We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 'orphan' small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease.We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice.14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.
Aim: To present a novel interpretation of the biexponential nature of chronic endothelial cell loss after penetrating keratoplasty (PK). We hypothesize that the fast component of endothelial cell loss reflects the endothelial cells of graft origin. The slow component might just reflect cell loss of the recipient endothelium. We investigate herein whether this hypothesis is in line with long-term survival in bullous keratopathy (BK: almost no endothelium in the recipient bed) and keratoconus (KK: recipient bed with plenty of endothelium). Methods: We reviewed endothelial graft failures in PK for BK (n = 88) and KK (n = 87). Patients with immune reactions or a history of glaucoma were excluded. We built a statistical model to predict graft failures from biexponential endothelial cell loss and compared this data to the actual outcomes. Results: After 15 years, the incidence of late endothelial failures was 8% in KK and 33% in BK. The 95% confidence intervals of the simulated outcomes corresponded completely to the actual outcomes during follow-up. Conclusions: Our novel interpretation of the biexponential model is in line with long-term data of PK for BK and KK. Our findings highlight the importance of the recipient bed endothelial reservoir on the long-term prognosis in PK.
Oculo-auriculo-vertebral spectrum (MIM 164210) is a term suggested by Gorlin to summarize the different phenotypic expressions of a continuum that has been known as hemifacial microsomia, Goldenhar syndrome, or first and second branchial arch anomalies. The different terms indicate the extremely variable clinical findings, including especially defects of aural, oral and mandibular development. Additionally, cardiac, renal, skeletal and other anomalies occur. The majority of oculo-auriculo-vertebral spectrum cases are sporadic; nevertheless, several families have been reported with proof of both autosomal dominant and autosomal recessive inheritance. We describe a family with transmission of oculo-auriculo-vertebral spectrum from a mother to her two daughters indicating an autosomal dominant mode of inheritance. Our literature review reveals that patients with autosomal dominant inheritance of oculo-auriculo-vertebral spectrum are more often bilaterally affected than patients with sporadic occurrence of oculo-auriculo-vertebral spectrum. In addition, hearing loss, absent or narrow external auditory canal, anomalies of the mouth and epibulbar dermoids seem to occur less frequently in patients with autosomal dominant oculo-auriculo-vertebral spectrum compared with sporadic oculo-auriculo-vertebral spectrum.
Activation of the alternative pathway (AP) of complement plays an important role in the pathogenesis of age-related macular degeneration (AMD), an important eye disease in the older people. Next to histological data also genetic data support this contribution with especially genetic variants of the AP inhibitor complement factor H (CFH) contributing to this disease. Since activation of the AP of the complement system is an important aspect of AMD and has been implicated in rheumatoid arthritis (RA) the authors wished to address the question whether the genetic risk factors of the AP inhibitor CFH for AMD would also be risk factors for RA.
Materials and methods
For this purpose the authors genotyped CFH single-nucleotide polymorphisms (SNPs) in a Dutch set of RA patients and controls. Likewise, a meta-analysis using a Spanish cohort of RA as well as six large genome-wide association studies was performed. For these SNPs the authors analysed over 6.000 patients and 20.000 controls.
Results
The CFH variants; I62V, Y402H, IVS1 and IVS10, that represent the highest risk alleles for AMD, did not show a significant association with the risk to develop RA despite a strong statistical power to detect such differences.
Conclusions
The major risk alleles of AMD in CFH do not have a similar effect on developing RA.
Abstract A hallmark of inflammatory diseases is the excessive recruitment and influx of monocytes to sites of tissue damage and their ensuing differentiation into macrophages. Numerous stimuli are known to induce transcriptional changes associated with macrophage phenotype, but posttranscriptional control of human macrophage differentiation is less well understood. Here we show that expression levels of the RNA-binding protein Quaking (QKI) are low in monocytes and early human atherosclerotic lesions, but are abundant in macrophages of advanced plaques. Depletion of QKI protein impairs monocyte adhesion, migration, differentiation into macrophages and foam cell formation in vitro and in vivo . RNA-seq and microarray analysis of human monocyte and macrophage transcriptomes, including those of a unique QKI haploinsufficient patient, reveal striking changes in QKI-dependent messenger RNA levels and splicing of RNA transcripts. The biological importance of these transcripts and requirement for QKI during differentiation illustrates a central role for QKI in posttranscriptionally guiding macrophage identity and function.
Data transformations prior to analysis may be beneficial in classification tasks. In this article we investigate a set of such transformations on 2D graph-data derived from facial images and their effect on classification accuracy in a high-dimensional setting. These transformations are low-variance in the sense that each involves only a fixed small number of input features. We show that classification accuracy can be improved when penalized regression techniques are employed, as compared to a principal component analysis (PCA) pre-processing step. In our data example classification accuracy improves from 47% to 62% when switching from PCA to penalized regression. A second goal is to visualize the resulting classifiers. We develop importance plots highlighting the influence of coordinates in the original 2D space. Features used for classification are mapped to coordinates in the original images and combined into an importance measure for each pixel. These plots assist in assessing plausibility of classifiers, interpretation of classifiers, and determination of the relative importance of different features.
Provide up-to-date insight in incidence of retinopathy of prematurity (ROP), logistics of screening and treatment in the Netherlands and influence of the new national ROP guideline in which more stringent screening criteria were implemented and the early treatment for ROP criteria (ETROP) were emphasised.Multicentre prospective nationwide study including all preterm infants, born in the Netherlands in 2017, and considered eligible for ROP screening. Anonymised data from ophthalmologists and paediatricians were merged. Outcome data were compared with the first national ROP inventory (NEDROP-1, 2009).In 2017, 1492 infants were live born with gestational age (GA) <32 weeks (2009: 1662); 1287 infants were eligible for screening (2009: 2033). Ophthalmologists screened 1085 infants, versus 1688 in 2009, corrected with factor 1.114 for the difference in number of live births, a 28.4% (479/1688) decrease in screened infants was seen. Among surviving infants with GA <32 week, ROP was found in 305/1492 babies, 20.4% (2009: 324/1662, 19.5%) of which 49/1492 stage ≥3, 3.3% (2009: 30/1662, 1.8%). In all infants, report on presence or absence of plus disease was provided, according to the ETROP criteria. Treatment was performed in 39 infants. Of infants with ROP stage ≥3, 3/49 (6.1%) progressed to retinal detachment (2009: 6/30, 20.0%).The overall ROP incidence expressed as a percentage, remained stable but the number of infants that developed severe ROP nearly doubled. A near one-third reduction in screened infants shows satisfactory implementation of the new screening criteria. A notable decrease in retinal detachment delineates improved treatment outcome.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
