Prospecting for new group A streptococcal vaccine candidates

Background & objectives: Most group A streptococcal (GAS) vaccine strategies focused on the surface M protein of the GAS. However, vaccine based on M protein have some drawbacks. In the present study, we used two approaches to identify new proteins and peptides that may have utility as vaccine candidates. Methods: A whole gel elution procedure was used to separate GAS surface antigens into 9 size fractionated pools. Mice were vaccinated with each pool and antibody titre, opsonic ability and protective capacity measured. In an alternative approach BioInformatics was used to identify putative GAS surface proteins. Peptides from within these proteins were then selected on the basis of predicted antigenicity or location. These peptides were conjugated to keyhole lymphocyanin (KLH) and immunogenicity measured in a mouse model. Results: One pool of GAS surface proteins (approximately 29kDa) induced antibodies that were both opsonic and potentially protective. Immunoflourescent microscopy demonstrated that these antibodies bound to the surface of M1 GAS. Amino acid sequencing subsequently identified superoxide dismutase as the major antigen in this pool. A BioInformatic search of the M1 GAS genome and subsequent analysis identified several peptides that fulfilled criteria as potential vaccine candidates. Each peptide when conjugated to KLH was able to induce a strong antibody response. Interpretation & conclusion: Several new antigens were identified that may have potential as vaccine targets. A future GAS vaccine may have multiple peptide epitopes, providing protection against multiple GAS strains

Advanced XPS characterization: XPS-based multi-technique analyses for comprehensive understanding of functional materials

X-ray photoelectron spectroscopy (XPS) has achieved maturity as an analytical technique in that it is a ubiquitous tool in the materials community, however as made apparent by recent reviews highlighting it's misuse as a means of chemical deduction, it is a practice which is greatly misunderstood even in its simplest form. Advanced XPS techniques, or a combination of XPS and a complementary surficial probe may elicit auxiliary information outside of the scope of the standard sphere of appreciation. This review aims to bring to the attention of the general materials audience a landscape of some atypical applications of lab-based XPS and combinatorial approaches of related surface analysis, such as ion scattering, ultraviolet photoelectron, electron energy loss and auger emission spectroscopies found on many lab-based instrument set-ups

Acute effects of exercise on appetite, ad libitum energy intake and appetite-regulatory hormones in lean and overweight/obese men and women

Background: Acute exercise does not elicit compensatory changes in appetite parameters in lean individuals; however, less is known about responses in overweight individuals. This study compared the acute effects of moderate-intensity exercise on appetite, energy intake and appetite-regulatory hormones in lean and overweight/obese individuals. Methods: Forty-seven healthy lean (n=22, 11 females; mean (s.d.) 37.5 (15.2) years; 22.4 (1.5) kg m−2) and overweight/obese (n=25, 11 females; 45.0 (12.4) years, 29.2 (2.9) kg m−2) individuals completed two, 8 h trials (exercise and control). In the exercise trial, participants completed 60 min treadmill exercise (59 (4)% peak oxygen uptake) at 0–1 h and rested thereafter while participants rested throughout the control trial. Appetite ratings and concentrations of acylated ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured at predetermined intervals. Standardised meals were consumed at 1.5 and 4 h and an ad libitum buffet meal was provided at 7 h. Results: Exercise suppressed appetite (95% confidence interval (CI) −3.1 to −0.5 mm, P=0.01), and elevated delta PYY (95% CI 10 to 17 pg ml−1, P<0.001) and GLP-1 (95% CI 7 to 10 pmol l−1, P<0.001) concentrations. Delta acylated ghrelin concentrations (95% CI −5 to 3 pg ml−1, P=0.76) and ad libitum energy intake (95% CI −391 to 346 kJ, P=0.90) were similar between trials. Subjective and hormonal appetite parameters and ad libitum energy intake were similar between lean and overweight/obese individuals (Pgreater than or equal to0.27). The exercise-induced elevation in delta GLP-1 was greater in overweight/obese individuals (trial-by-group interaction P=0.01), whereas lean individuals exhibited a greater exercise-induced increase in delta PYY (trial-by-group interaction P<0.001). Conclusions: Acute moderate-intensity exercise transiently suppressed appetite and increased PYY and GLP-1 in the hours after exercise without stimulating compensatory changes in appetite in lean or overweight/obese individuals. These findings underscore the ability of exercise to induce a short-term energy deficit without any compensatory effects on appetite regardless of weight status

Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation

Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2-8 h intervals and analysed by (1)H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies

Cost-Effective Use of Silver Dressings for the Treatment of Hard-to-Heal Chronic Venous Leg Ulcers

Aim To estimate the cost-effectiveness of silver dressings using a health economic model based on time-to-wound-healing in hard-to-heal chronic venous leg ulcers (VLUs). Background Chronic venous ulceration affects 1–3% of the adult population and typically has a protracted course of healing, resulting in considerable costs to the healthcare system. The pathogenesis of VLUs includes excessive and prolonged inflammation which is often related to critical colonisation and early infection. The use of silver dressings to control this bioburden and improve wound healing rates remains controversial. Methods A decision tree was constructed to evaluate the cost-effectiveness of treatment with silver compared with non-silver dressings for four weeks in a primary care setting. The outcomes: ‘Healed ulcer’, ‘Healing ulcer’ or ‘No improvement’ were developed, reflecting the relative reduction in ulcer area from baseline to four weeks of treatment. A data set from a recent meta-analysis, based on four RCTs, was applied to the model. Results Treatment with silver dressings for an initial four weeks was found to give a total cost saving (£141.57) compared with treatment with non-silver dressings. In addition, patients treated with silver dressings had a faster wound closure compared with those who had been treated with non-silver dressings. Conclusion The use of silver dressings improves healing time and can lead to overall cost savings. These results can be used to guide healthcare decision makers in evaluating the economic aspects of treatment with silver dressings in hard-to-heal chronic VLUs

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P&lt;0.02), COMT (P&lt;0.04), DRD3 (P&lt;0.05), DRD4 (P&lt;0.05), SLC6A3 (P&lt;0.05) and SLC6A4 (P&lt;0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P&lt;0.001) and DRD3 (P&lt;0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability

Individual and Area-Based Socioeconomic Factors Associated With Dementia Incidence in England: Evidence From a 12-Year Follow-up in the English Longitudinal Study of Ageing

This is the final version. Available from the AMA via the DOI in this record.This article was corrected on July 3, 2018, to clarify ambiguous statements in the Results section of the Abstract and the Findings section of the Key Points that affected interpretation. Correction available at: 10.1001/jamapsychiatry.2018.1696Importance: Lower educational attainment is associated with a higher risk of dementia. However, less clear is the extent to which other socioeconomic markers contribute to dementia risk. Objective: To examine the relationship of education, wealth, and area-based deprivation with the incidence of dementia over the last decade in England and investigate differences between people born in different periods. Design, Setting, and Participants: Data from the English Longitudinal Study of Ageing, a prospective cohort study that is representative of the English population, were used to investigate the associations between markers of socioeconomic status (wealth quintiles and the index of multiple deprivation) and dementia incidence. To investigate outcomes associated with age cohorts, 2 independent groups were derived using a median split (born between 1902-1925 and 1926-1943). Main Outcomes and Measures: Dementia as determined by physician diagnosis and the Informant Questionnaire on Cognitive Decline in the Elderly. Results: A total of 6220 individuals aged 65 years and older enrolled in the study (median [interquartile range] age at baseline, 73.2 [68.1-78.3] years; 3410 [54.8%] female). Of these, 463 individuals (7.4%) had new cases of dementia ascertained in the 12 years between 2002-2003 and 2014-2015. In the cohort born between 1926 and 1943, the hazard of developing dementia was 1.68 times higher (hazard ratio [HR] = 1.68 [95% CI, 1.05-2.86]) for those in the lowest wealth quintile compared with those in the highest quintile, independent of education, index of multiple deprivation, and health indicators. Higher hazards were also observed for those in the second-highest quintile of index of multiple deprivation (HR = 1.62 [95% CI, 1.06-2.46]) compared with those in the lowest (least deprived) quintile. Conclusions and Relevance: In an English nationally representative sample, the incidence of dementia appeared to be socioeconomically patterned primarily by the level of wealth. This association was somewhat stronger for participants born in later years.The work was supported by the National Institute on Aging (grants 5218182, RO1AG7644-01A1, and RO1AG017644). The English Longitudinal Study of Ageing is funded by the National Institute on Aging (grant RO1AG7644) and by a consortium of UK government departments coordinated by the Economic and Social Research Council (ESRC) and the Office for National Statistics. Dr Batty is also supported by the UK Medical Research Council