E-education in pathology including certification of e-institutions

E–education or electronically transferred continuous education in pathology is one major application of virtual microscopy. The basic conditions and properties of acoustic and visual information transfer, of teaching and learning processes, as well as of knowledge and competence, influence its implementation to a high degree. Educational programs and structures can be judged by access to the basic conditions, by description of the teaching resources, methods, and its program, as well as by identification of competences, and development of an appropriate evaluation system. Classic teaching and learning methods present a constant, usually non-reversible information flow. They are subject to personal circumstances of both teacher and student. The methods of information presentation need to be distinguished between static and dynamic, between acoustic and visual ones. Electronic tools in education include local manually assisted tools (language assistants, computer-assisted design, etc.), local passive tools (slides, movies, sounds, music), open access tools (internet), and specific tools such as Webinars. From the medical point of view information content can be divided into constant (gross and microscopic anatomy) and variable (disease related) items. Most open access available medical courses teach constant information such as anatomy or physiology. Mandatory teaching resources are image archives with user–controlled navigation and labelling, student–oriented user manuals, discussion forums, and expert consultation. A classic undergraduate electronic educational system is WebMic which presents with histology lectures. An example designed for postgraduate teaching is the digital lung pathology system. It includes a description of diagnostic and therapeutic features of 60 rare and common lung diseases, partly in multimedia presentation. Combining multimedia features with the organization structures of a virtual pathology institution will result in a virtual pathology education institution (VPEI), which can develop to a partly automated distant learning faculty in medicine

Global wave loads on a damaged ship

A computational tool was applied based on a two dimensional linear method to predict the hydrodynamic loads for damaged ships. Experimental tests on a ship model have also been carried out to predict the hydrodynamic loads in various design conditions. The results of the theoretical method and experimental tests are compared to validate the theoretical method. The extreme wave induced loads have been calculated by short term prediction. For the loads in intact condition, the prediction with duration of 20 years at sea state 5 is used, while for loads in damaged conditions the prediction in 96 hours exposure time at sea 3 is used. The maximum values of the most probable extreme amplitudes of dynamic wave induced loads in damaged conditions are much less than those in intact condition because of the reduced time. An opening could change the distribution of not only stillwater bending moment but also wave-induced bending moment. It is observed that although some cross sections are not structurally damaged, the total loads acting on these cross sections after damage may be increased dramatically compared to the original design load in intact condition

A single nucleotide polymorphism in the Bax gene promoter affects transcription and influences retinal ganglion cell death

Pro-apoptotic Bax is essential for RGC (retinal ganglion cell) death. Gene dosage experiments in mice, yielding a single wild-type Bax allele, indicated that genetic background was able to influence the cell death phenotype. DBA/2JBax+/− mice exhibited complete resistance to nerve damage after 2 weeks (similar to Bax−/− mice), but 129B6Bax+/− mice exhibited significant cell loss (similar to wild-type mice). The different cell death phenotype was associated with the level of Bax expression, where 129B6 neurons had twice the level of endogenous Bax mRNA and protein as DBA/2J neurons. Sequence analysis of the Bax promoters between these strains revealed a single nucleotide polymorphism (T129B6 to CDBA/2J) at position −515. A 1.5- to 2.5-fold increase in transcriptional activity was observed from the 129B6 promoter in transient transfection assays in a variety of cell types, including RGC5 cells derived from rat RGCs. Since this polymorphism occurred in a p53 half-site, we investigated the requirement of p53 for the differential transcriptional activity. Differential transcriptional activity from either 129B6 or DBA/2J Bax promoters were unaffected in p53−/− cells, and addition of exogenous p53 had no further effect on this difference, thus a role for p53 was excluded. Competitive electrophoretic mobility-shift assays identified two DNA–protein complexes that interacted with the polymorphic region. Those forming Complex 1 bound with higher affinity to the 129B6 polymorphic site, suggesting that these proteins probably comprised a transcriptional activator complex. These studies implicated quantitative expression of the Bax gene as playing a possible role in neuronal susceptibility to damaging stimuli

Acceleration of Solar Wind Ions by Nearby Interplanetary Shocks: Comparison of Monte Carlo Simulations with Ulysses Observations

The most stringent test of theoretical models of the first-order Fermi mechanism at collisionless astrophysical shocks is a comparison of the theoretical predictions with observational data on particle populations. Such comparisons have yielded good agreement between observations at the quasi-parallel portion of the Earth's bow shock and three theoretical approaches, including Monte Carlo kinetic simulations. This paper extends such model testing to the realm of oblique interplanetary shocks: here observations of proton and alpha particle distributions made by the SWICS ion mass spectrometer on Ulysses at nearby interplanetary shocks are compared with test particle Monte Carlo simulation predictions of accelerated populations. The plasma parameters used in the simulation are obtained from measurements of solar wind particles and the magnetic field upstream of individual shocks. Good agreement between downstream spectral measurements and the simulation predictions are obtained for two shocks by allowing the the ratio of the mean-free scattering length to the ionic gyroradius, to vary in an optimization of the fit to the data. Generally small values of this ratio are obtained, corresponding to the case of strong scattering. The acceleration process appears to be roughly independent of the mass or charge of the species.Comment: 26 pages, 6 figures, AASTeX format, to appear in the Astrophysical Journal, February 20, 199

Compartment-directed physical examination of the knee can predict articular cartilage abnormalities disclosed by needle arthroscopy

Objective . To determine whether physical examination maneuvers that focus on each knee compartment and assess crepitus at several distinct sites can specifically disclose articular cartilage abnormalities in the compartment being assessed. Methods . Twenty patients with knee pain were examined before needle arthroscopy. Crepitus was sought from the patellofemoral compartment, medial tibiofemoral compartment, and lateral tibiofemoral compartment. Any crepitus felt in the distal tibia during a tibiofemoral stress maneuver was recorded as transmitted bony crepitus (TBC). Needle arthroscopy assessed articular cartilage (5 sites) and both menisci in each knee. Results . Crepitus by conventional assessment revealed patellar cartilage disruption (69% sensitive, 50% specific) and abnormalities of tibiofemoral cartilage (67% sensitive, 40% specific) but could not indicate their location. Tibiofemoral crepitus found cartilage disruption in the compartment at a sensitivity of 22% and a specificity of 100%, and with added tibiofemoral stress, a sensitivity of 65% and a specificity of 94% (the one “false positive” had bare bone in the other compartment). TBC was detected in 7 compartments, all of which had focal bare bone on tibial and femoral surfaces; 6 other compartments had tibial bare bone without TBC. Thus, TBC was 54% sensitive and 100% specific for tibial bare bone, and 88% sensitive and 100% specific for bone-on-bone. Conclusion . Compartment-directed physical examination of the painful knee can locate and assess the severity of certain articular cartilage abnormalities that are not reliably found by conventional methods. Transmitted bony crepitus is a specific finding for bone-on-bone in the compartment being assessed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37803/1/1780380707_ftp.pd

The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families

Isolated complex I deficiency is the most frequently observed oxidative phosphorylation defect in children with mitochondrial disease, leading to a diverse range of clinical presentations, including Leigh syndrome. For most patients the genetic cause of the biochemical defect remains unknown due to incomplete understanding of the complex I assembly process. Nonetheless, a plethora of pathogenic mutations have been described to date in the seven mitochondrial-encoded subunits of complex I as well as in 12 of the nuclear-encoded subunits and in six assembly factors. Whilst several mitochondrial DNA mutations are recurrent, the majority of these mutations are reported in single families. We have sequenced core structural and functional nuclear-encoded subunits of complex I in a cohort of 34 paediatric patients with isolated complex I deficiency, identifying pathogenic mutations in 6 patients. These included a novel homozygous NDUFS1 mutation in an Asian child with Leigh syndrome, a previously identified NDUFS8 mutation (c.236C>T, p.P79L) in a second Asian child with Leigh-like syndrome and six novel, compound heterozygous NDUFS2 mutations in four white Caucasian patients with Leigh or Leigh-like syndrome. Three of these children harboured an identical NDUFS2 mutation (c.875T>C, p.M292T), which was also identified in conjunction with a novel NDUFS2 splice site mutation (c.866+4A>G) in a fourth Caucasian child who presented to a different diagnostic centre, with microsatellite and single nucleotide polymorphism analyses indicating that this was due to an ancient common founder event. Our results confirm that NDUFS2 is a mutational hotspot in Caucasian children with isolated complex I deficiency and recommend the routine diagnostic investigation of this gene in patients with Leigh or Leigh-like phenotypes

Differential Proteome Analysis of Bone Marrow Mesenchymal Stem Cells from Adolescent Idiopathic Scoliosis Patients

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine. The cause and pathogenesis of scoliosis and the accompanying generalized osteopenia remain unclear despite decades of extensive research. In this study, we utilized two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) to analyze the differential proteome of bone marrow mesenchymal stem cells (BM-MSCs) from AIS patients. In total, 41 significantly altered protein spots were detected, of which 34 spots were identified by MALDI-TOF/TOF analysis and found to represent 25 distinct gene products. Among these proteins, five related to bone growth and development, including pyruvate kinase M2, annexin A2, heat shock 27 kDa protein, γ-actin, and β-actin, were found to be dysregulated and therefore selected for further validation by Western blot analysis. At the protein level, our results supported the previous hypothesis that decreased osteogenic differentiation ability of MSCs is one of the mechanisms leading to osteopenia in AIS. In summary, we analyzed the differential BM-MSCs proteome of AIS patients for the first time, which may help to elucidate the underlying molecular mechanisms of bone loss in AIS and also increase understanding of the etiology and pathogenesis of AIS

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

The Inuit discovery of Europe? The Orkney Finnmen, preternatural objects and the re-enchantment of early-modern science.

The late-seventeenth century saw a peak in accounts of supposed encounters with ‘Finnmen’ in Orkney. These accounts have shaped the folklore of the Northern Isles. Scholars linked to the Royal Society suggested the accounts represented encounters with Inuit. Subsequent explanations included autonomous travel by Inuit groups and abduction and abandonment. These accounts should be understood as part of a European scientific tradition of preternatural philosophy, occupied with the deviations and errors of nature. Far from indicating the presence of Inuit individuals in Orkney waters, they provide evidence of the narrative instability of early-modern science and its habit of ‘thinking with things’. Captivated by Inuit artefacts, the natural philosophers and virtuosi of the Royal Society imagined Orkney as a site of reverse contact with the ‘primitive’. Nineteenth-century antiquarians and folklorists reliant on these texts failed to understand the extent to which objectivity was not an epistemic virtue in early-modern science