Real patient learning integrated in a preclinical block musculoskeletal disorders. Does it make a difference?

Although musculoskeletal disorders are the most common reason for general practitioner visits, training did not keep pace. Implementation of learning from patients with rheumatologic disorders linked together with the teaching of theoretical knowledge in the preclinical medical education might be an important step forward in the improvement of quality of care for these patients. The Leiden Medical School curriculum has implemented two non-obligatory real patient learning (RPL) practicals integrated within the preclinical block musculoskeletal disorders. This study investigates the educational effectiveness of the practicals, the expectations students have of RPL, and students’ satisfaction. Participants’ grades on the end-of-block test served as the test results of the educational effectiveness of the practicals and were compared with those of the non-participants. Qualitative data was collected by means of questionnaires generated by focus groups. The participants in practicals scored significantly higher at the end-of-block test. The expected effects of the contact with real patients concerned positive effects on cognition and skills. ‘Contextualizing of the theory’, ‘better memorizing of clinical pictures’, and ‘understanding of the impact of the disease’ were the most frequently mentioned effects of the practicals. Overall, the participants were (very) enthusiastic about this educational format. The RPL practicals integrated within a preclinical block musculoskeletal disorders are a valuable addition to the Leiden medical curriculum. This relatively limited intervention exhibits a strong effect on students’ performance in tests. Future research should be directed towards the long-term effects of this intervention

A One Base Pair Deletion in the Canine ATP13A2 Gene Causes Exon Skipping and Late-Onset Neuronal Ceroid Lipofuscinosis in the Tibetan Terrier

Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5–7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71–84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies

Occupancy by key transcription factors is a more accurate predictor of enhancer activity than histone modifications or chromatin accessibility

BACKGROUND: Regulated gene expression controls organismal development, and variation in regulatory patterns has been implicated in complex traits. Thus accurate prediction of enhancers is important for further understanding of these processes. Genome-wide measurement of epigenetic features, such as histone modifications and occupancy by transcription factors, is improving enhancer predictions, but the contribution of these features to prediction accuracy is not known. Given the importance of the hematopoietic transcription factor TAL1 for erythroid gene activation, we predicted candidate enhancers based on genomic occupancy by TAL1 and measured their activity. Contributions of multiple features to enhancer prediction were evaluated based on the results of these and other studies. RESULTS: TAL1-bound DNA segments were active enhancers at a high rate both in transient transfections of cultured cells (39 of 79, or 56%) and transgenic mice (43 of 66, or 65%). The level of binding signal for TAL1 or GATA1 did not help distinguish TAL1-bound DNA segments as active versus inactive enhancers, nor did the density of regulation-related histone modifications. A meta-analysis of results from this and other studies (273 tested predicted enhancers) showed that the presence of TAL1, GATA1, EP300, SMAD1, H3K4 methylation, H3K27ac, and CAGE tags at DNase hypersensitive sites gave the most accurate predictors of enhancer activity, with a success rate over 80% and a median threefold increase in activity. Chromatin accessibility assays and the histone modifications H3K4me1 and H3K27ac were sensitive for finding enhancers, but they have high false positive rates unless transcription factor occupancy is also included. CONCLUSIONS: Occupancy by key transcription factors such as TAL1, GATA1, SMAD1, and EP300, along with evidence of transcription, improves the accuracy of enhancer predictions based on epigenetic features. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13072-015-0009-5) contains supplementary material, which is available to authorized users

Holocene storage of siliciclastic sediment around islands on the middle shelf of the Great Barrier Reef Platform, north-east Australia

Thick sequences of sediment surround the Whitsunday Islands on the middle shelf of the Great Barrier Reef (GBR) Platform. Much of this sediment is siliciclastic material deposited since the sea-level highstand at around 6.5 ka. This raises a mass balance dilemma because modern terrigenous discharge to the GBR Platform is restricted to the inner shelf. Shallow seismic profiles and sediment samples were collected over 450 km 2 around the Whitsunday Islands to quantify the mass of siliciclastic sediment for a dynamic model of the shelf. The sea floor and pre-Holocene surfaces were mapped using 4584 stations along the seismic profiles and a graphical computer program. The total volume of sediment between these two surfaces is 3.67 ± 0.45 × 10 9 m 3. This volume is composed of buried reefs (0.13 ± 0.01 × 10 9 m 3), medium- (0.70 ± 0.30 × 10 9 m 3) and fine-grained shoals (2.84 ± 0.35 × 10 9 m 3). The volume estimates combined with measurements of carbonate concentration, density and porosity indicate that 1850 ± 380 Mt of Holocene siliciclastic sediment surround the Whitsunday Islands in medium- (510 ± 225 Mt) and fine-grained shoals (1340 ± 155 Mt). The total mass of siliciclastic material is 1.7-2.6 times that stored in Cleveland Bay, a similar sized repository on the inner shelf. A simple numerical model has been constructed to explain this large quantity of Holocene siliciclastic sediment. The model results in the appropriate siliciclastic mass next to the Whitsunday Islands by integrating regional shelf processes over time. Unlike the present day, rivers discharged sediment to the middle shelf during the early Holocene. This material was subsequently focused by northward transport into the vicinity of the islands, a geomorphologically complex region that serves as a sediment trap. Although direct riverine inputs to the middle shelf have stopped during the present sea-level highstand, previously deposited siliciclastic sediment is continually being winnowed from the middle shelf and redeposited next to the Whitsunday Islands. The transport and distribution of siliciclastic sediment on the GBR Platform is thus influenced significantly by storage around islands on the middle shelf