Metabonomics profile and corresponding immune parameters of HIV infected individuals

Background: Immunological events due to infection by the human immunodeficiency virus (HIV) perturb mitochondrial function which augments virus-induced metabolic imbalances. Organic acids, established biomarkers of mitochondrial dysfunction have not yet been studied as indicators of HIV-induced changes in this organelle. In this study, mass spectrometry (MS) was used to determine the organic acid profile and flow cytometry the corresponding immune changes in biofluids of clinically stable patients, with the aim of identifying HIV-influenced molecules which could potentially be developed into diagnostic and/or prognostic markers. Methodology and Results: Gas chromatography mass spectrometry (GC-MS) was used to determine HIV-induced mitochondrial dysfunction by means of organic acid profiling of sera, peripheral blood mononuclear cells (PBMCs) and urine. The Metabolomics Ion-based Data Extraction Algorithm (MET-IDEA) proved more suitable for data analysis than other software packages. The biofluids analyzed differed in the type of metabolites identified but provided related biological information. An overlap in the metabolic profiles of HIV seronegative (HIV-) and seropositive (HIV+) groups was observed. When cases in the advanced stage of the disease were included an improved separation between the groups was observed. Metabolites altered as a result of HIV infection were representative of disrupted mitochondrial metabolism, changes in lipid, sugar, energy and neurometabolism as well as oxidative stress. Metabolite detection was found to be influenced by viral load. Corresponding immune parameters were measured by detecting oxidative stress, apoptosis and cytokine changes. As expected, the HIV+ individuals experience constant oxidative stress. Significantly higher amounts of reactive oxygen species (ROS, p =0.004) were detected in infected sera. Apoptosis in the HIV+ cells was significantly higher than that occurring in the HIV- cells (p< 0.0001). When gating T cells, a greater percentage apoptosis was measured in the CD8 positive cell population (p=0.0269). Since the CD4 cells of the patient group were not depleted these cells were able to produce the soluble factor needed for apoptosis to occur in CD8 cells. In vitro stimulation of the infected PBMCs with viral peptides led to an increase in the percentage T cells which produced intracellular interferon gamma (IFN-γ). The T helper type 1 (Th1), Th2 and Th17 cytokine profile in aliquots of HIV and HIV+ sera measured using Cytometric Bead Array (CBA) technology and analyzed using multivariate statistics, correctly classified over 70 % of the cases as HIV- or HIV+. Interleukin (IL)-6 and IL-10 were found to be the key immune markers altered during HIV infection. Analyzing cytokines in this manner follows a cytokinomics approach. Conclusion: Organic acids detected agree with the oxidative, apoptotic and cytokine responses. The impact of HIV on the metabolic signature and immune system is detectable in the early asymptomatic phase of infection by using MS, flow cytometry and spectroscopy. The observed changes share a biochemical relationship and are supportive of the link between the metabolic and immune systems. The data was collected using different forms of spectroscopy and spectrometry and these approaches may therefore have a future in the management of HIV infection and the acquired immunodeficiency syndrome (AIDS).Thesis (PhD)--University of Pretoria, 2012.Biochemistryunrestricte

Metabonomic analysis of HIV-infected biofluids

Monitoring the progression of HIV infection to full-blown acquired immune deficiency syndrome (AIDS) and assessing responses to treatment will benefit greatly from the identification of novel biological markers especially since existing clinical indicators of disease are not infallible. Nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) are powerful methodologies used in metabonomic analyses for an approximation of HIV-induced changes to the phenotype of an infected individual. Although early in its application to HIV/AIDS, (biofluid) metabonomics has already identified metabolic pathways influenced by both HIV and/or its treatment. To date, biofluid NMR and MS data show that the virus and highly active antiretroviral treatment (HAART) mainly influence carbohydrate and lipid metabolism, suggesting that infected individuals are susceptible to very specific metabolic complications. A number of well-defined biofluid metabonomic studies clearly distinguished HIV negative, positive and treatment experienced patient profiles from one another. While many of the virus or treatment affected metabolites have been identified, the metabonomics measurements were mostly qualitative. The identities of the molecules were not always validated neither were the statistical models used to distinguish between groups. Assigning particular metabolic changes to specific drug regimens using metabonomics also remains to be done. Studies exist where identified metabolites have been linked to various disease states suggesting great potential for the use of metabonomics in disease prognostics. This review therefore examines the field of metabonomics in the context of HIV/AIDS, comments on metabolites routinely detected as being affected by the pathogen or treatment, explains what existing data suggest and makes recommendations on future research.This work was supported by grants from the Technology Innovation Agency (TIA) of South Africa.http://www.rsc.org/molecularbiosystemsam201

Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy

The Th1/Th2/Th17 cytokine profile of HIV-infected individuals : a multivariate cytokinomics approach

HIV infection causes the dysregulation of cytokine production. A cytokinomics approach employing cytometric bead array (CBA) technology, flow cytometry and multivariate analysis was applied to the investigation of HIV-induced T helper cell type 1 (Th1), Th2 and Th17 cytokine changes in the serum of treatment naive individuals. Stepwise linear discriminant analysis (LDA) and logistic regression identified interleukin (IL)-6 to be discriminatory for HIV infection with 74.6 and 71.2 % of the cases correctly classified. Analysis of variance (ANOVA) confirmed IL-6 and IL-10 concentrations to be significantly (p= 0.001 and p=0.025) different between the groups. A scatter plot of the log IL-6 and IL-10 concentrations for the groups largely overlapped, with improved differentiation where patients were advancing to the acquired immunodeficiency syndrome (AIDS). IL-17A levels were higher than other cytokines but did not significantly distinguish the groups suggesting that the HIV- and HIV+ individuals had similar immune profiles. This possibility was supported by other clinical indicators. Taken together, the measured cytokines (IL-6, 10 and 17) have potential prognostic value.This work was supported by the National Research Foundation, Technology Innovation Agency, Medical Research Council and the Faculty of Natural and Agricultural Sciences at the University of Pretoria.http://www.journals.elsevier.com/cytokinehb201

UPLC-MS metabonomics reveals perturbed metabolites in HIV-infected sera

Immune responses to infection by the human immunodeficiency virus (HIV) and the use of highly active antiretroviral therapy (HAART) to treat HIV infection, contributes to metabolic irregularities in the host. Current methods for the extraction and identification of metabolites in biofluids generally make use of laborious, time-consuming protocols. Here, 96-well Ostro™ plates and filtration under positive pressure was used to facilitate the simultaneous, reproducible extraction of metabolites from multiple serum samples which were then analyzed by ultra-performance liquid chromatography mass spectrometry (UPLC-MS). The easy to use solid phase extraction (SPE) protocol eliminated numerous potential contaminants while the UPLC-MS detection of metabolites produced visibly different chromatograms for HIV negative (n=16), HIV+ (n=13) and HIV+HAART+ (n=15) serum samples. Linear discriminant analysis (LDA) amplified these differences, classified the groups with 100% accuracy and identified biomarkers explaining the greatest variances between the groups. The 21 metabolites altered by HIV and/or HAART primarily represented those linked to lipid and energy pathways which is where known metabolic changes associated with HIV infection occur. This work demonstrated for the first time that OstroTM plates and UPLC-MS metabonomics was able to successfully identify distinct differences between the experimental groups and detected metabolites related to HAART and other drugs used in the treatment of HIV-associated conditions. The findings of this approach suggests a possible role for this methodology in disease prognosis as well as in the monitoring of treatment success or failure and linking treatment to metabolic complications.The Medical Research Council (MRC), Technology Innovation Agency (TIA) and the National Research Foundation (NRF) of South Africa.http://benthamscience.com/journal/index.php?journalID=cmbhb2017BiochemistryStatistic

Qualitative serum organic acid profiles of HIV-infected individuals not on antiretroviral treatment

The first application of gas chromatography mass spectrometry (GC–MS) metabolomics to the analysis of organic acid profiles in sera of asymptomatic human immunodeficiency virus (HIV)-infected individuals (n = 18) compared to uninfected controls (n = 21), is reported here. Several organic acids are well-established diagnostic biomarkers of mitochondrial dysfunction, making the analysis of the organic acid metabolome well suited to monitoring the progressive disruption of mitochondrial structure and function during HIV infection. Using a multifaceted analytical-bioinformatics procedure, at least 10 of these metabolites could be linked to (1) disrupted mitochondrial metabolism, (2) changes in lipid metabolism and (3) oxidative stress, all of which are aberrations caused by HIV infection. Because of the role of the mitochondria in apoptosis, higher levels of this type of cell death in infected (compared to uninfected) individuals was used to support GC–MS data. This study demonstrates that mass spectrometry metabolomics detects biomarkers of mitochondrial dysfunction which could potentially be developed into indicators of HIV infection, perhaps also to monitor disease progression and the response to antiretroviral treatment.The National Research Foundationhttp://www.springerlink.com/content/1573-3882/nf201

Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brain

Object: To determine the single spin-echo T 2 relaxation times of uncoupled and J-coupled metabolites in rat brain in vivo at 14.1 T and to compare these results with those previously obtained at 9.4 T. Materials and methods: Measurements were performed on five rats at 14.1 T using the SPECIAL sequence and TE-specific basis-sets for LCModel analysis. Results and conclusion: The T 2 of singlets ranged from 98 to 148ms and T 2 of J-coupled metabolites ranged from 72ms (glutamate) to 97ms (myo-inositol). When comparing the T 2s of the metabolites measured at 14.1 T with those previously measured at 9.4 T, a decreasing trend was found (p<0.0001). We conclude that the modest shortening of T 2 at 14.1 T has a negligible impact on the sensitivity of the 1H MRS when performed at TE shorter than 10m

Urban and rural differences in frequency of fruit, vegetable, and soft drink consumption among 6–9‐year‐old children from 19 countries from the WHO European region

In order to address the paucity of evidence on the association between childhood eating habits and urbanization, this cross-sectional study describes urban–rural differences in frequency of fruit, vegetable, and soft drink consumption in 123,100 children aged 6–9 years from 19 countries participating in the fourth round (2015-2017) of the WHO European Childhood Obesity Surveillance Initiative (COSI). Children's parents/caregivers completed food-frequency questionnaires. A multivariate multilevel logistic regression analysis was performed and revealed wide variability among countries and within macroregions for all indicators. The percentage of children attending rural schools ranged from 3% in Turkey to 70% in Turkmenistan. The prevalence of less healthy eating habits was high, with between 30–80% and 30–90% children not eating fruit or vegetables daily, respectively, and up to 45% consuming soft drinks on >3 days a week. For less than one third of the countries, children attending rural schools had higher odds (OR-range: 1.1–2.1) for not eating fruit or vegetables daily or consuming soft drinks >3 days a week compared to children attending urban schools. For the remainder of the countries no significant associations were observed. Both population-based interventions and policy strategies are necessary to improve access to healthy foods and increase healthy eating behaviors among children.The authors gratefully acknowledge support from a grant from the Russian Government in the context of the WHO European Office for the Prevention and Control of NCDs. Data collection in the countries was made possible through funding from Albania: WHO through the Joint Programme on Children, Food Security and Nutrition “Reducing Malnutrition in Children,” funded by the Millennium Development Goals Achievement Fund, and the Institute of Public Health; Austria: Federal Ministry of Social Affairs, Health, Care and Consumer Protection, Republic of Austria; Bulgaria: Ministry of Health, National Center of Public Health and Analyses, WHO Regional Office for Europe; Croatia: Ministry of Health, Croatian Institute of Public Health and WHO Regional Office for Europe; Ministry of Health of the Czech Republic, grant nr. AZV MZČR 17-31670 A and MZČR–RVO EÚ 00023761; Denmark: Danish Ministry of Health; Estonia: Ministry of Social Affairs, Ministry of Education and Research (IUT 42-2), WHO Country Office, and National Institute for Health Development; Georgia: WHO; Ireland: Health Service Executive; Italy: Ministry of Health and Italian National Institute of Health; Kazakhstan: Ministry of Health of the Republic of Kazakhstan and WHO Country Office; Kyrgyzstan: World Health Organization; Latvia: Ministry of Health, Centre for Disease Prevention and Control; Lithuania: Science Foundation of Lithuanian University of Health Sciences and Lithuanian Science Council and WHO; Malta: Ministry of Health; Montenegro: WHO and Institute of Public Health of Montenegro; North Macedonia: COSI in North Macedonia is funded by the Government of North Macedonia through National Annual Program of Public Health and implemented by the Institute of Public Health and Centers of Public Health in the country. WHO country office provides support for training and data management; Norway: Ministry of Health and Norwegian Institute of Public Health; Poland: National Health Programme, Ministry of Health; Portugal: Ministry of Health Institutions, the National Institute of Health, Directorate General of Health, Regional Health Directorates and the kind technical support from the Center for Studies and Research on Social Dynamics and Health (CEIDSS); Romania: Ministry of Health; Serbia: This study was supported by the World Health Organization (Ref. File 2015-540940); Slovakia: Biennial Collaborative Agreement between WHO Regional Office for Europe and Ministry of Health SR; Spain: Spanish Agency for Food Safety and Nutrition (AESAN); Tajikistan: WHO Country Office in Tajikistan and Ministry of Health and Social Protection; Turkmenistan: WHO Country Office in Turkmenistan and Ministry of Health; Turkey: Turkish Ministry of Health and World Bank.info:eu-repo/semantics/publishedVersio

Socioeconomic disparities in physical activity, sedentary behavior and sleep patterns among 6- to 9-year-old children from 24 countries in the WHO European region

Physical activity, sedentary behavior, and sleep are important predictors of children's health. This paper aimed to investigate socioeconomic disparities in physical activity, sedentary behavior, and sleep across the WHO European region. This cross-sectional study used data on 124,700 children aged 6 to 9 years from 24 countries participating in the WHO European Childhood Obesity Surveillance Initiative between 2015 and 2017. Socioeconomic status (SES) was measured through parental education, parental employment status, and family perceived wealth. Overall, results showed different patterns in socioeconomic disparities in children's movement behaviors across countries. In general, high SES children were more likely to use motorized transportation. Low SES children were less likely to participate in sports clubs and more likely to have more than 2 h/day of screen time. Children with low parental education had a 2.24 [95% CI 1.94-2.58] times higher risk of practising sports for less than 2 h/week. In the pooled analysis, SES was not significantly related to active play. The relationship between SES and sleep varied by the SES indicator used. Importantly, results showed that low SES is not always associated with a higher prevalence of "less healthy" behaviors. There is a great diversity in SES patterns across countries which supports the need for country-specific, targeted public health interventions.The authors gratefully acknowledge support from a grant from the Russian Government in the context of the WHO European Office for the Prevention and Control of NCDs. Data collection in the countries was made possible through funding from: Croatia: Ministry of Health, Croatian Institute of Public Health and WHO Regional Office for Europe. Albania: World Health Organization (WHO) Country Office Albania and the WHO Regional Office for Europe. Bulgaria: WHO Regional Office for Europe. Czech Republic: Ministry of Health of the Czech Republic, grant nr. AZV MZČR 17-31670 A and MZČR–RVO EÚ 00023761. Denmark: The Danish Ministry of Health. France: Santé publique France, the French Agency for Public Health. Georgia: WHO. Ireland: Health Service Executive. Italy: Italian Ministry of Health; Italian National Institute of Health (Istituto Superiore di Sanità). Kazakhstan: the Ministry of Health of the Republic of Kazakhstan within the scientific and technical program. Kyrgyzstan: World Health Organization. Latvia: Centre for Disease Prevention and Control, Ministry of Health, Latvia. Lithuania: Science Foundation of Lithuanian University of Health Sciences and Lithuanian Science Council and WHO. Malta: Ministry of Health. Montenegro: WHO and Institute of Public Health of Montenegro. Poland: National Health Programme, Ministry of Health. Portugal: Ministry of Health Institutions, the National Institute of Health, Directorate General of Health, Regional Health Directorates and the kind technical support from the Center for Studies and Research on Social Dynamics and Health (CEIDSS). Romania: Ministry of Health. Russian Federation: WHO. San Marino: Health Ministry. Spain: the Spanish Agency for Food Safety & Nutrition. Tajikistan: WHO Country Office in Tajikistan and Ministry of Health and Social Protection; Turkmenistan: WHO Country Office in Turkmenistan and Ministry of Health. Turkey: Turkish Ministry of Health and World Bank. Austria: Federal Ministry of Labor, Social Affairs, Health and Consumer Protection of Austria.info:eu-repo/semantics/publishedVersio

Parental Perceptions of Children’s Weight Status in 22 Countries: The WHO European Childhood Obesity Surveillance Initiative: COSI 2015/2017

Introduction: Parents can act as important agents of change and support for healthy childhood growth and development. Studies have found that parents may not be able to accurately perceive their child’s weight status. The purpose of this study was to measure parental perceptions of their child’s weight status and to identify predictors of potential parental misperceptions. Methods: We used data from the World Health Organization (WHO) European Childhood Obesity Surveillance Initiative and 22 countries. Parents were asked to identify their perceptions of their children’s weight status as “underweight,” “normal weight,” “a little overweight,” or “extremely overweight.” We categorized children’s (6–9 years; n = 124,296) body mass index (BMI) as BMI-for-age Z-scores based on the 2007 WHO-recommended growth references. For each country included in the analysis and pooled estimates (country level), we calculated the distribution of children according to the WHO weight status classification, distribution by parental perception of child’s weight status, percentages of accurate, overestimating, or underestimating perceptions, misclassification levels, and predictors of parental misperceptions using a multilevel logistic regression analysis that included only children with overweight (including obesity). Statistical analyses were performed using Stata version 15 1. Results: Overall, 64.1% of parents categorized their child’s weight status accurately relative to the WHO growth charts. However, parents were more likely to underestimate their child’s weight if the child had overweight (82.3%) or obesity (93.8%). Parents were more likely to underestimate their child’s weight if the child was male (adjusted OR [adjOR]: 1.41; 95% confidence intervals [CI]: 1.28–1.55); the parent had a lower educational level (adjOR: 1.41; 95% CI: 1.26–1.57); the father was asked rather than the mother (adjOR: 1.14; 95% CI: 0.98–1.33); and the family lived in a rural area (adjOR: 1.10; 95% CI: 0.99–1.24). Overall, parents’ BMI was not strongly associated with the underestimation of children’s weight status, but there was a stronger association in some countries. Discussion/Conclusion: Our study supplements the current literature on factors that influence parental perceptions of their child’s weight status. Public health interventions aimed at promoting healthy childhood growth and development should consider parents’ knowledge and perceptions, as well as the sociocultural contexts in which children and families live.The authors gratefully acknowledge support from a grant from the Russian Government in the context of the WHO European Office for the Prevention and Control of NCDs. Data collection in the countries was made possible through funding by: Albania: World Health Organization through the Joint Programme on Children, Food Security and Nutrition “Reducing Malnutrition in Children,” funded by the Millennium Development Goals Achievement Fund, and the Institute of Public Health; Bulgaria: Ministry of Health, National Center of Public Health and Analyses, World Health Organization Regional Office for Europe; Croatia: Ministry of Health, Croatian Institute of Public Health and World Health Organization Regional Office for Europe; Czechia: Grants AZV MZČR 17-31670 A and MZČR – RVO EÚ 00023761; Denmark: Danish Ministry of Health; France: French Public Health Agency; Georgia: World Health Organization; Ireland: Health Service Executive; Italy: Ministry of Health; Istituto Superiore di sanità (National Institute of Health); Kazakhstan: Ministry of Health of the Republic of Kazakhstan and World Health Organization Country Office; Latvia: n/a; Lithuania: Science Foundation of Lithuanian University of Health Sciences and Lithuanian Science Council and World Health Organization; Malta: Ministry of Health; Montenegro: World Health Organization and Institute of Public Health of Montenegro; Poland: National Health Programme, Ministry of Health; Portugal: Ministry of Health Institutions, the National Institute of Health, Directorate General of Health, Regional Health Directorates and the kind technical support of Center for Studies and Research on Social Dynamics and Health (CEIDSS); Romania: Ministry of Health; Russia (Moscow): n/a; San Marino: Health Ministry; Educational Ministry; Social Security Institute; the Health Authority; Spain: Spanish Agency for Food Safety and Nutrition (AESAN); Tajikistan: World Health Organization Country Office in Tajikistan and Ministry of Health and Social Protection; and Turkmenistan: World Health Organization Country Office in Turkmenistan and Ministry of Health. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.info:eu-repo/semantics/publishedVersio