Screening for pickiness - a validation study

Picky eating is prevalent in childhood and is associated with negative health outcomes. Therefore early detection of pickiness is pertinent. Because no psychometric measure of picky/fussy eating has been validated, we aimed to examine the screening efficiency of the 6-item ‘Food Fussiness’ (FF) scale from the Children’s Eating Behavior Questionnaire using structured psychiatric interviews (the Preschool Age Psychiatric Interview), providing meaningful cut-off values based on a large, representative sample of Norwegian 6 year olds (n = 752). Screening efficiency was evaluated using receiver operating characteristic curve analysis, revealing excellent discrimination. The cut-point maximizing the sum of sensitivity and specificity for the scale was found at a score of 3.33 for severe cases and 3.00 when both moderate and severe pickiness were included. The results suggest that the FF scale may provide a tool for identification of clinically significant picky eating, although further assessment may be needed to separate moderate from severe cases

Drug Development for Alzheimer's Disease: Recent Progress

Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development

Comparison of Pharmacological Modulation of APP Metabolism in Primary Chicken Telencephalic Neurons and in a Human Neuroglioma Cell Line

Sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases and the formation of Aβ peptides are pivotal for Alzheimer's disease. Therefore, a large number of drugs has been developed targeting APP metabolism. However, many pharmacological compounds have been identified in vitro in immortalized APP overexpressing cell lines rather than in primary neurons. Here, we compared the effect of already characterized secretase inhibitors and modulators on Aβ formation in primary chicken telencephalic neurons and in a human neuroglioma cell line (H4) ectopically expressing human APP with the Swedish double mutation. Primary chicken neurons replicated the effects of a β-secretase inhibitor (β-secretase inhibitor IV), two γ-secretase inhibitors (DAPM, DAPT), two non-steroidal-anti-inflammatory drugs (sulindac sulfide, CW), and of the calpain inhibitor calpeptin. With the exception of the two γ-secretase inhibitors, all tested compounds were more efficacious in primary chicken telencephalic neurons than in the immortalized H4 cell line. Moreover, H4 cells failed to reproduce the effect of calpeptin. Hence, primary chicken telencephalic neurons represent a suitable cell culture model for testing drugs interfering with APP processing and are overall more sensitive to pharmacological interference than immortalized H4 cells ectopically expressing mutant human APP

An iconic language for the graphical representation of medical concepts

<p>Abstract</p> <p>Background</p> <p>Many medication errors are encountered in drug prescriptions, which would not occur if practitioners could remember the drug properties. They can refer to drug monographs to find these properties, however drug monographs are long and tedious to read during consultation. We propose a two-step approach for facilitating access to drug monographs. The first step, presented here, is the design of a graphical language, called VCM.</p> <p>Methods</p> <p>The VCM graphical language was designed using a small number of graphical primitives and combinatory rules. VCM was evaluated over 11 volunteer general practitioners to assess if the language is easy to learn, to understand and to use. Evaluators were asked to register their VCM training time, to indicate the meaning of VCM icons and sentences, and to answer clinical questions related to randomly generated drug monograph-like documents, supplied in text or VCM format.</p> <p>Results</p> <p>VCM can represent the various signs, diseases, physiological states, life habits, drugs and tests described in drug monographs. Grammatical rules make it possible to generate many icons by combining a small number of primitives and reusing simple icons to build more complex ones. Icons can be organized into simple sentences to express drug recommendations. Evaluation showed that VCM was learnt in 2 to 7 hours, that physicians understood 89% of the tested VCM icons, and that they answered correctly to 94% of questions using VCM (versus 88% using text, <it>p </it>= 0.003) and 1.8 times faster (<it>p </it>< 0.001).</p> <p>Conclusion</p> <p>VCM can be learnt in a few hours and appears to be easy to read. It can now be used in a second step: the design of graphical interfaces facilitating access to drug monographs. It could also be used for broader applications, including the design of interfaces for consulting other types of medical document or medical data, or, very simply, to enrich medical texts.</p

Regulation of Mycobacterium tuberculosis virulence

During infection, Mycobacterium tuberculosis delivers critical ESX-1 virulence factors that modulate host cell function and stimulate adaptive immunity. Precise control of ESX-1 secretion may be essential for determining M. tuberculosis pathogenesis. Here we report the crystal structure for EspR, a key transcriptional regulator of ESX-1 secretion. The helix-turn-helix (HTH) domains of EspR are arranged in an unusual conformation in which they are splayed at an oblique angle to each other, suggesting that EspR binds DNA in a profoundly different way than most other known HTH regulators. By mapping the EspR binding sites in the espACD promoter, using both in vivo and in vitro binding assays, we showed that the EspR operators are located unusually far from the promoter. The EspR dimer binds to these sites cooperatively, but the two "half-sites" contacted by each DNA recognition motif are separated by 177 base pairs. The distinctive structure of EspR and the exceptional arrangement of its operator contacts suggest that it could promote DNA looping in its target promoter. Here we present multiple pieces of data that, taken together, support the direct looping model. With a transcription reporter assay, we showed that EspR activity is DNA phase-dependent, consistent with looping between its sites. Using ChIP-chip, we determined the global binding landscape of EspR, which includes regions important for ESX-1 secretion, PDIM synthesis, and control of its own promoter. Through independent in vivo and in vitro methods, we identified the EspR consensus binding site, and find that its distribution and spacing throughout the genome is consistent with EspR-mediated looping as a widespread phenomenon. Finally, we found a key mechanistic clue by concurrent studies of another transcriptional regulator, Lsr2, which appears to be epistatic to EspR for espACD transcription. By comparing the genome-wide binding sites and determining the complete transcriptional regulons of EspR and Lsr2, we found that the function of these two factors is linked at many sites throughout the genome. We discuss potential mechanisms for global co-regulation by EspR and Lsr2

Drama, politics, and news in the Earl of Sussex's entertainment of Elizabeth at New Hall, 1579

In September 1579, at the height of an intense political debate over her prospective marriage to the duke of Anjou, Elizabeth I visited New Hall, the country seat of the match’s greatest supporter within England, Thomas Radcliffe, third earl of Sussex. Her entertainment on that occasion, hitherto completely unknown, was described in a letter, printed here, from one Norfolk gentleman, Sir Edward Clere, to another, Bassingbourne Gawdy. The letter describes the dramatic performances and other entertainments provided for the queen, which included coded but unmistakeable encouragements for her to proceed with the marriage. This article discusses the ways in which this was done and their consequences for our knowledge of the Anjou marriage debate as a political episode, suggesting that Sussex sought to use the entertainment to boost the participation of more conservative members of the nobility in government. It also explores how this evidence affects our picture of Elizabethan courtly entertainments, and particularly their non-dramatic elements. Finally, it discusses Clere’s letter itself as an insight into the nature of gentry news culture, particularly with regard to matters of high politics