Comparison of accelerometer measured levels of physical activity and sedentary time between obese and non-obese children and adolescents: a systematic review

Background: Obesity has been hypothesized to be associated with reduced moderate-to-vigorous physical activity (MVPA) and increased sedentary time (ST). It is important to assess whether, and the extent to which, levels of MVPA and ST are suboptimal among children and adolescents with obesity. The primary objective of this study was to examine accelerometer-measured time spent in MVPA and ST of children and adolescents with obesity, compared with MVPA recommendations, and with non-obese peers. Methods: An extensive search was carried out in Medline, Cochrane library, EMBASE, SPORTDiscus, and CINAHL, from 2000 to 2015. Study selection and appraisal: studies with accelerometer-measured MVPA and/or ST (at least 3 days and 6 h/day) in free-living obese children and adolescents (0 to 19 years) were included. Study quality was assessed formally. Meta-analyses were planned for all outcomes but were precluded due to the high levels of heterogeneity across studies. Therefore, narrative syntheses were employed for all the outcomes. Results: Out of 1503 records, 26 studies were eligible (n = 14,739 participants; n = 3523 with obesity); 6/26 studies involved children aged 0 to 9 years and 18/26 involved adolescents aged 10.1 to19 years. In the participants with obesity, the time spent in MVPA was consistently below the recommended 60 min/day and ST was generally high regardless of the participant’s age and gender. Comparison with controls suggested that the time spent in MVPA was significantly lower in children and adolescents with obesity, though differences were relatively small. Levels of MVPA in the obese and non-obese were consistently below recommendations. There were no marked differences in ST between obese and non-obese peers. Conclusions: MVPA in children and adolescents with obesity tends to be well below international recommendations. Substantial effort is likely to be required to achieve the recommended levels of MVPA among obese individuals in obesity treatment interventions

MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis

Objectives: To test the hypothesis that miR-155 regulates monocyte migratory potential via modulation of chemokine and chemokine receptor expression in rheumatoid arthritis (RA); and thereby is associated with disease activity. Methods: miR-155 copy-number in monocytes from peripheral blood (PB) of healthy (n=22), RA (n=24), and RA synovial fluid (SF; n=11) were assessed by real time- PCR using synthetic miR-155 as quantitative standard. To evaluate the functional impact of miR-155, human monocytes were transfected with control or miR-155 mimic and the effect on transcript levels, and production of chemokines was evaluated by TLDA and multiplex assays. A comparative study evaluated constitutive chemokine receptor expression in miR-155-/- and wild-type murine (CD115+Ly6C+Ly6G-) monocytes. Results: Compared with healthy monocytes, miR-155 copy-number was higher in RA PB and SF monocytes (PB p<0.01, and SF p<0.0001). MiR-155 copy-number in RA PB monocytes were higher in ACPA positive compared with ACPA negative patients (p=0.033) and correlated (95% C.I.) with DAS28 (ESR), R=0.728 (0.460, 0.874), with tender, R=0.631 (0.306, 0.824) and swollen, R=0.503 (0.125, 0.753) joint counts. Enforced-expression of miR-155 in RA monocytes stimulated the production of CCL3, CCL4, CCL5, CCL8; up-regulated CCR7 expression and down-regulated CCR2. Conversely, miR155-/- monocytes showed down-regulated CCR7 and upregulated CCR2 expression. Conclusions: Given the observed correlations with disease activity, these data provide strong evidence that miR-155 can contribute to RA pathogenesis by regulating chemokine production and pro-inflammatory chemokine receptor expression, thereby promoting inflammatory cell recruitment and retention in the RA synovium

Threshold Models for Genome-wide Association Mapping of Familial Breast Cancer Incidence in Humans

Breast cancer is the second most fatal cancer in the world and one of the most highly harmful cancers from which people suffer. Breast cancer studies have been able to uncover some knowledge about genetic susceptibility for familial breast cancer in humans. Hence, determining genetic factors may potentially help track the disease, as well as discover the cancer in early stages, or perhaps before it starts. In addition, this may allow early determination of possible treatment strategies which will make it easier to prevent the disease. In this context, it is important to determine whether the heritability of breast cancer incidence is greater than zero, which can be investigated if there is a potential genetic component playing a role in the incidence of the disease. Traits with zero heritability are said to be completely subject to environmental factors, so genetics has no effect at all. Heritability is important because it indicates the extent of genetic variations which could provide a reason for the infection. In the case that heritability is found to be greater than zero, it is useful to estimate the single nucleotide polymorphism (SNP) effects, which may potentially determine the genes or the genomic regions that are associated with the incidence of breast cancer. This study used data for three families with BRCAx as exome sequences provided by the University of Nebraska Medical Center and the Institutional Review Boards of Creighton University. Specifically, the data consisted of pedigree information for 167 individuals from three families, including information on whether each person had breast cancer or not (binary trait, positive or negative). Genomic data was available for 22 individuals among the 167. Theoretically, heritability as well as SNP effects can be estimated using a variety of approaches, but given the data available for this study, the best strategy was to combine both the pedigree-based data and the genomic data in one matrix. This matrix offers an advantage over other approaches that use only one of these datasets. The data was analyzed using a threshold model and Gibbs sampling algorithm to estimate the heritability of breast cancer incidence, as well as to predict SNP effects. The binary response variable for breast cancer incidence was modeled such that gender (2 levels) and family (3 levels) were the fixed effects. The effect of the subjects was the only random effect in the model. The heritability estimate was approximately 28%, indicating that there is a considerable genetic component underlying the incidence of breast cancer. In addition, the Genome-Wide Association Study (GWAS) analysis revealed that breast cancer is a complex trait, possibly controlled by many genes. However, some areas on the genome (specifically, chromosomes 1, 2, 4, 8, 14 and 16) may include candidate genes associated with breast cancer incidence. These genes might be responsible for this type of cancer and play important roles in susceptibility for the disease. The 20 SNPs with highest effects explained more than 3.5 % of the genetic variance, which is a good indicator that their genes are associated with breast cancer. The results of this study open the door for more research on breast cancer incidence. Despite the limitations related to the small sample used, the results of this study could be considered a first step for future work and investigation. Further studies using larger data sets may reveal more information on this complex trait

Causes of Miscarriage: Evidence from Logistic Regression Analysis

The unexpected end of a pregnancy before the birth is called Miscarriage. The miscarriage rate among pregnant women is about 15 to 20%. The first step in emotional recovery is to gain a better understanding of miscarriages. Next, it’s important to identify the factors that can elevate the risk of miscarriage. The objective of this study was employing a logistic regression model to evaluate the impact of various factors, including maternal age, embryo weight, chronic conditions, the number of previous miscarriages, and the embryo's gender. Our analysis reveals that when we control for these characteristics, the findings based on the data sample show that maternal age, chronic conditions, and the number of previous miscarriages have statistically significant impact on the incidence of miscarriage

MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis

MicroRNA-155 (miR-155) is an important regulator of B cells in mice. B cells have a critical role in the pathogenesis of rheumatoid arthritis (RA). Here we show that miR-155 is highly expressed in peripheral blood B cells from RA patients compared with healthy individuals, particularly in the IgD-CD27- memory B-cell population in ACPA+ RA. MiR-155 is highly expressed in RA B cells from patients with synovial tissue containing ectopic germinal centres compared with diffuse synovial tissue. MiR-155 expression is associated reciprocally with lower expression of PU.1 at B-cell level in the synovial compartment. Stimulation of healthy donor B cells with CD40L, anti-IgM, IL-21, CpG, IFN-α, IL-6 or BAFF induces miR-155 and decreases PU.1 expression. Finally, inhibition of endogenous miR-155 in B cells of RA patients restores PU.1 and reduces production of antibodies. Our data suggest that miR-155 is an important regulator of B-cell activation in RA

Influence of dietary antioxidants on luminal nitrite chemistry under conditions simulating the gastro-oesophageal junction

Abstract The second half of the twenties century saw a sharp worldwide decline in the both incidence and mortality of gastric cancer. Despite this the condition remains the world’s second leading cause of cancer mortality, second only to lung cancer. Although most gastric cancers arise in the antrum and body (non-cardia) of the stomach, the incidence of proximal tumours of the cardia and distal oesophagus have increased dramatically over the last fifty years throughout the world. This major change in the pattern of the disease suggests that gastric cancer (cardia versus non-cardia) is not one but two separate disorders with regard to cause and pathogenesis. Over the last fifty years there has been concern about luminal nitrite, derived from dietary nitrate, as a risk factor for upper gastro-intestinal malignancies. This has arisen from evidence that the salivary nitrite is rapidly converted to nitrosating species and (in the presence of ascorbic acid) nitric oxide (NO), which are both potentially mutagenics. Thus this study aimed to investigate the influence of ascorbic acid (AA), sodium thiocyanate (NaSCN), oxygen (O2) and pH (1.5, 2.5 and 3.0) on the nitrite chemistry in simulated gastric juice. Another aim of the present study was to investigate the influence of a range of water-soluble dietary phenolics antioxidants on the nitrite chemistry to compare their effect with that of ascorbic acid. The capacity of dietary phenolics and ascorbic acid to reduce the acidified nitrite to nitric oxide was also investigated under both aerobic and anaerobic conditions. These studies were performed in a newly designed closed bench-top model reproducing the chemical environment occurring at the human gastro-oesophageal junction. Each of the experiments was performed with and without NaSCN at different pH values (1.5, 2.5 and 3.0) under both aerobic and anaerobic conditions. The studies were focused on the measurement of NO formation and O2 consumption by electrochemical detection, according to the antioxidant present in the system (ascorbic acid, ferulic acid, caffeic acid, gallic acid or chlorogenic acid, in a range of concentrations). Nitric oxide production increased with increasing ascorbic acid concentration, and was greatest at the lowest pH of 1.5. The absence of oxygen in the system markedly increased nitric oxide levels in the presence of ascorbic acid, while the addition of NaSCN enhanced nitric oxide production and oxygen consumption. A different pattern of nitric oxide production was seen with the dietary phenolics compared with ascorbic acid. In addition, two different patterns of nitric oxide response were seen with ferulic acid and caffeic acid and another with gallic acid and chlorogenic acid. Ferulic and caffeic acids produced only a small initial increase in nitric oxide, which was not sustained under either aerobic or anaerobic conditions. In contrast, gallic and chlorogenic acids produced a much more marked rise in nitric oxide, which remained elevated under both aerobic and anaerobic conditions. The only phenolic experiment in which an equivalent concentration of nitric oxide to that with ascorbic acid was observed was with high concentration of gallic acid under anaerobic conditions. These studies indicated that nitrite in the simulated GOJ environment is converted to varying extents to nitric oxide and factors influencing this include luminal pH, thiocyanate, oxygen tension and presence of antioxidants. We have also found that the capacity of antioxidants to convert acidified nitrite to nitric oxide varies as does the temporal profile of the nitric oxide concentration generated by them

Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells

Acute inflammation is a complex and tightly regulated homeostatic process that includes leukocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro-resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as Rheumatoid Arthritis (RA) it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti-inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets

New pathways in the pathogenesis of rheumatoid arthritis

Rheumatoid Arthritis (RA) is a common chronic autoimmune disease that is characterized by synovial tissue inflammation eventually leading to joint destruction with severe functional deterioration and increased mortality – the underlying pathogenesis of RA remains unsolved. The principle of new therapeutic development is to define and characterize a molecular pathway both in terms of its basic biology and also its context-dependent effects in the synovial compartment. A hallmark pathological feature of RA is a rapid influx and accumulation of immune cells such as monocytes/macrophages into the synovium. Monocytes/ macrophages are major effector cells in RA synovitis, principally acting by releasing TNF-α, IL-6 and other inflammatory cytokines and chemokines. The recruitment of effectors cells is an important step in RA progression and is mediated by chemokines and their receptors. Two pathways will be studied in this project, both with potential relevance to the accumulation and activation of inflammatory leukocytes to the synovium, namely microRNAs and sphingolipid enzymes. MicroRNAs are a recently discovered class of post-transcriptional regulators that induce mRNA target degradation or translation inhibition. They have been shown to be involved in the regulation of the immune response and the development of autoimmunity. Of particular interest in the context of RA is miR-155, which is upregulated in RA synovial macrophages where it regulates cytokine expression such as TNF-α. Until now little was known about the role of miR-155 in regulating monocyte migration. Therefore, we sought to focus on the functional contribution of miR-155 in monocyte migration by the modulation of the expression of chemokines and their reciprocal chemokine receptors. Firstly the absolute copy numbers of miR- 155 transcripts in peripheral blood (PB) and synovial fluid (SF) monocytes of RA and healthy controls were assessed. To examine the role of miR-155 in monocyte migration and retention in the joint space, I overexpressed miR-155 in PB CD14+ monocytes of healthy controls and RA patients and examined the expression of chemokines and chemokine receptors mRNA levels by taqman low-density array (TLDA) and quantified the production of these chemokines in culture supernatant by multiplex assay. The role of miR-155 was investigated further using bone marrow monocytes (BMMO) from miR-155−/− and wild type (WT) mice. RA PB and SF CD14+ monocytes expressed higher copy numbers of miR-155 compared with healthy controls. RA SF monocytes exhibited the highest expression levels of miR- 155. The copy number of miR-155 expression was significantly increased in anti- citrullinated protein antibody (ACPA) positive RA compared with ACPA negative RA. The RA PB monocyte miR-155 copy number correlated positively and significantly with DAS28. Overexpression of miR-155 in PB monocytes led to an increased production of chemokines (CCL3/MIP-1α, CCL4/MIP-1β, CCL5/ RANTES, and CCL8/MCP2) and a reduction in expression of inflammatory chemokine receptor CCR2 while homeostatic CCR7 was up regulated. Commensurate with this, these receptors were expressed in an opposite direction inBMMO from miR-155 deficient cells; CCR7 was significantly down regulated and CCR2 expression level was increased. These observations suggest that CCR2 and CCR7 were under the tight control of miR-155 and that this regulation is preserved across the species; together suggesting that miR-155 can act as an important regulator of these receptors. We conclude that deregulation of miR- 155 in RA monocytes contributes to monocyte retention at sites of inflammation due to induction of chemokine production and down-regulation of inflammatory chemokine receptors. Furthermore, these data imply that miR-155 levels may reflect RA disease activity and could be a potential diagnostic or clinical disease activity biomarker for RA. Sphingosine kinases (SPHKs), SPHK1 and SPHK2, are isozymes that phosphorylate sphingosine into sphingosine-1- phosphate (S1P). S1P, a pleiotropic lipid mediator of inflammation, subsequently binds with any of the five G-protein coupled protein S1P receptors (S1PR1-5) and stimulates an array of cellular responses. Defects in S1P/S1PRs signalling have been shown to be associated with various pathologies. Until now however, no comprehensive analysis of expression of its components in RA has been performed. My data show that S1P concentrations were significantly elevated in the serum of RA patients with active disease compared to RA patients in remission and in healthy controls. Moreover, S1P1, S1P3, S1P5 and SPHK1 were differentially regulated in RA immune cell subsets, such as neutrophils, monocytes (CD14+), lymphocytes (CD4+ and CD8+) compared to healthy controls. In addition, compared with osteoarthritis (OA) pathological control, RA synovial tissues were strongly positive for the SPHK1, S1P1, and S1P3. Interestingly, RA patients treated with biological DMARDs had attenuated levels of SPHK1, S1P3 and S1P5, but not S1P1, when compared with patients treated with conventional DMARDs. Therefore, my study warrants further investigation of the clinical significance of S1P as a biomarker for disease activity and to explore the utility of novel therapeutic tools available to modulate the SPHK/S1PR/S1P axis in RA with a view to defining new therapeutic possibilities

Comparison of accelerometer measured levels of physical activity and sedentary time between obese and non-obese children and adolescents : a systematic review

Background: Obesity has been hypothesized to be associated with reduced moderate-to-vigorous physical activity (MVPA) and increased sedentary time (ST). It is important to assess whether, and the extent to which, levels of MVPA and ST are suboptimal among children and adolescents with obesity. The primary objective of this study was to examine accelerometer-measured time spent in MVPA and ST of children and adolescents with obesity, compared with MVPA recommendations, and with non-obese peers. Method: An extensive search was carried out in Medline, Cochrane library, EMBASE, SPORTDiscus, and CINAHL, from 2000-2015. Study selection and appraisal: studies with accelerometer-measured MVPA and/or ST (at least 3 days and 6 hours/day) in free-living obese children and adolescents (0-19 years) were included. Study quality was assessed formally. Meta-analyses were planned for all outcomes but were precluded due to the high levels of heterogeneity across studies. Therefore, narrative syntheses were employed for all the outcomes. Results: Out of 1503 records, 26 studies were eligible with a total (n =14739 participants; n =3523 with obesity); 6/26 studies involved children aged 0-9 years and 18/26 involved adolescents aged 10.1-19 years. In the participants with obesity, the time spent in MVPA was consistently below the recommended 60 minutes/day and ST was generally high regardless of the participant’s age and gender. Comparison with controls suggested that the time spent in MVPA was significantly lower in children and adolescents with obesity, though differences were relatively small. Levels of MVPA in the obese and non-obese were consistently below recommendations. There were no marked differences in ST between obese and non-obese peers. Conclusions: MVPA in children and adolescents with obesity tends to be well below international recommendations. Substantial effort is likely to be required to achieve the recommended levels of MVPA among obese individuals in obesity treatment interventions

Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions