Familial amyloid precursor protein mutants cause caspase-6-dependent but amyloid β-peptide-independent neuronal degeneration in primary human neuron cultures.

Although familial Alzheimer disease (AD)-associated autosomal dominant mutants have been extensively studied, little is known about the underlying molecular mechanisms of neurodegeneration induced by these mutants in AD. Wild-type, Swedish or London amyloid precursor protein (APP) transfection in primary human neurons induced neuritic beading, in which several co-expressed proteins, such as enhanced green fluorescent protein, red fluorescent protein (RFP)-tau and RFP-ubiquitin, accumulated. APP-induced neuritic beading was dependent on caspase-6 (Casp6), because it was inhibited with 5 μM z-VEID-fmk or with dominant-negative Casp6. Neuritic beading was independent from APP-mediated amyloid β-peptide (Aβ) production, because the APPM596V (APPMV) mutant, which cannot generate Aβ, still induced Casp6-dependent neuritic beading. However, the beaded neurons underwent Casp6- and Aβ-dependent cell death. These results indicate that overexpression of wild-type or mutant APP causes Casp6-dependent but Aβ-independent neuritic degeneration in human neurons. Because Casp6 is activated early in AD and is involved in axonal degeneration, these results suggest that the inhibition of Casp6 may represent an efficient early intervention against familial forms of AD. Furthermore, these results indicate that removing Aβ without inhibiting Casp6 may have little effect in preventing the progressive dementia associated with sporadic or familial AD

Implementing shared decision-making in nutrition clinical practice: A theory-based approach and feasibility study

<p>Abstract</p> <p>Background</p> <p>There are a growing number of dietary treatment options to choose from for the management of many chronic diseases. Shared decision making represents a promising approach to improve the quality of the decision making process needed for dietary choices that are informed by the best evidence and value-based. However, there are no studies reporting on theory-based approaches that foster the implementation of shared decision making in health professions allied to medicine. The objectives of this study are to explore the integration of shared decision making within real nutritional consultations, and to design questionnaires to assess dieticians' intention to adopt two specific behaviors related to shared decision making using the Theory of Planned Behavior.</p> <p>Methods</p> <p>Forty dieticians will audiotape one clinical encounter to explore the presence of shared decision making within the consultation. They will also participate to one of five to six focus groups that aim to identify the salient beliefs underlying the determinants of their intention to present evidence-based dietary treatment options to their patients, and clarify the values related to dietary choices that are important to their patients. These salient beliefs will be used to elaborate the items of two questionnaires. The internal consistency of theoretical constructs and the temporal stability of their measurement will be checked using the test-retest method by asking 35 dieticians to complete the questionnaire twice within a two-week interval.</p> <p>Discussion</p> <p>The proposed research project will be the first study to: provide preliminary data about the adoption of shared decision making by dieticians and theirs patients; elicit dieticians' salient beliefs regarding the intention to adopt shared decision making behaviors, report on the development of a specific questionnaire; explore dieticians' views on the implementation of shared decision making; and compare their views regarding the implementation of shared decision making in different clinical settings.</p> <p>It is anticipated that the results generated by the proposed research project will significantly contribute to the emergence of shared decision making in nutrition through a theory-based approach.</p

A Viral Vectored Prime-Boost Immunization Regime Targeting the Malaria Pfs25 Antigen Induces Transmission-Blocking Activity

The ookinete surface protein Pfs25 is a macrogamete-to-ookinete/ookinete stage antigen of Plasmodium falciparum, capable of exerting high-level anti-malarial transmission-blocking activity following immunization with recombinant protein-in-adjuvant formulations. Here, this antigen was expressed in recombinant chimpanzee adenovirus 63 (ChAd63), human adenovirus serotype 5 (AdHu5) and modified vaccinia virus Ankara (MVA) viral vectored vaccines. Two immunizations were administered to mice in a heterologous prime-boost regime. Immunization of mice with AdHu5 Pfs25 at week 0 and MVA Pfs25 at week 10 (Ad-MVA Pfs25) resulted in high anti-Pfs25 IgG titers, consisting of predominantly isotypes IgG1 and IgG2a. A single priming immunization with ChAd63 Pfs25 was as effective as AdHu5 Pfs25 with respect to ELISA titers at 8 weeks post-immunization. Sera from Ad-MVA Pfs25 immunized mice inhibited the transmission of P. falciparum to the mosquito both ex vivo and in vivo. In a standard membrane-feeding assay using NF54 strain P. falciparum, oocyst intensity in Anopheles stephensi mosquitoes was significantly reduced in an IgG concentration-dependent manner when compared to control feeds (96% reduction of intensity, 78% reduction in prevalence at a 1 in 5 dilution of sera). In addition, an in vivo transmission-blocking effect was also demonstrated by direct feeding of immunized mice infected with Pfs25DR3, a chimeric P. berghei line expressing Pfs25 in place of endogenous Pbs25. In this assay the density of Pfs25DR3 oocysts was significantly reduced when mosquitoes were fed on vaccinated as compared to control mice (67% reduction of intensity, 28% reduction in prevalence) and specific IgG titer correlated with efficacy. These data confirm the utility of the adenovirus-MVA vaccine platform for the induction of antibodies with transmission-blocking activity, and support the continued development of this alternative approach to transmission-blocking malaria subunit vaccines

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Bifidobacterium Infantis 35624 Protects Against Salmonella-Induced Reductions in Digestive Enzyme Activity in Mice by Attenuation of the Host Inflammatory Response

OBJECTIVES: Salmonella-induced damage to the small intestine may decrease the villi-associated enzyme activity, causing malabsorption of nutrients and diarrhea, and thus contribute to the symptoms of infection. The objective of this study was to determine the mechanism by which different doses and durations of Salmonella infection and lipopolysaccharide (LPS) affect brush border enzyme activity in the mouse, and to determine if the probiotic Bifidobacterium longum subspecies infantis 35624 could attenuate the intestinal damage. METHODS: BALB/c mice were challenged with Salmonella enterica serovar Typhimurium UK1 at various doses (10(2)-10(8) colony-forming unit (CFU)) and durations (10(6) CFU for 1-6 days). Mice were also treated with B. longum subsp. infantis 35624 for 2 weeks before and during a 6-day S. Typhimurium challenge (10(6) CFU), or before injection of LPS. The small intestine was assessed for morphological changes, mRNA expression of cytokines, and activity of the brush border enzymes sucrase-isomaltase, maltase, and alkaline phosphatase. RESULTS: S. Typhimurium infection significantly reduced the activity of all brush border enzymes in a dose- and time-dependent manner (P<0.05). This also occurred following injection of LPS. Pre-treatment with B. longum subsp. infantis 35624 prevented weight loss, protected brush border enzyme activity, reduced the small intestinal damage, and inhibited the increase in interleukin (IL)-10 and IL-8 expression due to Salmonella challenge. CONCLUSIONS: Salmonella infection reduces the small intestinal brush border enzyme activity in mice, with the level of reduction and associated weight loss increasing with dose and duration of infection. B. longum subsp. infantis 35624 treatment attenuated the effect of Salmonella infection on brush border enzyme activity and weight loss, which may be due to modulation of the host immune response

Focus on the management of thunderclap headache: from nosography to treatment

Thunderclap headache (TCH) is an excruciating headache characterized by a very sudden onset. Recognition and accurate diagnosis of TCH are important in order to rule out the various, serious underlying brain disorders that, in a high percentage of cases, are the real cause of the headache. Primary TCH, which may recur intermittently and generally has a spontaneous, benign evolution, can thus be diagnosed only when all other potential underlying causes have been excluded through accurate diagnostic work up. In this review, we focus on the management of TCH, paying particular attention to the diagnostic work up and treatment of the condition

Bath Breakfast Project (BBP) - Examining the role of extended daily fasting in human energy balance and associated health outcomes: Study protocol for a randomised controlled trial [ISRCTN31521726]

<p>Abstract</p> <p>Background</p> <p>Current guidance regarding the role of daily breakfast in human health is largely grounded in cross-sectional observations. However, the causal nature of these relationships has not been fully explored and what limited information is emerging from controlled laboratory-based experiments appears inconsistent with much existing data. Further progress in our understanding therefore requires a direct examination of how daily breakfast impacts human health under free-living conditions.</p> <p>Methods/Design</p> <p>The Bath Breakfast Project (BBP) is a randomised controlled trial comparing the effects of daily breakfast consumption relative to extended fasting on energy balance and human health. Approximately 70 men and women will undergo extensive laboratory-based assessments of their acute metabolic responses under fasted and post-prandial conditions, to include: resting metabolic rate, substrate oxidation, dietary-induced thermogenesis and systemic concentrations of key metabolites/hormones. Physiological and psychological indices of appetite will also be monitored both over the first few hours of the day (i.e. whether fed or fasted) and also following a standardised test lunch used to assess voluntary energy intake under controlled conditions. Baseline measurements of participants' anthropometric characteristics (e.g. DEXA) will be recorded prior to intervention, along with an oral glucose tolerance test and acquisition of adipose tissue samples to determine expression of key genes and estimates of tissue-specific insulin action. Participants will then be randomly assigned either to a group prescribed an energy intake of ≥3000 kJ before 1100 each day or a group to extend their overnight fast by abstaining from ingestion of energy-providing nutrients until 1200 each day, with all laboratory-based measurements followed-up 6 weeks later. Free-living assessments of energy intake (via direct weighed food diaries) and energy expenditure (via combined heart-rate/accelerometry) will be made during the first and last week of intervention, with continuous glucose monitors worn both to document chronic glycaemic responses to the intervention and to verify compliance.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN31521726">ISRCTN31521726</a>.</p

Secreted Human Amyloid Precursor Protein Binds Semaphorin 3a and Prevents Semaphorin-Induced Growth Cone Collapse

The amyloid precursor protein (APP) is well known for giving rise to the amyloid-β peptide and for its role in Alzheimer's disease. Much less is known, however, on the physiological roles of APP in the development and plasticity of the central nervous system. We have used phage display of a peptide library to identify high-affinity ligands of purified recombinant human sAPPα695 (the soluble, secreted ectodomain from the main neuronal APP isoform). Two peptides thus selected exhibited significant homologies with the conserved extracellular domain of several members of the semaphorin (Sema) family of axon guidance proteins. We show that sAPPα695 binds both purified recombinant Sema3A and Sema3A secreted by transfected HEK293 cells. Interestingly, sAPPα695 inhibited the collapse of embryonic chicken (Gallus gallus domesticus) dorsal root ganglia growth cones promoted by Sema3A (Kd≤8·10−9 M). Two Sema3A-derived peptides homologous to the peptides isolated by phage display blocked sAPPα binding and its inhibitory action on Sema3A function. These two peptides are comprised within a domain previously shown to be involved in binding of Sema3A to its cellular receptor, suggesting a competitive mechanism by which sAPPα modulates the biological action of semaphorins

TRAIL-receptor preferences in pancreatic cancer cells revisited: Both TRAIL-R1 and TRAIL-R2 have a licence to kill

Background TRAIL is a potent and specific inducer of apoptosis in tumour cells and therefore is a possible new cancer treatment. It triggers apoptosis by binding to its cognate, death-inducing receptors, TRAIL-R1 and TRAIL-R2. In order to increase its activity, receptor-specific ligands and agonistic antibodies have been developed and some cancer types, including pancreatic cancer, have been reported to respond preferentially to TRAIL-R1 triggering. The aim of the present study was to examine an array of TRAIL-receptor specific variants on a number of pancreatic cancer cells and test the generality of the concept of TRAIL-R1 preference in these cells. Methods TRAIL-R1 and TRAIL-R2 specific sTRAIL variants were designed and tested on a number of pancreatic cancer cells for their TRAIL-receptor preference. These sTRAIL variants were produced in HEK293 cells and were secreted into the medium. After having measured and normalised the different sTRAIL variant concentrations, they were applied to pancreatic and control cancer cells. Twenty-four hours later apoptosis was measured by DNA hypodiploidy assays. Furthermore, the specificities of the sTRAIL variants were validated in HCT116 cells that were silenced either for TRAIL-R1 or TRAIL-R2. Results Our results show that some pancreatic cancer cells use TRAIL-R1 to induce cell death, whereas other pancreatic carcinoma cells such as AsPC-1 and BxPC-3 cells trigger apoptosis via TRAIL-R2. This observation extended to cells that were naturally TRAIL-resistant and had to be sensitised by silencing of XIAP (Panc1 cells). The measurement of TRAIL-receptor expression by FACS revealed no correlation between receptor preferences and the relative levels of TRAIL-R1 and TRAIL-R2 on the cellular surface. Conclusions These results demonstrate that TRAIL-receptor preferences in pancreatic cancer cells are variable and that predictions according to cancer type are difficult and that determining factors to inform the optimal TRAIL-based treatments still have to be identified