Genetic testing in dementia — utility and clinical strategies

Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information

Micro-milling work-holding devices employing adhesive forces

IngenieursweseBedryfsingenieursweseMicro-parts are often very fragile rendering conventional, mechanical work-holding fixtures unsuitable for them since they exert large straining forces. Furthermore, macroworkholding devices occupy a large space which impedes high precision required in micromilling. Although some micro-clamping fixtures exist, they are limited to specific part shapes and in most cases expensive to manufacture. Hence this paper focuses on the application of adhesive forces namely electrostatic, surface tension and van-der-Waals forces; in work-holding strategies for micro-milling operations. An analysis is given as to their applicability with reference to micro-milling cutting forces

Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there is little guidance available about their use in clinical practice. Guidelines on which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared to those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalizable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These publicly-available data should provide a basis for informed counselling and clinical decision making

Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust

Applying the LCC method to DB track

W Centrum Badawczo-Technologicznym kolei niemieckich (Forschungs-und Technologie-Zentrum der DB AG) do oceny torów kolejowych ma zostać wprowadzona metoda polegająca na przeprowadzeniu analizy kosztu cyklu życia (life cycle coat - LCC). Bazująca na cyklicznych wpłatach i wypłatach metoda zintegrowana jest z zestawem narzędzi programowych TETrAs. W oparciu o zweryfikowane modele symulacyjne i szerokie podstawy naukowe można uzyskać wiarygodne informacje o zakresie i czasie wypłat przypadających na różne zespoły kosztów

Study on applicability of adhesive forces for micro-material handling in production technology

The original publication is available at http://www.isem.org.za/index.php/isem/isem2011Conference of the ISEM 2011 Proceedings, Stellenbosch, South Africa, 21 - 23 September 2011.Conference theme - Innovative Systems Thinking: Unravelling Complexity for Successful Solutions.Micro-material handling and micro-assembly becomes increasingly important in largevolume manufacturing of products like sensors in automotive applications. Smaller dimensions of the micro-objects lead to problems with regard to the reliability of the manufacturing process because adhesive forces become predominant over gravity for objects whose dimensions are in the micro-range. In contrast to the common approach of minimizing those adhesive forces, this paper focuses on the use of the three main adhesive forces, van-der-Waals, electrostatic and surface tension forces, as gripping principles. These forces are compared to conventional vacuum grippers with regard to gripping forces and complexity of application. Modelling of the forces is executed for separation distances in the range of 1x10-12 m - 1x10-3 m. Even though vacuum forces dominate in magnitude over others within the whole range, there are several disadvantages of using them. On the other hand adhesive forces are advantageous in that they require little amount of energy and they do not mechanically strain the micro-parts being handled.Publishers' Versio