Is disturbed clearance of apoptotic keratinocytes responsible for UVB-induced inflammatory skin lesions in systemic lupus erythematosus?

Apoptotic cells are thought to play an essential role in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesise that delayed or altered clearance of apoptotic cells after UV irradiation will lead to inflammation in the skin of SLE patients. Fifteen SLE patients and 13 controls were irradiated with two minimal erythemal doses (MEDs) of ultraviolet B light (UVB). Subsequently, skin biopsies were analysed (immuno)histologically, over 10 days, for numbers of apoptotic cells, T cells, macrophages, and deposition of immunoglobulin and complement. Additionally, to compare results with cutaneous lesions of SLE patients, 20 biopsies of lupus erythematosus (LE) skin lesions were analysed morphologically for apoptotic cells and infiltrate. Clearance rate of apoptotic cells after irradiation did not differ between patients and controls. Influx of macrophages in dermal and epidermal layers was significantly increased in patients compared with controls. Five out of 15 patients developed a dermal infiltrate that was associated with increased epidermal influx of T cells and macrophages but not with numbers of apoptotic cells or epidermal deposition of immunoglobulins. Macrophages were ingesting multiple apoptotic bodies. Inflammatory lesions in these patients were localised near accumulations of apoptotic keratinocytes similar as was seen in the majority of LE skin lesions. In vivo clearance rate of apoptotic cells is comparable between SLE patients and controls. However, the presence of inflammatory lesions in the vicinity of apoptotic cells, as observed both in UVB-induced and in LE skin lesions in SLE patients, suggests that these lesions result from an inflammatory clearance of apoptotic cells

Genome-wide screening for cis-regulatory variation using a classical diallel crossing scheme

Large-scale screening studies carried out to date for genetic variants that affect gene regulation are generally limited to descriptions of differences in allele-specific expression (ASE) detected in vivo. Allele-specific differences in gene expression provide evidence for a model whereby cis-acting genetic variation results in differential expression between alleles. Such gene surveys for regulatory variation are a first step in identifying the specific nucleotide changes that govern gene expression differences, but they leave the underlying mechanisms unexplored. Here, we propose a quantitative genetics approach to perform a genome-wide analysis of ASE differences (GASED). The GASED approach is based on a diallel design that is often used in plant breeding programs to estimate general combining abilities (GCA) of specific inbred lines and to identify high-yielding hybrid combinations of parents based on their specific combining abilities (SCAs). In a context of gene expression, the values of GCA and SCA parameters allow cis- and trans-regulatory changes to be distinguished and imbalances in gene expression to be ascribed to cis-regulatory variation. With this approach, a total of 715 genes could be identified that are likely to carry allelic polymorphisms responsible for at least a 1.5-fold allelic expression difference in a total of 10 diploid Arabidopsis thaliana hybrids. The major strength of the GASED approach, compared to other ASE detection methods, is that it is not restricted to genes with allelic transcript variants. Although a false-positive rate of 9/41 was observed, the GASED approach is a valuable pre-screening method that can accelerate systematic surveys of naturally occurring cis-regulatory variation among inbred lines for laboratory species, such as Arabidopsis, mouse, rat and fruitfly, and economically important crop species, such as corn

AUT788065_Lay_Abstract – Supplemental material for The Dutch Glasgow Sensory Questionnaire: Psychometric properties of an autism-specific sensory sensitivity measure

<p>Supplemental material, AUT788065_Lay_Abstract for The Dutch Glasgow Sensory Questionnaire: Psychometric properties of an autism-specific sensory sensitivity measure by Marieke WM Kuiper, Elisabeth WM Verhoeven and Hilde M Geurts in Autism</p

Genetic dissection of transcriptional regulation by cDNA-AFLP

This study demonstrates that cDNA-AFLP is a powerful gel-based genome-scale transcript profiling technique to generate quantitative gene expression profiles for eQTL mapping. We used cDNA-AFLP to monitor the relative abundance of 912 transcripts across 50 Arabidopsis thaliana recombinant inbred lines. Estimates for heritability of cDNA-AFLP intensity polymorphisms were high, with a median of 0.30 and an interquartile range of 0.21-0.44. A total of 198 expression polymorphisms were significantly linked to specific chromosomal regions ( P < 0.05). Both cis- and trans-acting loci correlated with the variation in gene expression levels were found. Some of the trans-acting loci correlated to multiple expression polymorphisms, suggesting trans-acting alleles with widespread transcriptional effects. Here, we have illustrated that cDNA-AFLP constitutes a powerful transcript profiling method that can be utilized for 'multifactorial genomics' analysis of any plant or animal species for which segregating populations and molecular marker maps are available

Long-term efficacy of clinical hunger provocation to wean feeding tube dependent children

Background & aims: The incidence of tube feeding dependency seems to increase worldwide, and these children may remain on prolonged tube feeding for many months to years. The multidisciplinary clinical hunger provocation (CHP) program is an intensive inpatient intervention of usually 2–3 weeks, aimed at weaning children from tube feeding. CHP has been proven highly effective on the short term (80–86%), particularly when applied before the age of two years but long-term data are lacking. The aims of our study were to determine the long-term efficacy of the CHP program and factors associated with success or failure and to assess anthropometrics, feeding behavior, and medical outcomes at long-term follow-up. Methods: All tube-dependent children who underwent CHP at a tertiary hospital in Amsterdam, the Netherlands, between 2001 and 2014, and had a minimum follow-up of 12-months in 2015, were eligible to participate in this retrospective cohort study. During the CHP program, tube feeding is ceased stepwise to create appetite, according to a strict protocol. The program was defined successful if patients achieved oral intake and could be fully weaned from tube feeding following the CHP program. Acute malnourishment was defined as weight for height 1 SD within 3 months, chronic malnourishment as height for age <2 SD and both acute and chronic malnourishment as both a height for age and weight for height <2 SD. Long-term efficacy (tube free at varying follow-up periods), anthropometrics (height for age, weight for height), feeding behavior and medical outcomes were assessed by a structured cross-sectional parental interview. Results: In total, 57 patients were admitted to the CHP program. Fifty-two patients could be contacted of whom 42 participated in the study (response rate 81%) with a median age at admittance of 19 (IQR 13–22) months (62% female). The program was initially successful in 36/42 (86% (Bca CI 95% 75.0–95.2)) patients. A younger age upon initiation of tube feeding was negatively correlated with success (p 0.016). At follow-up, a median period of 67.0 (IQR 37.0–101.5) months after discharge, long-term efficacy was 32/41 (78% (Bca CI 95% 64.1–90.0)) (1 missing data). Patients with a successful CHP had beneficial outcomes compared to those with an unsuccessful CHP, showing less selective eating behavior (p 0.025), nocturnal feeding (p 0.044), forced feeding (p 0.044) and hospital admissions (p 0.028). However, 44% of successfully weaned patients fulfilled the criteria for malnourishment at long-term follow-up (13% acute, 22% chronic, and 9% both acute and chronic (compared to 22% at admittance: 13% acute, 6% chronic, and 3% both)). 59.4% of successfully weaned patients showed signs of developmental delays or were diagnosed with new medical diagnoses (43.8%) at long-term follow-up. Conclusions: The multidisciplinary CHP is a highly effective short-term (86%) and long-term (78%) intervention to wean young children from tube feeding, with beneficial feeding outcomes. However, at long-term follow-up, many successfully weaned patients were malnourished, showed signs of developmental delay, and were diagnosed with new medical diagnoses. For these reasons, patients should be monitored carefully during and after tube weaning, also after successful CHP. Tube dependency might be an early expression of medical diagnoses