Peroxisome Proliferator-Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors

The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy

Non-Natural Born lecturers: How to survive teaching in Dutch higher education

[EN] Teaching in Higher Education Institutions (HEI) requests training and skills as researching. Unfortunately, on an international level the teaching training programme is not always crystal and clear, or even worse, not requested. Often researchers are asked to provide lectures without receiving proper formation. This approach creates sensible depletion in the educational quality. Offering an overview on how the Dutch HEIs are tackling the problem, the aim of this study is twofold: (i) presenting the University Teaching Qualification (UTQ) from a career development perspective and (ii) giving a qualitative evaluation of the entire process from the point of view of UTQ supervisors and lecturers. Finally concluding the relevance of such a professionalization programme.http://ocs.editorial.upv.es/index.php/HEAD/HEAD18Oude Alink, C.; Martinetti, A.; Karahanoğlu, A.; Hahnen-Florijn, M. (2018). Non-Natural Born lecturers: How to survive teaching in Dutch higher education. Editorial Universitat Politècnica de València. 1205-1213. https://doi.org/10.4995/HEAD18.2018.8177OCS1205121

Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition

Spinal muscular atrophy (SMA), a common neuromuscular disorder, is caused by homozygous absence of the survival motor neuron gene 1 (SMN1), while the disease severity is mainly influenced by the number of SMN2 gene copies. This correlation is not absolute, suggesting the existence of yet unknown factors modulating disease progression. We demonstrate that the SMN2 gene is subject to gene silencing by DNA methylation. SMN2 contains four CpG islands which present highly conserved methylation patterns and little interindividual variations in SMN1-deleted SMA patients. The comprehensive analysis of SMN2 methylation in patients suffering from severe versus mild SMA carrying identical SMN2 copy numbers revealed a correlation of CpG methylation at the positions −290 and −296 with the disease severity and the activity of the first transcriptional start site of SMN2 at position −296. These results provide first evidence that SMN2 alleles are functionally not equivalent due to differences in DNA methylation. We demonstrate that the methyl-CpG-binding protein 2, a transcriptional repressor, binds to the critical SMN2 promoter region in a methylation-dependent manner. However, inhibition of SMN2 gene silencing conferred by DNA methylation might represent a promising strategy for pharmacologic SMA therapy. We identified histone deacetylase (HDAC) inhibitors including vorinostat and romidepsin which are able to bypass SMN2 gene silencing by DNA methylation, while others such as valproic acid and phenylbutyrate do not, due to HDAC isoenzyme specificities. These findings indicate that DNA methylation is functionally important regarding SMA disease progression and pharmacological SMN2 gene activation which might have implications for future SMA therapy regimens

The Accuracy of Blood Pressure Measurement by Two Cuff-Less Wearable and Portable Health Devices

Introduction: Wearable and portable devices that claim to measure blood pressure without the need of a cuff are becoming increasingly popular among consumers. Given that hypertension is the leading cause for cardiovascular mortality worldwide, a portable technology that allows consumers to easily measure their BP several times a day would be of great value. However, the convenience that portable health technology provides is useless, and even dangerous, if the measurements are inaccurate. Objective: Investigate the accuracy of two popular commercial cuff-less BP device, the Bodimetrics Performance Monitor and Everlast TR10 watch. Methods: A sample of 127 ambulatory patients (\u3e18y) were recruited from the Thomas Jefferson University Hospital Preadmission Testing Center. Following the 2013 ANSI/AAMI/ISO standard protocol for evaluating non-invasive automated sphygmomanometers, four reference and three investigational BP measurements were obtained after a five minute initial rest period. Reference measurements were taken with the validated Cardiocap 5 sphygmomanometer. Results: 85 subjects met inclusion criteria. The average absolute differences (SD) between the Everlast watch and reference were 22.7 (27.4) mmHg for SBP and 6.9 (6.2) mmHg for DBP. The average absolute difference (SD) between the BodiMetrics Performance Monitor and the reference was 5.3 (4.7) mmHg for systolic BP. Discussion: The Everlast fitness watch tested is not accurate enough to be used as BP measurement device. The Bodimetrics device was more accurate, likely due to calibration immediately prior to validation, but even with this advantage the BP device failed to meet accuracy guidelines. Widespread use of this technology likely results in the misclassification of patients’ BP status

The Accuracy of Blood Pressure Measurement by a Smartwatch and a Portable Health Device

Introduction: Hypertension is a leading cause of mortality. Proper blood pressure (BP) control can be achieved by lifestyle modification, pharmacotherapy, and frequent measurements. With the growing popularity of cuffless blood pressure monitors, it is important to independently validate their accuracy. Objective: We evaluated two cuffless blood pressure monitors, The Everlast TR10 fitness watch and the BodiMetrics Performance Monitor, for their accuracy and precision in BP measurements. Methods: Using a protocol derived from the ANSI/AAMI/ISO 2013 standard for evaluating automated sphygmomanometers, we measured the blood pressures of 85 patients recruited from the Thomas Jefferson University Hospital Preadmission Testing Center with two experimental devices and a validated automated sphygmomanometer cuff. We compared the mean absolute differences in measurements between the investigational and reference devices. Comparisons were analyzed with Spearman correlation and T-test, p\u3c0.05. Results: The BodiMetrics Performance Monitor SBP measurements correlated well with the reference SBP measurements (ρ = 0.88, P \u3c 0.01), whereas the Everlast TR10 fitness watch did not (SBP: ρ = -0.19, P \u3c 0.01; DBP: ρ = -0.01, P \u3c 0.01). The BodiMetrics performance monitor reported a hypertensive BP (≥140 mm Hg) for 80% of the hypertensive reference SBP measurements, whereas the Everlast watch measured no hypertensive BP values for any of the hypertensive reference SBP or DBP measurements. Discussion: The Everlast fitness watch and BodiMetrics Performance Monitor are not accurate enough to use for blood pressure monitoring. Use of these devices will likely result in misclassifying patients with hypertension as normotensive, which is a public health concern

Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model

NOTICE: this is the author’s version of a work that was accepted for publication in Neurobiology of Disease. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication.Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder caused by GAA repeat expansion within the FXN gene, leading to epigenetic changes and heterochromatin-mediated gene silencing that result in a frataxin protein deficit. Histone deacetylase (HDAC) inhibitors, including pimelic o-aminobenzamide compounds 106, 109 and 136, have previously been shown to reverse FXN gene silencing in short-term studies of FRDA patient cells and a knock-in mouse model, but the functional consequences of such therapeutic intervention have thus far not been described. We have now investigated the long-term therapeutic effects of 106, 109 and 136 in our GAA repeat expansion mutation-containing YG8R FRDA mouse model. We show that there is no overt toxicity up to 5 months of treatment and there is amelioration of the FRDA-like disease phenotype. Thus, while the neurological deficits of this model are mild, 109 and 106 both produced an improvement of motor coordination, whereas 109 and 136 produced increased locomotor activity. All three compounds increased global histone H3 and H4 acetylation of brain tissue, but only 109 significantly increased acetylation of specific histone residues at the FXN locus. Effects on FXN mRNA expression in CNS tissues were modest, but 109 significantly increased frataxin protein expression in brain tissue. 109 also produced significant increases in brain aconitase enzyme activity, together with reduction of neuronal pathology of the dorsal root ganglia (DRG). Overall, these results support further assessment of HDAC inhibitors for treatment of Friedreich ataxia.This work was supported by Repligen Corporation; Muscular Dystrophy Association (MDA) USA; Ataxia UK; Friedreich's Ataxia Research Alliance (FARA); GoFAR; and the Wellcome Trust [089757]

Fiscal Instruments for Sustainable Development: The Case of Land Taxes

Economists argue that land rent taxation is an ideal form of taxation as it causes no deadweight losses and has therefore no adverse effects on growth. Nevertheless, pure land rent taxation is rarely applied and, if so, revenues collected remain rather small. Property taxes share some of the characteristics of land taxes and generate small revenues, inter alia also in developing countries. This report revisits the case of land taxation for developing countries that are often characterized by large informal sectors, low public spending and poor tax or land administration institutions. We first provide a comprehensive overview of direct and indirect welfare and development effects of land rent taxation, ranging from increased efficiency in the fiscal system and in financing infrastructure, over environmental effects due to changes in land use to distributional effects. Barriers and constraints of implementing land taxes are also discussed, particularly the existence of a land registry, the role of administrative costs, compliance, evasion and political economy aspects. We extend this review with an in-depth analysis of current land tax systems and reform options in six case study countries. For four countries, we provide an additional quantitative analysis based on micro-simulations with household data that allow us to quantify revenues and distributional effects of various land tax regimes. Our main finding is that land taxes provide a large and untapped potential for financing governments. Formalizing and securing land tenure by establishing a land registry is a pre-condition that further provides substantial co-benefits for various sustainable development objectives. Widespread concerns regarding the feasibility and costs of implementing land taxes are rarely valid, as land taxes are in these aspects comparable to other taxes. Political will and investment in the quality of administration are, however, decisive. Considering some key principles in designing the land tax can help reduce administrative costs, avoid adverse distributional effects and increase compliance