Global similarity with local differences in linkage disequilibrium between the Dutch and HapMap–CEU populations

The HapMap project has facilitated the selection of tagging single nucleotide polymorphisms (tagSNPs) for genome-wide association studies (GWAS) under the assumption that linkage disequilibrium (LD) in the HapMap populations is similar to the populations under investigation. Earlier reports support this assumption, although in most of these studies only a few loci were evaluated. We compared pair-wise LD and LD block structure across autosomes between the Dutch population and the CEU-HapMap reference panel. The impact of sampling distribution on the estimation of LD blocks was studied by bootstrapping. A high Pearson correlation (genome-wide; 0.93) between pair-wise

Deleterious GRM1 Mutations in Schizophrenia

We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies

Chronic plaque psoriasis

Chronic plaque psoriasis, the most common form of psoriasis, is a papulosquamous disease defined by erythematous plaques with a silvery scale. The diagnosis usually is clinical, but occasionally a biopsy is necessary. Psoriasis affects 0.6 to 4.8 percent of the U.S. population, and about 30 percent of affected patients have a first-degree relative with the disease. Psoriasis is a T-cell-mediated autoimmune disease, but certain medications and infections are well-known risk factors. Management of psoriasis includes education about chronicity, realistic expectations, and use of medication. Steroids and vitamin D derivatives (e.g., calcipotriene) are the mainstays of topical therapy. Topical steroids and calcipotriene together may work better than either agent alone. Patients with psoriasis involving more than 20 percent of their skin or those not responding to topical therapy are candidates for light therapy; traditional systemic therapy; or systemic treatment with immunomodulatory drugs such as alefacept, efalizumab, and etanercept. For full text, click here:South African Family Practice2006;48(9):30-3

Mixed treatment comparison of a two-compound formulation (TCF) product containing calcipotriol and betamethasone dipropionate with other topical treatments in psoriasis vulgaris.

Item does not contain fulltextOBJECTIVE: The efficacy of the two-compound formulation (TCF) product containing calcipotriol and betamethasone dipropionate applied once daily in psoriasis has been demonstrated in phase III trials but no randomised clinical trial comparing all commonly used topical treatments exists. The aim of the study was to compare the efficacy of once-daily use of the TCF product relative to other commonly used topical agents in plaque psoriasis. RESEARCH DESIGN AND METHODS: Data on change in Psoriasis Area and Severity Index (PASI) score from baseline and PASI 75 (percentage of patients achieving a 75% reduction in PASI score), after 4 weeks of treatment were obtained by means of a systematic literature review of randomised controlled trials and synthesised with a Bayesian mixed treatment comparison meta-analysis. RESULTS: Relative to all active interventions, except for the unlicensed twice-daily application of the TCF product, the TCF once daily showed a greater efficacy based on PASI 75 response (relative risk ranging from 1.22 to 3.18) and improvement in PASI score from baseline (difference in % CFB PASI between TCF once daily and other active interventions ranged from 4.01 to 49.68). CONCLUSION: Among topical therapies evaluated, TCF once daily can be considered the most efficacious treatment for plaque psoriasis.1 januari 201

Advanced AI search techniques in modern digital circuit synthesis

Progress in microelectronic technology is extremely fast and it is outstripping the designers' abilities to make use of the created opportunities. Development and application of new more suitable design methods and tools is therefore very important for the modern system industry. This paper shows the importance of the AI search techniques for the circuits and systems design space exploration, explains what sorts of search techniques are useful for this aim, and discusses the place, role and way of use of these techniques in circuit and system design. In particular, the paper explains the importance and usage of the heuristic search techniques for the automatic construction and selection of the most promising solutions to the circuit synthesis problems. The discussion and conclusions of the paper are illustrated with examples of three effective and efficient search algorithms, and experimental results from their application to two important circuit synthesis problems. The knowledge presented in the paper combines numerous valuable concepts of modern system engineering and artificial intelligence, and forms a base for further research and application of the AI search techniques to design of complex circuits and systems