Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.

IntroductionDisruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).MethodsWe examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS-AD), 43 who met criteria for mild cognitive impairment (DS-MCI), and 211 who were cognitively unaffected and stable (CS).ResultsWe measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate-corrected q< 0.05. From the DE features, a nine-feature classifier model classified the CS and DS-AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two-feature model classified the DS-MCI and DS-AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism.DiscussionOur results reveal metabolic alterations in DS-AD that are similar to those seen in LOAD. The pattern of results in this cross-sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non-demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS-AD

Determining a new alignment scoring matrix for disordered proteins

Intrinsically disordered proteins (IDPs) are polypeptide sequences that do not form a rigid three dimensional structure when isolated in the cytosol of the cell. These sequences are very common in most genomes, and usually are involved in many protein-protein interactions. IDPs also play a key role in many diseases, including cancer and Huntington\u27s disease. However, IDPs are difficult to study because of their amorphous shape, high mutation rate, and unique amino acid composition. These obstacles make homology studies especially difficult. This study focused on generating a new substitution matrix designed to aid in homology studies of IDPs. The matrix was generated using a genetic algorithm (GA). GAs are alternative hill-climbing methods for finding solutions in complex problem spaces. To achieve this goal, a GA models the evolutionary process found in nature by breeding solutions to the problem until one of sufficient quality is produced. The GA implemented in this study produced a substitution matrix for use in differentiation between homologous and non-homologous proteins containing disordered regions. The matrix showed some correlation to the patterns of evolution found in disordered proteins and their general sequence makeup. However, when compared to a commonly used substitution matrix, BLOSUM, the GA\u27s solution did not show significant improvement. But the results here do show a general proof of concept, and that given modifications to the GA, more time, or more resources, a substitution matrix capable of out-performing BLOSUM is potentially possible

Definitions and clinical guidance on the enteral dependence component of the avoidant/restrictive food intake disorder diagnostic criteria in children

The aim of the current paper is to offer definitive guidance on weaning children who are reliant on nasogastric/gastrostomy feeding tubes. To date, no internationally recognised definitions or principles for interventions exist and clinics have been reliant on creating their own unique intervention criteria. To achieve the aim, two goals are set out within the current paper. The first goal was to definitively define the process of tube weaning. In order to achieve this, both tube dependency and oral eating also required definitions. It is necessary for these two additional definitions to fully understand the process of tube weaning and the transition that the child is making within these clinical interventions. The second goal of this paper was to propose a set of minimum measurement criteria within a tube weaning protocol so that different clinical practices and perspectives may be measured accurately. This would then allow outcomes from different clinical services to be compared for efficacy. The culmination of this paper is a set of five core principles that should govern clinics that adhere to the auspices of evidence-based practice. These principles, if adopted, will provide the basis of a set of internationally recognised criteria within this field of paediatric gastroenterology

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event

Methylphenidate Treatment in Children with Borderline IQ and Mental Retardation: Analysis of Three Aggregated Studies

Objective: To determine response of low-IQ children with attention deficit hyperactivity disorder (ADHD) symptoms to methylphenidate (MPH). Methods: An aggregated analysis was conducted in 90 children with low IQ who received the same dose regimen of MPH in three independent, placebo-controlled studies. Active drug and placebo were given from 2 to 4 weeks each. Outcome measures included teacher and parent ratings on standardized behavior scales (mean n = 84), performance on computer-controlled cognitive-motor tests (n = 62), and measures of cardiovascular response (n = 85). Results: Both teachers and parents rated the children consistently as being improved on subscales assessing attention, overactivity, and conduct problems. Some 44% of the subjects showed at least a 30% reduction compared with placebo on teacher ratings. MPH improved accuracy on several cognitive tests, response speed was increased on some, and seat activity declined for one of three tests; heart rate was mildly increased (3.9 beats/minute) with MPH. Analyses of IQ and mental age as moderator variables suggested that lower functional level (especially lower IQ) may be associated with a less favorable response to MPH. Conclusions: Children with low IQ and ADHD clearly respond to MPH, but their rate of beneficial response appears to be well under that of normal-IQ children and more varied. Different attentional mechanisms may moderate response to psychostimulants

Differential effects of film on preschool children's behaviour dependent on editing pace

Aim: Evidence on how the pace of television and film editing affects children?s behaviour and attention is inconclusive. We examined whether a fast-paced film affected how preschool-aged children interacted with toys. Methods: The study comprised 70 children (36 girls) aged 2-4.5 years who attended preschools in Essex, United Kingdom. The children were paired up and tested with either a fast- or a slow-paced film of a narrator reading a children?s story. The fast-paced version had 102 camera cuts and 16 still images and the slow-paced version had 22 camera cuts and four still images. Each dyad took part in two video-recorded free-play sessions, before and after they watched one of the specially edited four-minute films. The number of toys the children played with before and and after the film sessions was recorded. Results: Before they watched the films, the children?s behaviour did not differ between the groups. However, after watching the film, the children in the fast-paced group shifted their attention between toys more frequently than the children who watched the slow-paced film. Conclusion: Even a brief exposure to differently paced films had an immediate effect on how the children interacted with their toys

Cognitive Effects of Risperidone in Children with Autism and Irritable Behavior

Objective: The objective of this research was to explore the effects of risperidone on cognitive processes in children with autism and irritable behavior. Method: Thirty-eight children, ages 5-17 years with autism and severe behavioral disturbance, were randomly assigned to risperidone (0.5 to 3.5 mg/day) or placebo for 8 weeks. This sample of 38 was a subset of 101 subjects who participated in the clinical trial; 63 were unable to perform the cognitive tasks. A double-blind placebo-controlled parallel groups design was used. Dependent measures included tests of sustained attention, verbal learning, hand-eye coordination, and spatial memory assessed before, during, and after the 8-week treatment. Changes in performance were compared by repeated measures ANOVA. Results: Twenty-nine boys and 9 girls with autism and severe behavioral disturbance and a mental age ≥18 months completed the cognitive part of the study. No decline in performance occurred with risperidone. Performance on a cancellation task (number of correct detections) and a verbal learning task (word recognition) was better on risperidone than on placebo (without correction for multiplicity). Equivocal improvement also occurred on a spatial memory task. There were no significant differences between treatment conditions on the Purdue Pegboard (hand-eye coordination) task or the Analog Classroom Task (timed math test). Conclusion: Risperidone given to children with autism at doses up to 3.5 mg for up to 8 weeks appears to have no detrimental effect on cognitive performance

Food Waste to Bio-Products

The goal of this project was to design and evaluate a project for the collection and processing of food waste and spent oil in Philadelphia. The project was designed to handle 5% of the total commercial waste generated in Philadelphia. This amounted to approximately 9,700 tons/year of food waste and 73,000 gallons/year of spent oil. The process was designed to utilize a BIOFerm™ Dry Fermentation Digestion System. Following the digestion, the biogas produced is passed through a Caterpillar CG132-12 Generator Set, producing electricity to be sold back to the local grid. The digestate from the anaerobic digestion is used to produce compost, providing an additional revenue stream. In addition to handling the solid food waste, the project is designed to convert the collected spent oil into biodiesel using prepackaged processing units by Springboard Biodiesel. The facility is anticipated to annually produce 2,541 tons of biogas, 5,184,000 kWh of electricity, 14,756 tons of compost, and 59,616 gallons of biodiesel. A rigorous profitability analysis was conducted in order to project cash flows for fifteen years. The total capital investment of the plant is $5.6MM and the expected NPV of the project is -($682,000). The estimated IRR of the project is 12% and the 3-year ROI is 7%. Given the project’s negative NPV, our recommendation is to adopt such a process solely for environmentally beneficial waste management purposes. A key takeway is that in order for such a project to be profitable it would need to target more than just 5% of the total commercial food waste produced

Ultraviolet resonance raman spectroscopy for characterization of RNA structure and thermodynamics

Raman spectroscopy is a technique well suited for the study of biological molecules such as proteins, peptides, or RNAs. By utilizing an ultraviolet resonance Raman (UVRR) instrument, we are afforded a tremendous increase in sensitivity because of resonance enhancement. Additionally, this technique does not require any labeling. Moreover, this technique is better suited for studying biological systems than infrared absorption due to reduced interference from water. In this study, we apply techniques we have developed for the study of protein and peptide fibrillation to a model RNA homodimer. We demonstrate that UVRR spectroscopy is uniquely suited to monitoring the free energy changes of RNA with base-pair resolution. This presents the opportunity for novel studies investigating biologically relevant RNAs, RNAs with modifications and labels, and interactions of RNA with proteins and small molecules