780-1784) weakened the Dutch East India Company so much that it turned for financial and military support to the highest political institution in the Dutch Republic:... Show moreThe Fourth Dutch-Anglo War (1780-1784) weakened the Dutch East India Company so much that it turned for financial and military support to the highest political institution in the Dutch Republic: the States General. It was decided that an independent Military Commission should carry out a thorough military investigation of the Dutch overseas possessions. The Prussian-born military engineer Carl Friedrich Reimer became a member of this Commission. He kept a diary of the journey for his superiors in Batavia. An extract of this diary is preserved at the National Archives of The Netherlands. It is a valuable source since it contains not only observations on the primary activities of the Military Commission, but also of many remarkable occurrences during the trip. The manuscript includes reflections on the size and origins of Hindu monuments on Java, remarks on the use of locally cultivated gambir at Riau (Tanjung Pinang), espionage activities during a visit to Madras (Chennai), where the English fortifications were observed and the crops in the botanical garden of EIC-surgeon James Anderson were discussed. Reimer even added his personal thoughts about slavery in the diary, reasoning why, in his opinion, many Javanese were unfit as slaves, describing them as «children of nature». These subjects had little to do with the main tasks of the Military Commission. Yet, C.F. Reimer gathered all this information for his superiors to judge on its «usefulness». Also, there are indications that he may have wanted to publish some of his findings. This paper will highlight some extracts from the diary and discuss the reasons behind this kind of intelligence gathering, the choice of keeping a diary, and the possible reasons why this manuscript, and its content, remained unknown. Show less
Housing the largest Dutch East India Company (VOC) and Dutch West India Company (WIC) archive, the National Archives of the Netherlands also preserves many hand drawn maps, plans and topographical... Show moreHousing the largest Dutch East India Company (VOC) and Dutch West India Company (WIC) archive, the National Archives of the Netherlands also preserves many hand drawn maps, plans and topographical views of the Dutch overseas settlements. Between 2005 and 2012 these were reproduced in the monumental series of the Comprehensive Atlas of the VOC and WIC. Nevertheless, a hitherto unknown plan was recently uncovered from obscurity. Show less
Boorn, J. van den; Tjin, E.; Picavet, D.; Veen, H. van; Konijnenberg, D.; Swieten, P. van; ... ; Luiten, R. 2011
Low-grade inflammation in different tissues, including activation of the nuclear factor kappa B pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular... Show moreLow-grade inflammation in different tissues, including activation of the nuclear factor kappa B pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular diseases (CVDs). In this study, we investigated the relation between chronic hepatocyte-specific overexpression of IkB kinase (IKK)-beta and hypertriglyceridemia, an important risk factor for CVD, by evaluating whether activation of IKK-beta only in the hepatocyte affects VLDL-triglyceride (TG) metabolism directly. Transgenic overexpression of constitutively active human IKK-beta specifically in hepatocytes of hyperlipidemic APOE*3-Leiden mice clearly induced hypertriglyceridemia. Mechanistic in vivo studies revealed that the hypertriglyceridemia was caused by increased hepatic VLDL-TG production rather than a change in plasma VLDL-TG clearance. Studies in primary hepatocytes showed that IKK-beta overexpression also enhances TG secretion in vitro, indicating a direct relation between IKK-beta activation and TG production within the hepatocyte. Hepatic lipid analysis and hepatic gene expression analysis of pathways involved in lipid metabolism suggested that hepatocyte- specific IKK-beta overexpression increases VLDL production not by increased steatosis or decreased FA oxidation, but most likely by carbohydrate-responsive element binding protein-mediated upregulation of Fas expression.jlr These findings implicate that specific activation of inflammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK-beta pathway as a possible target to treat hypertriglyceridemia. van Diepen, J. A., M. C. Wong, B. Guigas, J. Bos, R. Stienstra, L. Hodson, S. E. Shoelson, J. F. P. Berbee, P. C. N. Rensen, J. A. Romijn, L. M. Havekes, and P. J. Voshol. Hepatocyte-specific IKK-beta activation enhances VLDL-triglyceride production in APOE*3-Leiden mice. J. Lipid Res. 2011. 52: 942-950. Show less
Low-grade inflammation in different tissues, including activation of the nuclear factor κB (NF-κB) pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular... Show moreLow-grade inflammation in different tissues, including activation of the nuclear factor κB (NF-κB) pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular diseases (CVD). In this study we investigated the relation between chronic hepatocyte-specific overexpression of IKK-β and hypertriglyceridemia, an important risk factor for CVD, by evaluating whether activation of IKK-β only in the hepatocyte affects VLDL-triglyceride (TG) metabolism directly. Transgenic overexpression of constitutively active human IκB kinase (IKK-β) specifically in hepatocytes of hyperlipidemic APOE*3-Leiden mice clearly induced hypertriglyceridemia. Mechanistic in vivo studies revealed that the hypertriglyceridemia was caused by increased hepatic VLDL-TG production, rather than a change in plasma VLDL-TG clearance. Studies in primary hepatocytes showed that IKK-β overexpression also enhances TG secretion in vitro, indicating a direct relation between IKK-β activation and TG production within the hepatocyte. Hepatic lipid analysis and hepatic gene expression analysis of pathways involved in lipid metabolism suggested that hepatocyte specific IKK-β overexpression increases VLDL production not by increased steatosis or decreased FA oxidation, but most likely by ChREBP-mediated upregulation of Fas expression. These findings implicate that specific activation of inflammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK-β pathway as a possible target to treat hypertriglyceridemia. Show less
Linden-van der Zwaag, H.M.J. van der; Bos, J.; Heide, H.J.L. van der; Nelissen, R.G.H.H. 2010
Rotation of the femoral component in total knee arthroplasty (TKA) is of high importance in respect of the balancing of the knee and the patellofemoral joint. Though it is shown that computer... Show moreRotation of the femoral component in total knee arthroplasty (TKA) is of high importance in respect of the balancing of the knee and the patellofemoral joint. Though it is shown that computer assisted surgery (CAOS) improves the anteroposterior (AP) alignment in TKA, it is still unknown whether navigation helps in finding the accurate rotation or even improving rotation. Therefore the aim of our study was to evaluate the postoperative femoral component rotation on computed tomography (CT) with the intraoperative data of the navigation system. In 20 navigated TKAs the difference between the intraoperative stored rotation data of the femoral component and the postoperative rotation on CT was measured using the condylar twist angle (CTA). This is the angle between the epicondylar axis and the posterior condylar axis. Statistical analysis consisted of the intraclass correlation coefficient (ICC) and Bland-Altman plot. The mean intraoperative rotation CTA based on CAOS was 3.5 degrees (range 2.4-8.6 degrees ). The postoperative CT scan showed a mean CTA of 4.0 degrees (1.7-7.2). The ICC between the two observers was 0.81, and within observers this was 0.84 and 0.82, respectively. However, the ICC of the CAOS CTA versus the postoperative CT CTA was only 0.38. Though CAOS is being used for optimising the position of a TKA, this study shows that the (virtual) individual rotational position of the femoral component using a CAOS system is significantly different from the position on a postoperative CT scan. Show less
