Relating cardiorespiratory responses to work rate during incremental ramp exercise on treadmill in children and adolescents: sex and age differences

PURPOSE: Evaluation of cardiopulmonary exercise testing (CPET) slopes such as [Formula: see text] (cardiac/skeletal muscle function) and [Formula: see text] (O2 delivery/utilization), using treadmill protocols is limited because the difficulties in measuring the total work rate ([Formula: see text]). To overcome this limitation, we proposed a new method in quantifying [Formula: see text] to determine CPET slopes.METHODS: CPET's were performed by healthy patients, (n=674, 9-18year) 300 female (F) and 374 male (M), using an incremental ramp protocol on a treadmill. For this protocol, a quantitative relationship based on biomechanical principles of human locomotion, was used to quantify the [Formula: see text] of the subject. CPET slopes were determined by linear regression of the data recorded until the gas exchange threshold occurred.RESULTS: The method to estimate [Formula: see text] was substantiated by verifying that: [Formula: see text] for treadmill exercise corresponded to an efficiency of muscular work similar to that of cycle ergometer; [Formula: see text] (mL min-1W-1) was invariant with age and greater in M than F older than 12 years old (13-14years: 9.6±1.5(F) vs. 10.5±1.8(M); 15-16years: 9.7±1.7(F) vs. 10.6±2.2(M); 17-18years: 9.6±1.7(F) vs. 11.0±2.3(M), p<0.05); similar to cycle ergometer exercise, [Formula: see text] was inversely related to body weight (BW) (r=0.71) or [Formula: see text] (r=0.66) and [Formula: see text] was not related to BW (r=- 0.01), but had a weak relationship with [Formula: see text] (r=0.28).CONCLUSION: The proposed approach can be used to estimate [Formula: see text] and quantify CPET slopes derived from incremental ramp protocols at submaximal exercise intensities using the treadmill, like the cycle ergometer, to infer cardiovascular and metabolic function in both healthy and diseased states

Gender differences in V˙O2 and HR kinetics at the onset of moderate and heavy exercise intensity in adolescents

The majority of the studies on (V)over dotO(2) kinetics in pediatric populations investigated gender differences in prepubertal children during submaximal intensity exercise, but studies are lacking in adolescents. The purpose of this study was to test the hypothesis that gender differences exist in the (V)over dotO(2) and heart rate (HR) kinetic responses to moderate (M) and heavy (H) intensity exercise in adolescents. Twenty-one healthy African-American adolescents (9 males, 15.8 +/- 1.1 year; 12 females, 15.7 +/- 1 year) performed constant work load exercise on a cycle ergometer at M and H. The (V)over dotO(2) kinetics of the male group was previously analyzed (Lai et al., Appl. Physiol. Nutr. Metab. 33:107-117, 2008b). For both genders, (V)over dotO(2) and HR kinetics were described with a single exponential at M and a double exponential at H. The fundamental time constant (tau(1)) of (V)over dotO(2) was significantly higher in female than male at M (45 +/- 7 vs. 36 +/- 11 sec, P < 0.01) and H (41 +/- 8 vs. 29 +/- 9 sec, P < 0.01), respectively. The functional gain (G(1)) was not statistically different between gender at M and statistically higher in females than males at H: 9.7 +/- 1.2 versus 10.9 +/- 1.3 mL min(-1) W-1, respectively. The amplitude of the slow component was not significantly different between genders. The HR kinetics were significantly (tau(1), P < 0.01) slower in females than males at M (61 +/- 16 sec vs. 45 +/- 20 sec, P < 0.01) and H (42 +/- 10 sec vs. 30 +/- 8 sec, P = 0.03). The G(1) of HR was higher in females than males at M: 0.53 +/- 0.11 versus 0.98 +/- 0.2 bpm W-1 and H: 0.40 +/- 0.11 versus 0.73 +/- 0.23 bpm W-1, respectively. Gender differences in the (V)over dotO(2) and HR kinetics suggest that oxygen delivery and utilization kinetics of female adolescents differ from those in male adolescents

Gender Differences in VO2 and HR Kinetics at the Onset of Moderate and Heavy Exercise Intensity in Adolescents

The majority of the studies on VO2 kinetics in pediatric populations investigated gender differences in prepubertal children during submaximal intensity exercise, but studies are lacking in adolescents. The purpose of this study was to test the hypothesis that gender differences exist in the VO2 and heart rate (HR) kinetic responses to moderate (M) and heavy (H) intensity exercise in adolescents. Twenty-one healthy African-American adolescents (9 males, 15.8 ± 1.1 year; 12 females, 15.7 ± 1 year) performed constant work load exercise on a cycle ergometer at M and H. The VO2 kinetics of the male group was previously analyzed (Lai et al., Appl. Physiol. Nutr. Metab. 33:107–117, 2008b). For both genders, VO2 and HR kinetics were described with a single exponential at M and a double exponential at H. The fundamental time constant (τ1) of VO2 was significantly higher in female than male at M (45 ± 7 vs. 36 ± 11 sec, P \u3c 0.01) and H (41 ± 8 vs. 29 ± 9 sec, P \u3c 0.01), respectively. The functional gain (G1) was not statistically different between gender at M and statistically higher in females than males at H: 9.7 ± 1.2 versus 10.9 ± 1.3 mL min−1 W−1, respectively. The amplitude of the slow component was not significantly different between genders. The HR kinetics were significantly (τ1, P \u3c 0.01) slower in females than males at M (61 ± 16 sec vs. 45 ± 20 sec, P \u3c 0.01) and H (42 ± 10 sec vs. 30 ± 8 sec, P = 0.03). The G1 of HR was higher in females than males at M: 0.53 ± 0.11 versus 0.98 ± 0.2 bpm W−1 and H: 0.40 ± 0.11 versus 0.73 ± 0.23 bpm W−1, respectively. Gender differences in the VO2 and HR kinetics suggest that oxygen delivery and utilization kinetics of female adolescents differ from those in male adolescents. © 2016 The Authors

The interaction between C 5a and both C 5a R and C 5 L 2 receptors is required for production of G ‐ CSF during acute inflammation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99020/1/eji2635.pd

Immune Cell–Derived C3 Is Required for Autoimmune Diabetes Induced by Multiple Low Doses of Streptozotocin

OBJECTIVE: The complement system contributes to autoimmune injury, but its involvement in promoting the development of autoimmune diabetes is unknown. In this study, our goal was to ascertain the role of complement C3 in autoimmune diabetes. RESEARCH DESIGN AND METHODS: Susceptibility to diabetes development after multiple low-dose streptozotocin treatment in wild-type (WT) and C3-deficient mice was analyzed. Bone marrow chimeras, luminex, and quantitative reverse transcription PCR assays were performed to evaluate the phenotypic and immunologic impact of C3 in the development of this diabetes model. RESULTS: Coincident with the induced elevations in blood glucose levels, we documented alternative pathway complement component gene expression within the islets of the diabetic WT mice. When we repeated the experiments with C3-deficient mice, we observed complete resistance to disease, as assessed by the absence of histologic insulitis and the absence of T-cell reactivity to islet antigens. Studies of WT chimeras bearing C3-deficient bone marrow cells showed that bone marrow cell-derived C3, and not serum C3, is involved in the induction of diabetes in this model. CONCLUSIONS: The data reveal a key role for immune cell-derived C3 in the pathogenesis of murine multiple low-dose streptozotocin-induced diabetes and support the concept that immune cell mediated diabetes is in part complement-dependen

DNA melting by RNA polymerase at the T7A1 promoter precedes the rate-limiting step at 37°C and results in the accumulation of an off-pathway intermediate

The formation of a transcriptionally active complex by RNA polymerase involves a series of short-lived structural intermediates where protein conformational changes are coupled to DNA wrapping and melting. We have used time-resolved KMnO4 and hydroxyl-radical X-ray footprinting to directly probe conformational signatures of these complexes at the T7A1 promoter. Here we demonstrate that DNA melting from m12 to m4 precedes the rate-limiting step in the pathway and takes place prior to the formation of full downstream contacts. In addition, on the wild-type promoter, we can detect the accumulation of a stable off-pathway intermediate that results from the absence of sequence-specific contacts with the melted non-consensus –10 region. Finally, the comparison of the results obtained at 37°C with those at 20°C reveals significant differences in the structure of the intermediates resulting in a different pathway for the formation of a transcriptionally active complex

Intrinsic NLRP3 inflammasome activity is critical for normal adaptive immunity via regulation of IFN-γ in CD4+ T cells

The NLRP3 inflammasome controls interleukin-1b maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described.We found that the NLRP3 inflammasome assembles in human CD4+ Tcells and initiates caspase-1–dependent interleukin-1b secretion, thereby promoting interferon-g production and T helper 1 (TH1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in Tcells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to “innate immune cells” but is an integral component of normal adaptive TH1 responses

Complement drives Th17 cell differentiation and triggers autoimmune arthritis

Activation of serum complement triggers Th17 cell–dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or β-glucan, both of which activate serum complement, evoked Th17 cell–mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or β-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)−/− mice but not in C5aR-deficient RAG−/− recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease

General transfer matrix formalism to calculate DNA–protein–drug binding in gene regulation: application to OR operator of phage λ

The transfer matrix methodology is proposed as a systematic tool for the statistical–mechanical description of DNA–protein–drug binding involved in gene regulation. We show that a genetic system of several cis-regulatory modules is calculable using this method, considering explicitly the site-overlapping, competitive, cooperative binding of regulatory proteins, their multilayer assembly and DNA looping. In the methodological section, the matrix models are solved for the basic types of short- and long-range interactions between DNA-bound proteins, drugs and nucleosomes. We apply the matrix method to gene regulation at the OR operator of phage λ. The transfer matrix formalism allowed the description of the λ-switch at a single-nucleotide resolution, taking into account the effects of a range of inter-protein distances. Our calculations confirm previously established roles of the contact CI–Cro–RNAP interactions. Concerning long-range interactions, we show that while the DNA loop between the OR and OL operators is important at the lysogenic CI concentrations, the interference between the adjacent promoters PR and PRM becomes more important at small CI concentrations. A large change in the expression pattern may arise in this regime due to anticooperative interactions between DNA-bound RNA polymerases. The applicability of the matrix method to more complex systems is discussed

A Novel Role for CD55 in Granulocyte Homeostasis and Anti-Bacterial Host Defense

Background: In addition to its complement-regulating activity, CD55 is a ligand of the adhesion class G protein-coupled receptor CD97; however, the relevance of this interaction has remained elusive. We previously showed that mice lacking a functional CD97 gene have increased numbers of granulocytes. Methodology/Results: Here,wedemonstratethatCD55-deficientmicedisplay a comparable phenotype with about two-fold more circulating granulocytes in the blood stream, the marginated pool, and the spleen. This granulocytosis was independent of increased complement activity. Augmented numbers of Gr-1-positive cells in cell cycle in the bone marrow indicated a higher granulopoietic activity in mice lacking either CD55 or CD97. Concomitant with the increase in blood granulocyte numbers, Cd55-/mice challenged with the respiratory pathogen Streptococcus pneumoniae developed less bacteremia and died later after infection. Conclusions: Collectively, these data suggest that complement-independent interaction of CD55 with CD97 is functionall