Impaired physical function associated with childhood obesity: How should we intervene?

- Background This study examined relationships between adiposity, physical functioning and physical activity. - Methods Obese (N=107) and healthy-weight (N=132) children aged 10-13 years underwent assessments of percent body fat (%BF, dual energy X-ray absorptiometry), knee extensor strength (KE, isokinetic dynamometry), cardiorespiratory fitness (CRF, peak oxygen uptake by cycle ergometry), physical health-related quality of life (HRQOL), worst pain intensity and walking capacity [six-minute walk (6MWT)]. Structural equation modelling was used to assess relationships between variables. - Results Moderate relationships were observed between %BF and 6MWT, KE strength corrected for mass and CRF relative to mass (r -.36 to -.69, P≤.007). Weak relationships were found between: %BF and physical HRQOL (r -.27, P=.008); CRF relative to mass and physical HRQOL (r -.24, P=.003); physical activity and 6MWT (r .17, P=.004). Squared multiple correlations showed that 29.6% variance in physical HRQOL was explained by %BF, pain and CRF relative to mass, while 28% variance in 6MWT was explained by %BF and physical activity. - Conclusions It appears that children with a higher body fat percentage have poorer KE strength, CRF and overall physical functioning. Reducing percent fat appears to be the best target to improve functioning. However, a combined approach to intervention, targeting reductions in body fat percentage, pain and improvements in physical activity and CRF may assist physical functioning.

The mechanisms of human renal epithelial cell modulation of autologous dendritic cell phenotype and function

Proximal tubule epithelial cells (PTEC) of the kidney line the proximal tubule downstream of the glomerulus and play a major role in the re-absorption of small molecular weight proteins that may pass through the glomerular filtration process. In the perturbed disease state PTEC also contribute to the inflammatory disease process via both positive and negative mechanisms via the production of inflammatory cytokines which chemo-attract leukocytes and the subsequent down-modulation of these cells to prevent uncontrolled inflammatory responses. It is well established that dendritic cells are responsible for the initiation and direction of adaptive immune responses. Both resident and infiltrating dendritic cells are localised within the tubulointerstitium of the renal cortex, in close apposition to PTEC, in inflammatory disease states. We previously demonstrated that inflammatory PTEC are able to modulate autologous human dendritic cell phenotype and functional responses. Here we extend these findings to characterise the mechanisms of this PTEC immune-modulation using primary human PTEC and autologous monocyte-derived dendritic cells (MoDC) as the model system. We demonstrate that PTEC express three inhibitory molecules: (i) cell surface PD-L1 that induces MoDC expression of PD-L1; (ii) intracellular IDO that maintains the expression of MoDC CD14, drives the expression of CD80, PD-L1 and IL-10 by MoDC and inhibits T cell stimulatory capacity; and (iii) soluble HLA-G (sHLA-G) that inhibits HLA-DR and induces IL-10 expression by MoDC. Collectively the results demonstrate that primary human PTEC are able to modulate autologous DC phenotype and function via multiple complex pathways. Further dissection of these pathways is essential to target therapeutic strategies in the treatment of inflammatory kidney disorders.

Age-related changes in hepatic function: An update on implications for drug therapy

The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

Time evolution of graphene growth on SiC as a function of annealing temperature

We followed by X-ray Photoelectron Spectroscopy (XPS) the time evolution of graphene layers obtained by annealing 3C SiC(111)/Si(111) crystals at different temperatures. The intensity of the carbon signal provides a quantification of the graphene thickness as a function of the annealing time, which follows a power law with exponent 0.5. We show that a kinetic model, based on a bottom-up growth mechanism, provides a full explanation to the evolution of the graphene thickness as a function of time, allowing to calculate the effective activation energy of the process and the energy barriers, in excellent agreement with previous theoretical results. Our study provides a complete and exhaustive picture of Si diffusion into the SiC matrix, establishing the conditions for a perfect control of the graphene growth by Si sublimation.

Exercise and vascular function in child obesity: A meta-analysis

CONTEXT: Conduit artery flow-mediated dilation (FMD) is a noninvasive index of preclinical atherosclerosis in humans. Exercise interventions can improve FMD in both healthy and clinical populations. OBJECTIVE: This systematic review and meta-analysis aimed to summarize the effect of exercise training on FMD in overweight and obese children and adolescents as well as investigate the role of cardiorespiratory fitness (peak oxygen consumption [Vo2peak]) on effects observed. DATA SOURCES: PubMed, Medline, Embase, and Cinahl databases were searched from the earliest available date to February 2015. STUDY SELECTION: Studies of children and/or adolescents who were overweight or obese were included. DATA EXTRACTION: Standardized data extraction forms were used for patient and intervention characteristics, control/comparator groups, and key outcomes. Procedural quality of the studies was assessed using a modified version of the Physiotherapy Evidence Base Database scale. RESULTS: A meta-analysis involving 219 participants compared the mean difference of pre- versus postintervention vascular function (FMD) and Vo2peak between an exercise training intervention and a control condition. There was a significantly greater improvement in FMD (mean difference 1.54%, P < .05) and Vo2peak (mean difference 3.64 mL/kg/min, P < .05) after exercise training compared with controls. LIMITATIONS: Given the diversity of exercise prescriptions, participant characteristics, and FMD measurement protocols, varying FMD effect size was noted between trials. CONCLUSIONS: Exercise training improves vascular function in overweight and obese children, as indicated by enhanced FMD. Further research is required to establish the optimum exercise program for maintenance of healthy vascular function in this at-risk pediatric population.

A Bayesian latent class safety performance function for identifying motor vehicle crash blackspots

The current state of the practice in Blackspot Identification (BSI) utilizes safety performance functions based on total crash counts to identify transport system sites with potentially high crash risk. This paper postulates that total crash count variation over a transport network is a result of multiple distinct crash generating processes including geometric characteristics of the road, spatial features of the surrounding environment, and driver behaviour factors. However, these multiple sources are ignored in current modelling methodologies in both trying to explain or predict crash frequencies across sites. Instead, current practice employs models that imply that a single underlying crash generating process exists. The model mis-specification may lead to correlating crashes with the incorrect sources of contributing factors (e.g. concluding a crash is predominately caused by a geometric feature when it is a behavioural issue), which may ultimately lead to inefficient use of public funds and misidentification of true blackspots. This study aims to propose a latent class model consistent with a multiple crash process theory, and to investigate the influence this model has on correctly identifying crash blackspots. We first present the theoretical and corresponding methodological approach in which a Bayesian Latent Class (BLC) model is estimated assuming that crashes arise from two distinct risk generating processes including engineering and unobserved spatial factors. The Bayesian model is used to incorporate prior information about the contribution of each underlying process to the total crash count. The methodology is applied to the state-controlled roads in Queensland, Australia and the results are compared to an Empirical Bayesian Negative Binomial (EB-NB) model. A comparison of goodness of fit measures illustrates significantly improved performance of the proposed model compared to the NB model. The detection of blackspots was also improved when compared to the EB-NB model. In addition, modelling crashes as the result of two fundamentally separate underlying processes reveals more detailed information about unobserved crash causes.

Influence of interleukin-1 beta on platelet-poor plasma clot formation: A potential impact on early bone healing

Objectives Hematoma quality (especially the fibrin matrix) plays an important role in the bone healing process. Here, we investigated the effect of interleukin-1 beta (IL-1β) on fibrin clot formation from platelet-poor plasma (PPP). Methods Five-milliliter of rat whole-blood samples were collected from the hepatic portal vein. All blood samples were firstly standardized via a thrombelastograph (TEG), blood cell count, and the measurement of fibrinogen concentration. PPP was prepared by collecting the top two-fifths of the plasma after centrifugation under 400 × g for 10min at 20°C. The effects of IL-1β cytokines on artificial fibrin clot formation from PPP solutions were determined by scanning electronic microscopy (SEM), confocal microscopy (CM), turbidity, and clot lysis assays. Results The lag time for protofibril formation was markedly shortened in the IL-1β treatment groups (243.8 ± 76.85 in the 50 pg/mL of IL-1β and 97.5 ± 19.36 in the 500 pg/mL of IL-1β) compared to the control group without IL-1β (543.8 ± 205.8). Maximal turbidity was observed in the control group. IL-1β (500 pg/mL) treatment significantly decreased fiber diameters resulting in smaller pore sizes and increased density of the fibrin clot structure formed from PPP (P < 0.05). The clot lysis assay revealed that 500 pg/mL IL-1β induced a lower susceptibility to dissolution due to the formation of thinner and denser fibers. Conclusion IL-1β can significantly influence PPP fibrin clot structure, which may affect the early bone healing process.

Cognitive function in schizophrenia: Conflicting findings and future directions

Introduction Schizophrenia is a severe mental disorder with multiple psychopathological domains being affected. Several lines of evidence indicate that cognitive impairment serves as the key component of schizophrenia psychopathology. Although there have been a multitude of cognitive studies in schizophrenia, there are many conflicting results. We reasoned that this could be due to individual differences among the patients (i.e. variation in the severity of positive vs. negative symptoms), different task designs, and/or the administration of different antipsychotics. Methods We thus review existing data concentrating on these dimensions, specifically in relation to dopamine function. We focus on most commonly used cognitive domains: learning, working memory, and attention. Results We found that the type of cognitive domain under investigation, medication state and type, and severity of positive and negative symptoms can explain the conflicting results in the literature. Conclusions This review points to future studies investigating individual differences among schizophrenia patients in order to reveal the exact relationship between cognitive function, clinical features, and antipsychotic treatment.

Excel’s Sumif and Sumifs function

As accountants, we are all familiar with the SUM function, which calculates the sum in a range of numbers. However, there are instances where we might want to sum numbers in a given range based on a specified criteria. In this instance the SUM IF function can achieve this objective.

The effect of internal audit function quality and internal audit contribution to external audit on audit fees

Corporate governance mandates and listing rules identify internal audit functions (IAF) as a central internal control mechanism. External audits are expected to assess the quality of IAF before placing reliance on its work. We provide evidence on the effect of IAF quality and IAF contribution to external audit on audit fees. Using data from a matched survey of both external and internal audits, we extend prior research which is based mainly on internal audits' assessment and conducted predominantly in highly developed markets. We find a positive relationship between IAF quality and audit fees as well as a reduction in audit fees as a result of external auditors' reliance on IAF. The interaction between IAF quality and IAF contribution to external audit suggests that high quality IAF induces greater external auditor reliance on internal auditors' work and thus result in lower external audit fees.

Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 2. Biochemical analyses

Platelet endothelial cell adhesion molecule 1 (PECAM-1) (CD31), a member of the immunoglobulin (Ig) superfamily of cell adhesion molecules with six Ig-like domains, has a range of functions, notably its contributions to leukocyte extravasation during inflammation and in maintaining vascular endothelial integrity. Although PECAM-1 is known to mediate cell adhesion by homophilic binding via domain 1, a number of PECAM-1 heterophilic ligands have been proposed. Here, the possibility that heparin and heparan sulfate (HS) are ligands for PECAM-1 was reinvestigated. The extracellular domain of PECAM-1 was expressed first as a fusion protein with the Fc region of human IgG1 fused to domain 6 and second with an N-terminal Flag tag on domain 1 (Flag-PECAM-1). Both proteins bound heparin immobilized on a biosensor chip in surface plasmon resonance (SPR) binding experiments. Binding was pH-sensitive but is easily measured at slightly acidic pH. A series of PECAM-1 domain deletions, prepared in both expression systems, were tested for heparin binding. This revealed that the main heparin-binding site required both domains 2 and 3. Flag-PECAM-1 and a Flag protein containing domains 1-3 bound HS on melanoma cell surfaces, but a Flag protein containing domains 1-2 did not. Heparin oligosaccharides inhibited Flag-PECAM-1 from binding immobilized heparin, with certain structures having greater inhibitory activity than others. Molecular modeling similarly identified the junction of domains 2 and 3 as the heparin-binding site and further revealed the importance of the iduronic acid conformation for binding. PECAM-1 does bind heparin/HS but by a site that is distinct from that required for homophilic binding.

Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 1. Molecular modeling studies

Platelet endothelial cell adhesion molecule 1 (PECAM-1) has many functions, including its roles in leukocyte extravasation as part of the inflammatory response and in the maintenance of vascular integrity through its contribution to endothelial cell−cell adhesion. PECAM-1 has been shown to mediate cell−cell adhesion through homophilic binding events that involve interactions between domain 1 of PECAM-1 molecules on adjacent cells. However, various heterophilic ligands of PECAM-1 have also been proposed. The possible interaction of PECAM-1 with glycosaminoglycans (GAGs) is the focus of this study. The three-dimensional structure of the extracellular immunoglobulin (Ig) domains of PECAM-1 were constructed using homology modeling and threading methods. Potential heparin/heparan sulfate-binding sites were predicted on the basis of their amino acid consensus sequences and a comparison with known structures of sulfate-binding proteins. Heparin and other GAG fragments have been docked to investigate the structural determinants of their protein-binding specificity and selectivity. The modeling has predicted two regions in PECAM-1 that appear to bind heparin oligosaccharides. A high-affinity binding site was located in Ig domains 2 and 3, and evidence for a low-affinity site in Ig domains 5 and 6 was obtained. These GAG-binding regions were distinct from regions involved in PECAM-1 homophilic interactions.

Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function

Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases. Copyright © 2010 by The American Association of Immunologists, Inc.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case–control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of ‘pore’ function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln–270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory ‘pore’ function.