Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-β oligomers

The cellular prion protein (PrPC) is a key neuronal receptor for amyloid-β oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor. Conversely, siRNA-mediated ADAM10 knockdown reduced PrPC shedding and increased AβO binding, which was blocked by the PrPC-specific antibody 6D11. The retinoic acid receptor analog acitretin, which up-regulates ADAM10, also promoted PrPC shedding and decreased AβO binding in the neuroblastoma cells and in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Pretreatment with acitretin abolished activation of Fyn kinase and prevented an increase in reactive oxygen species caused by AβO binding to PrPC Besides blocking AβO binding and toxicity, acitretin also increased the non-amyloidogenic processing of APP. However, in the iPSC-derived neurons, Aβ and other amyloidogenic processing products did not exhibit a reciprocal decrease upon acitretin treatment. These results indicate that by promoting the shedding of PrPC in human neurons, ADAM10 activation prevents the binding and cytotoxicity of AβO, revealing a potential therapeutic benefit of ADAM10 activation in AD

Extubation process in bed-ridden elderly intensive care patients receiving inspiratory muscle training: a randomized clinical trial

Samária Ali Cader,1 Rodrigo Gomes de Souza Vale,1 Victor Emmanuel Zamora,2 Claudia Henrique Costa,2 Estélio Henrique Martin Dantas11Laboratory of Human Kinetics Bioscience, Federal University of Rio de Janeiro State, 2Pedro Ernesto University Hospital, School of Medicine, State University of Rio de Janeiro, Rio de Janeiro, BrazilBackground: The purpose of this study was to evaluate the extubation process in bed-ridden elderly intensive care patients receiving inspiratory muscle training (IMT) and identify predictors of successful weaning.Methods: Twenty-eight elderly intubated patients in an intensive care unit were randomly assigned to an experimental group (n = 14) that received conventional physiotherapy plus IMT with a Threshold IMT® device or to a control group (n = 14) that received only conventional physiotherapy. The experimental protocol for muscle training consisted of an initial load of 30% maximum inspiratory pressure, which was increased by 10% daily. The training was administered for 5 minutes, twice daily, 7 days a week, with supplemental oxygen from the beginning of weaning until extubation. Successful extubation was defined by the ventilation time measurement with noninvasive positive pressure. A vacuum manometer was used for measurement of maximum inspiratory pressure, and the patients' Tobin index values were measured using a ventilometer.Results: The maximum inspiratory pressure increased significantly (by 7 cm H2O, 95% confidence interval [CI] 4–10), and the Tobin index decreased significantly (by 16 breaths/min/L, 95% CI −26 to 6) in the experimental group compared with the control group. The Chi-squared distribution did not indicate a significant difference in weaning success between the groups (Χ2 = 1.47; P = 0.20). However, a comparison of noninvasive positive pressure time dependence indicated a significantly lower value for the experimental group (P = 0.0001; 95% CI 13.08–18.06). The receiver-operating characteristic curve showed an area beneath the curve of 0.877 ± 0.06 for the Tobin index and 0.845 ± 0.07 for maximum inspiratory pressure.Conclusion: The IMT intervention significantly increased maximum inspiratory pressure and significantly reduced the Tobin index; both measures are considered to be good extubation indices. IMT was associated with a reduction in noninvasive positive pressure time in the experimental group.Keywords: inspiratory muscle training, rehabilitation, extubatio

Good friends and good partners : the 'new' face of China-Africa co-operation.

The purpose of this paper is to discuss methodology for mapping quantitative trait loci (QTLs) in behavior genetics. Specifically, methods of linkage and association mapping of continuous and disease traits are presented, along with examples of their application. Variance components and regression based methods for analysis of continuous traits with be discussed. In addition, methods for dealing with complex disease data will also be presented. Practical considerations in genomewide association (GWA) studies will be discussed, through the presentation of a genomewide association study of a complex disease

Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds.

The age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD)=4.29) and 2q35 (LOD=3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD=2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD=3.31 at 5p14 and LOD=3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD

A causal role for TRESK loss of function in migraine mechanisms

The two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. Furthermore, using CRISPR-Cas9 engineering to correct the F139WfsX2 mutation, we show a reversal of the heightened neuronal excitability, linking the phenotype to the mutation. In contrast we find no change in excitability in induced pluripotent stem cell derived nociceptors with the C110R mutation and preserved TRESK current; thereby confirming that only the frameshift mutation is associated with loss of function and a migraine relevant cellular phenotype. We then demonstrate the importance of TRESK to pain states by showing that the TRESK activator, cloxyquin, can reduce the spontaneous firing of nociceptors in an in vitro human pain model. Using the chronic nitroglycerine rodent migraine model, we demonstrate that mice lacking TRESK develop exaggerated nitroglycerine-induced mechanical and thermal hyperalgesia, and furthermore, show that cloxyquin conversely is able to prevent sensitization. Collectively, our findings provide evidence for a role of TRESK in migraine pathogenesis and its suitability as a therapeutic target

Additive value for ultrasonographic signal in a screening algorithm for patients presenting with acute mono-/oligoarthritis in whom gout is suspected

Item does not contain fulltextCrystal arthritides such as gout can be detected by ultrasonography (US). This study reveals the performance of joint US (double contour sign (DCS), tophus (T), hyperechoic spots cq. "snow storm" (SS)) for diagnosing gout and calcium pyrophosphate dihydrate crystal deposition disease (CPPD) in patients with acute mono- or oligoarthritis (MOA). The gold standard is the presence of monosodium urate (MSU)/CPPD crystals. Fifty-four Dutch patients had an acute MOA. US was performed on the following six joints maximum: the arthritic joint, the contra lateral side, metatarsophalangeal (MTP)-1, and knees bilaterally in case of arthritis in one of these joints. In case of wrist/PIP/MCP-arthritis, the knees and MTP-1 were scanned. These were examined for DCS, T, SS, and intercartilage rim (CPPD). Synovial fluid was aspirated from the affected joint for MSU proof. Twenty-six of the 54 (48 %) patients with MOA had MSU-proven gout. Sensitivity of DCS and any US abnormality (DCS, T, SS) was 77 and 96 %, respectively. The positive likelihood ratio (LR+) for DCS and any ultrasonographic abnormality (USabn) was 3.08 and 2.99, respectively, and the LR- was 0.31 and 0.06, respectively. In MSU-proven gout patients where the affected joint is not MTP-1, MTP-1 still showed USabn in 42 % of the patients. None of the CPPD patients had an intercartilage rim. In dedicated hands, ultrasonography deserves a place early in a screening algorithm of MOA patients, particularly if specificity is high enough to make punctures abundant or when microscopy is not available. In 86 % of the MSU-proven gout patients, the DCS is not present in another joint other than the affected or MTP-1 joint