Rapid Effector Function in CD8+ Memory T Cells

The nature of the CD8+ T cells that underlie antiviral protective immunological memory in vivo is unclear. We have characterized peptide-specific CD8+ T lymphocytes directly ex vivo from peripheral blood in humans with past exposure to influenza virus, using single cell interferon γ (IFN-γ) release as a measure of effector function. In individuals in the memory state with respect to influenza virus infection, unrestimulated antigen-specific CD8+ T cells displayed IFN-γ release within 6 h of antigen contact, identifying a population of memory CD8+ T cells that exhibit effector function without needing to divide and differentiate over several days. We have quantified circulating CD8+ effector T cells specific for six different MHC class I–restricted influenza virus epitopes. Enumeration of these CD8+ T cells gives frequencies of peptide-specific T cells that correlate with, but are in general severalfold higher than, CTL precursor frequencies derived from limiting dilution analysis, indicating that this novel population of memory CD8+ T cells has hitherto been undetected by standard means. The phenotype of these cells, which persist at a low frequency long after recovery from an acute viral infection, suggests that they play a role in protective immunological memory

Understanding the direct and indirect mechanisms of xylanase action on starch digestion in broilers

The objective of the current study was to investigate the mechanisms of xylanase action in a maize-soya diet and its effect on starch digestion. A total of 60 broilers were divided into 6 treatment groups; a control group without xylanase, and five other groups supplemented with xylanase (Econase XT 25; 100 g/t) from 1, 2, 3, 4 or 5 weeks before slaughter. At the end of the experiment, digesta was collected from the gizzard, upper and lower small intestine, and both caeca. Digesta pH ranged from pH 2.2-4.4, 5.9-6.6, 6.7-7.8 and 5.7-7.3 in the gizzard, upper small intestine, lower small intestine, and both caeca, respectively, with no effect of xylanase (P > 0.05). Scanning Electron Microscope (SEM) images along with total starch measurements showed the progression of starch digestion through the tract. The SEM did not show any greater disruption to cell wall material with xylanase supplementation. This suggests that xylanase was not working directly on the cell wall and provides evidence for the hypothesis that xylanase works through an indirect mechanism. Peptide YY (PYY) concentration in the blood was higher during the first few weeks of supplementation, with longer periods of supplementation nulling this effect, implying that xylanase may be acting through a prebiotic mechanism. The RT-q PCR results revealed a numerical increase in glucose transporter (GLUT2 and SGLT1) expression at 2 and 3 weeks of xylanase supplementation, respectively, which might suggest a greater absorption capacity of birds. From these results, a potential mechanism of xylanase action in maize-based diets has been proposed

The Effect of 12-Weeks Recreational Football (Soccer) for Health Intervention on Functional Movement in Older Adults

There is growing evidence that recreational football offers health benefits for older adults and an important pathway for physical activity for older adult groups. Despite anecdotal evidence that recreational football is beneficial for older adults, no empirical data are available to support this assertion. This study addressed this issue and examined the effects of a 12‐week recreational football intervention on the functional fitness of older adults. Using a pre–post case–control design, thirteen males, aged 61–73 years (mean age ± SD = 66 ± 4 years) undertook a twice‐weekly, 12‐week recreational football for health intervention, and were matched with a control group, comprising thirteen males, aged 62–78 years (mean age ± SD = 66 ± 4 years) who maintained their typical exercise habits during the intervention period. Pre‐ and postintervention, participants underwent assessment of functional fitness, using the Rikli and Jones functional fitness battery as well as an assessment of body fatness, via bioelectrical impedance analysis and dominant handgrip strength using handgrip dynamometry. Results from a series of 2 (pre–post) X 2 (intervention vs. control) repeated‐measures ANOVAs indicate significant pre–post X group interactions for the 30‐second chair stand (p = 0.038, Pƞ2 = 0.168), 8‐foot timed up and go (p = 0.001, Pƞ2 = 0.577) and 6 min walk test (p = 0.036, Pƞ2 = 0.171). In all cases, performance improved significantly after the intervention for the football intervention group but not the control group. There were no significant differences in the 30 s arm curl test or dominant handgrip strength (p > 0.05). There was a non‐significant trend (p = 0.07, Pƞ2 = 0.127) towards a pre–post X group interaction for body fatness, showing a decreased percent body fat for the intervention group over the control group. The results of the present study demonstrate the utility of recreational football as a physical activity intervention in older adults to improve functional movement

Extensive Plasmid Library to Prepare Tau Protein Variants and Study Their Functional Biochemistry

Tau neurofibrillary tangles are key pathological features of Alzheimer’s disease and other tauopathies. Recombinant protein technology is vital for studying the structure and function of tau in physiology and aggregation in pathophysiology. However, open-source and well-characterized plasmids for efficiently expressing and purifying different tau variants are lacking. We generated 44 sequence-verified plasmids including those encoding full length (FL) tau-441, its four-repeat microtubule-binding (K18) fragment, and their respective selected familial pathological variants (N279K, V337M, P301L, C291R, and S356T). Moreover, plasmids for expressing single (C291A), double (C291A/C322A), and triple (C291A/C322A/I260C) cysteine-modified variants were generated to study alterations in cysteine content and locations. Furthermore, protocols for producing representative tau forms were developed. We produced and characterized the aggregation behavior of the triple cysteine-modified tau-K18, often used in real-time cell internalization and aggregation studies because it can be fluorescently labeled on a cysteine outside the microtubule-binding core. Similar to the wild type (WT), triple cysteine-modified tau-K18 aggregated by progressive β-sheet enrichment, albeit at a slower rate. On prolonged incubation, cysteine-modified K18 formed paired helical filaments similar to those in Alzheimer’s disease, sharing morphological phenotypes with WT tau-K18 filaments. Nonetheless, cysteine-modified tau-K18 filaments were significantly shorter (p = 0.002) and mostly wider than WT filaments, explainable by their different principal filament elongation pathways: vertical (end-to-end) and lateral growth for WT and cysteine-modified, respectively. Cysteine rearrangement may therefore induce filament polymorphism. Together, the plasmid library, the protein production methods, and the new insights into cysteine-dependent aggregation should facilitate further studies and the design of antiaggregation agents

Dissemination of Clinical Practice Guidelines : A Content Analysis of Patient Versions

Financial support for this study was provided to Nancy Santesso from a Canadian Institutes of Health Research Fellowship in Knowledge Translation. Financial support for this study was provided by the Canadian Institutes of Health Research Fellowship in Knowledge Translation and for the DECIDE project from the European Union’s Seventh Framework Programme under grant agreement number 258583. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report.Peer reviewedPostprin

Recognition memory, self-other source memory, and theory-of-mind in children with autism spectrum disorder.

This study investigated semantic and episodic memory in autism spectrum disorder (ASD), using a task which assessed recognition and self-other source memory. Children with ASD showed undiminished recognition memory but significantly diminished source memory, relative to age- and verbal ability-matched comparison children. Both children with and without ASD showed an “enactment effect”, demonstrating significantly better recognition and source memory for self-performed actions than other-person-performed actions. Within the comparison group, theory-of-mind (ToM) task performance was significantly correlated with source memory, specifically for other-person-performed actions (after statistically controlling for verbal ability). Within the ASD group, ToM task performance was not significantly correlated with source memory (after controlling for verbal ability). Possible explanations for these relations between source memory and ToM are considered

Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study.

BACKGROUND: Many investigators have suggested that malaria infection predisposes individuals to bacteraemia. We tested this hypothesis with mendelian randomisation studies of children with the malaria-protective phenotype of sickle-cell trait (HbAS). METHODS: This study was done in a defined area around Kilifi District Hospital, Kilifi, Kenya. We did a matched case-control study to identify risk factors for invasive bacterial disease, in which cases were children aged 3 months to 13 years who were admitted to hospital with bacteraemia between Sept 16, 1999, and July 31, 2002. We aimed to match two controls, by age, sex, location, and time of recruitment, for every case. We then did a longitudinal case-control study to assess the relation between HbAS and invasive bacterial disease as malaria incidence decreased. Cases were children aged 0-13 years who were admitted to hospital with bacteraemia between Jan 1, 1999, and Dec 31, 2007. Controls were born in the study area between Jan 1, 2006, and June 23, 2009. Finally, we modelled the annual incidence of bacteraemia against the community prevalence of malaria during 9 years with Poisson regression. RESULTS: In the matched case-control study, we recruited 292 cases-we recruited two controls for 236, and one for the remaining 56. Sickle-cell disease, HIV, leucocyte haemozoin pigment, and undernutrition were positively associated with bacteraemia and HbAS was strongly negatively associated with bacteraemia (odds ratio 0·36; 95% CI 0·20-0·65). In the longitudinal case-control study, we assessed data from 1454 cases and 10,749 controls. During the study period, the incidence of admission to hospital with malaria per 1000 child-years decreased from 28·5 to 3·45, with a reduction in protection afforded by HbAS against bacteraemia occurring in parallel (p=0·0008). The incidence of hospital admissions for bacteraemia per 1000 child-years also decreased from 2·59 to 1·45. The bacteraemia incidence rate ratio associated with malaria parasitaemia was 6·69 (95% CI 1·31-34·3) and, at a community parasite prevalence of 29% in 1999, 62% (8·2-91) of bacteraemia cases were attributable to malaria. INTERPRETATION: Malaria infection strongly predisposes individuals to bacteraemia and can account for more than half of all cases of bacteraemia in malaria-endemic areas. Interventions to control malaria will have a major additional benefit by reducing the burden of invasive bacterial disease. FUNDING: Wellcome Trust

Risk of pneumococcal bacteremia in Kenyan children with glucose-6-phosphate dehydrogenase deficiency

Abstract Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency state in humans. The clinical phenotype is variable and includes asymptomatic individuals, episodic hemolysis induced by oxidative stress, and chronic hemolysis. G6PD deficiency is common in malaria-endemic regions, an observation hypothesized to be due to balancing selection at the G6PD locus driven by malaria. G6PD deficiency increases risk of severe malarial anemia, a key determinant of invasive bacterial disease in malaria-endemic settings. The pneumococcus is a leading cause of invasive bacterial infection and death in African children. The effect of G6PD deficiency on risk of pneumococcal disease is undefined. We hypothesized that G6PD deficiency increases pneumococcal disease risk and that this effect is dependent upon malaria. Methods We performed a genetic case-control study of pneumococcal bacteremia in Kenyan children stratified across a period of falling malaria transmission between 1998 and 2010. Results Four hundred twenty-nine Kenyan children with pneumococcal bacteremia and 2677 control children were included in the study. Among control children, G6PD deficiency, secondary to the rs1050828 G>A mutation, was common, with 11.2% (n = 301 of 2677) being hemi- or homozygotes and 33.3% (n = 442 of 1329) of girls being heterozygotes. We found that G6PD deficiency increased the risk of pneumococcal bacteremia, but only during a period of high malaria transmission (P = 0.014; OR 2.33, 95% CI 1.19–4.57). We estimate that the population attributable fraction of G6PD deficiency on risk of pneumococcal bacteremia in areas under high malaria transmission is 0.129. Conclusions Our data demonstrate that G6PD deficiency increases risk of pneumococcal bacteremia in a manner dependent on malaria. At the population level, the impact of G6PD deficiency on invasive pneumococcal disease risk in malaria-endemic regions is substantial. Our study highlights the infection-associated morbidity and mortality conferred by G6PD deficiency in malaria-endemic settings and adds to our understanding of the potential indirect health benefits of improved malaria control

COVID-19-Induced Myocarditis: Pathophysiological Roles of ACE2 and Toll-like Receptors

The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs)