Severe childhood malaria syndromes defined by plasma proteome profiles

BACKGROUND Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore it is important to understand the pathology underlying the development of CM and SMA, as opposed to uncomplicated malaria (UM). Different host responses to infection are likely to be reflected in plasma proteome-patterns that associate with clinical status and therefore provide indicators of the pathogenesis of these syndromes. METHODS AND FINDINGS Plasma and comprehensive clinical data for discovery and validation cohorts were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, an urban and densely populated holoendemic malaria area in Nigeria. A total of 946 children participated in this study. Plasma was subjected to high-throughput proteomic profiling. Statistical pattern-recognition methods were used to find proteome-patterns that defined disease groups. Plasma proteome-patterns accurately distinguished children with CM and with SMA from those with UM, and from healthy or severely ill malaria-negative children. CONCLUSIONS We report that an accurate definition of the major childhood malaria syndromes can be achieved using plasma proteome-patterns. Our proteomic data can be exploited to understand the pathogenesis of the different childhood severe malaria syndromes

Analysis of 22,655 presentations with back pain to Perth emergency departments over five years

BACKGROUND: Back pain is a significant cause of disability in the community, but the impact on Emergency Departments (EDs) has not been formally studied. Patients with back pain often require significant time and resources in the ED. AIMS: To examine the characteristics of patients presenting with back pain to the ED, including final diagnosis, demographics of those attending and temporal distribution of presentations. METHODS: Emergency presentations in the metropolitan area of Perth, Western Australia, for 2000-2004 were searched using a linked database covering all the major hospitals (Emergency Care Hospitalisation and Outcome Study database). All presentations with the triage code for back pain were extracted and analysed. RESULTS: A total of 22,655 presentations with back pain were identified, representing 1.9% of total presentations. Simple muscular or non-specific back pain accounted for only 43.8% of presentations, with other causes such as renal colic and pyelonephritis accounting for the majority. The young (75 years old) were more likely to have non-muscular causes for their back pain. Muscular back pain presentations occurred mostly between 0800 and 1600, with high proportions presenting on the weekends. Patients with simple muscular back pain spent a mean of 4.4 h in the ED, representing a significant outlay of resources. CONCLUSION: Back pain has a significant impact on EDs, and staff should be alert for another pathology presenting as back pain. There is a need for multidisciplinary back pain teams to be available 7 days a week, but only during the day

Modelling mammalian energetics: the heterothermy problem

Global climate change is expected to have strong effects on the world’s flora and fauna. As a result, there has been a recent increase in the number of meta-analyses and mechanistic models that attempt to predict potential responses of mammals to changing climates. Many models that seek to explain the effects of environmental temperatures on mammalian energetics and survival assume a constant body temperature. However, despite generally being regarded as strict homeotherms, mammals demonstrate a large degree of daily variability in body temperature, as well as the ability to reduce metabolic costs either by entering torpor, or by increasing body temperatures at high ambient temperatures. Often, changes in body temperature variability are unpredictable, and happen in response to immediate changes in resource abundance or temperature. In this review we provide an overview of variability and unpredictability found in body temperatures of extant mammals, identify potential blind spots in the current literature, and discuss options for incorporating variability into predictive mechanistic models

Online dietary intake estimation : The food4me food frequency questionnaire

Copyright ©Hannah Forster, Rosalind Fallaize, Caroline Gallagher, Clare B O’Donovan, Clara Woolhead, Marianne C Walsh, Anna L Macready, Julie A Lovegrove, John C Mathers, Michael J Gibney, Lorraine Brennan, Eileen R Gibney. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 09.06.2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.Dietary assessment methods are important tools for nutrition research. Online dietary assessment tools have the potential to become invaluable methods of assessing dietary intake because, compared with traditional methods, they have many advantages including the automatic storage of input data and the immediate generation of nutritional outputs. Objective: The aim of this study was to develop an online food frequency questionnaire (FFQ) for dietary data collection in the Food4Me study and to compare this with the validated European Prospective Investigation of Cancer (EPIC) Norfolk printed FFQ. Methods: The Food4Me FFQ used in this analysis was developed to consist of 157 food items. Standardized color photographs were incorporated in the development of the Food4Me FFQ to facilitate accurate quantification of the portion size of each food item. Participants were recruited in two centers (Dublin, Ireland and Reading, United Kingdom) and each received the online Food4Me FFQ and the printed EPIC-Norfolk FFQ in random order. Participants completed the Food4Me FFQ online and, for most food items, participants were requested to choose their usual serving size among seven possibilities from a range of portion size pictures. The level of agreement between the two methods was evaluated for both nutrient and food group intakes using the Bland and Altman method and classification into quartiles of daily intake. Correlations were calculated for nutrient and food group intakes. Results: A total of 113 participants were recruited with a mean age of 30 (SD 10) years (40.7% male, 46/113; 59.3%, 67/113 female). Cross-classification into exact plus adjacent quartiles ranged from 77% to 97% at the nutrient level and 77% to 99% at the food group level. Agreement at the nutrient level was highest for alcohol (97%) and lowest for percent energy from polyunsaturated fatty acids (77%). Crude unadjusted correlations for nutrients ranged between .43 and .86. Agreement at the food group level was highest for other fruits (eg, apples, pears, oranges) and lowest for cakes, pastries, and buns. For food groups, correlations ranged between .41 and .90. Conclusions: The results demonstrate that the online Food4Me FFQ has good agreement with the validated printed EPIC-Norfolk FFQ for assessing both nutrient and food group intakes, rendering it a useful tool for ranking individuals based on nutrient and food group intakes.Peer reviewedFinal Published versio

Effects of a web-based personalized intervention on physical activity in European adults: a randomized controlled trial

Background: The high prevalence of physical inactivity worldwide calls for innovative and more effective ways to promote physical activity (PA). There are limited objective data on the effectiveness of Web-based personalized feedback on increasing PA in adults. Objective: It is hypothesized that providing personalized advice based on PA measured objectively alongside diet, phenotype, or genotype information would lead to larger and more sustained changes in PA, compared with nonpersonalized advice. Methods: A total of 1607 adults in seven European countries were randomized to either a control group (nonpersonalized advice, Level 0, L0) or to one of three personalized groups receiving personalized advice via the Internet based on current PA plus diet (Level 1, L1), PA plus diet and phenotype (Level 2, L2), or PA plus diet, phenotype, and genotype (Level 3, L3). PA was measured for 6 months using triaxial accelerometers, and self-reported using the Baecke questionnaire. Outcomes were objective and self-reported PA after 3 and 6 months. Results: While 1270 participants (85.81% of 1480 actual starters) completed the 6-month trial, 1233 (83.31%) self-reported PA at both baseline and month 6, but only 730 (49.32%) had sufficient objective PA data at both time points. For the total cohort after 6 months, a greater improvement in self-reported total PA (P=.02) and PA during leisure (nonsport) (P=.03) was observed in personalized groups compared with the control group. For individuals advised to increase PA, we also observed greater improvements in those two self-reported indices (P=.006 and P=.008, respectively) with increased personalization of the advice (L2 and L3 vs L1). However, there were no significant differences in accelerometer results between personalized and control groups, and no significant effect of adding phenotypic or genotypic information to the tailored feedback at month 3 or 6. After 6 months, there were small but significant improvements in the objectively measured physical activity level (P<.05), moderate PA (P<.01), and sedentary time (P<.001) for individuals advised to increase PA, but these changes were similar across all groups. Conclusions: Different levels of personalization produced similar small changes in objective PA. We found no evidence that personalized advice is more effective than conventional “one size fits all” guidelines to promote changes in PA in our Web-based intervention when PA was measured objectively. Based on self-reports, PA increased to a greater extent with more personalized advice. Thus, it is crucial to measure PA objectively in any PA intervention study

Changes in physical activity following a genetic-based internet-delivered personalized intervention: randomized controlled trial (Food4Me)

Background: There is evidence that physical activity (PA) can attenuate the influence of the fat mass- and obesity-associated (FTO) genotype on the risk to develop obesity. However, whether providing personalized information on FTO genotype leads to changes in PA is unknown. Objective: The purpose of this study was to determine if disclosing FTO risk had an impact on change in PA following a 6-month intervention. Methods: The single nucleotide polymorphism (SNP) rs9939609 in the FTO gene was genotyped in 1279 participants of the Food4Me study, a four-arm, Web-based randomized controlled trial (RCT) in 7 European countries on the effects of personalized advice on nutrition and PA. PA was measured objectively using a TracmorD accelerometer and was self-reported using the Baecke questionnaire at baseline and 6 months. Differences in baseline PA variables between risk (AA and AT genotypes) and nonrisk (TT genotype) carriers were tested using multiple linear regression. Impact of FTO risk disclosure on PA change at 6 months was assessed among participants with inadequate PA, by including an interaction term in the model: disclosure (yes/no) × FTO risk (yes/no). Results: At baseline, data on PA were available for 874 and 405 participants with the risk and nonrisk FTO genotypes, respectively. There were no significant differences in objectively measured or self-reported baseline PA between risk and nonrisk carriers. A total of 807 (72.05%) of the participants out of 1120 in the personalized groups were encouraged to increase PA at baseline. Knowledge of FTO risk had no impact on PA in either risk or nonrisk carriers after the 6-month intervention. Attrition was higher in nonrisk participants for whom genotype was disclosed (P=.01) compared with their at-risk counterparts. Conclusions: No association between baseline PA and FTO risk genotype was observed. There was no added benefit of disclosing FTO risk on changes in PA in this personalized intervention. Further RCT studies are warranted to confirm whether disclosure of nonrisk genetic test results has adverse effects on engagement in behavior change

Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria: Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 µM; 95% CI 0.74–0.96) compared to those with MSM (0.54 µM; 95%CI 0.5–0.56) and HCs (0.64 µM; 95%CI 0.58–0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0–181; p = 0.01). ADMA was independently associated with decreased exhaled NO (rs = −0.31) and endothelial function (rs = −0.32) in all malaria patients, and with reduced exhaled NO (rs = −0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria

Mutations in the Polycomb Group Gene polyhomeotic Lead to Epithelial Instability in both the Ovary and Wing Imaginal Disc in Drosophila

Most human cancers originate from epithelial tissues and cell polarity and adhesion defects can lead to metastasis. The Polycomb-Group of chromatin factors were first characterized in Drosophila as repressors of homeotic genes during development, while studies in mammals indicate a conserved role in body plan organization, as well as an implication in other processes such as stem cell maintenance, cell proliferation, and tumorigenesis. We have analyzed the function of the Drosophila Polycomb-Group gene polyhomeotic in epithelial cells of two different organs, the ovary and the wing imaginal disc.Clonal analysis of loss and gain of function of polyhomeotic resulted in segregation between mutant and wild-type cells in both the follicular and wing imaginal disc epithelia, without excessive cell proliferation. Both basal and apical expulsion of mutant cells was observed, the former characterized by specific reorganization of cell adhesion and polarity proteins, the latter by complete cytoplasmic diffusion of these proteins. Among several candidate target genes tested, only the homeotic gene Abdominal-B was a target of PH in both ovarian and wing disc cells. Although overexpression of Abdominal-B was sufficient to cause cell segregation in the wing disc, epistatic analysis indicated that the presence of Abdominal-B is not necessary for expulsion of polyhomeotic mutant epithelial cells suggesting that additional polyhomeotic targets are implicated in this phenomenon.Our results indicate that polyhomeotic mutations have a direct effect on epithelial integrity that can be uncoupled from overproliferation. We show that cells in an epithelium expressing different levels of polyhomeotic sort out indicating differential adhesive properties between the cell populations. Interestingly, we found distinct modalities between apical and basal expulsion of ph mutant cells and further studies of this phenomenon should allow parallels to be made with the modified adhesive and polarity properties of different types of epithelial tumors

Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors

Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. METHODS: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. RESULTS: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10- 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10- 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10- 6 and P = 3 × 10- 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10- 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. CONCLUSION: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts

Effect of a Dual Task on Postural Control in Dyslexic Children

Several studies have examined postural control in dyslexic children; however, their results were inconclusive. This study investigated the effect of a dual task on postural stability in dyslexic children. Eighteen dyslexic children (mean age 10.3±1.2 years) were compared with eighteen non-dyslexic children of similar age. Postural stability was recorded with a platform (TechnoConcept®) while the child, in separate sessions, made reflex horizontal and vertical saccades of 10° of amplitude, and read a text silently. We measured the surface and the mean speed of the center of pressure (CoP). Reading performance was assessed by counting the number of words read during postural measures. Both groups of children were more stable while performing saccades than while reading a text. Furthermore, dyslexic children were significantly more unstable than non-dyslexic children, especially during the reading task. Finally, the number of words read by dyslexic children was significantly lower than that of non-dyslexic children and, in contrast to the non-dyslexic children. In line with the U-shaped non-linear interaction model, we suggest that the attention consumed by the reading task could be responsible for the loss of postural control in both groups of children. The postural instability observed in dyslexic children supports the hypothesis that such children have a lack of integration of multiple sensorimotor inputs