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Disruptive behaviour disorders (DBDs)—which can include or be comorbid with disorders such as attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder and disruptive mood dysregulation disorder—are commonly seen in paediatric practice. Given increases in the prescribing of atypical antipsychotics for children and youth, it is imperative that paediatric trainees in Canada receive adequate education on the optimal treatment of DBDs. We describe the development, dissemination, and evaluation of a novel paediatric resident curriculum for the assessment and treatment of DBDs in children and adolescents. Pre–post-evaluation of the curriculum showed improved knowledge in participants.

Purpose Persons with advanced cancers experience high rates of pain. Nursing interventions for pain, which are tailored to the individual patient, may support motivation to engage in self-management and should include setting of realistic functional goals. For patients with advanced cancer, functional pain goals include personally important activities, measurable across clinical encounters. However, limited evidence exists regarding nursing assessment of functional pain goals. To address this gap, we piloted use of a motivational interviewing intervention. Motivational interviewing is a clinical technique for clarifying goals and related impediments, such as cognitive and emotional factors underlying pain management behaviors. Design Pilot feasibility testing. Methods Palliative care patients with cancer-related pain completed up to four intervention sessions, the Pain Self-Efficacy Questionnaire, and an author-developed acceptability questionnaire. Feasibility success was determined by 60% of participants completing at least two interventions. Fidelity to the intervention was assessed using the Motivational Interviewing Skills for Healthcare Encounters tool. Results Sixty-seven percent completed two interventions. Participants reported that interventions were helpful, worthwhile, and recommended. Mean pain self-efficacy scores (0-60 possible) rose from 31.5 (SD = 11.2) at intervention 1 to 35.5 (SD = 13) after intervention 4. Intervention fidelity was maintained. Conclusions Participants were willing to engage in multiple motivational interviewing conversations focused on pain management behaviors related to functional goals. Based on these findings about motivational interviewing for functional goals and patient willingness to set them, these conversations may have a place in clinical care as an element of pain assessment and intervention tailoring.

Background Numerous practice guidelines (PGs) relevant to child and youth mental health (CYMH) are available, but their quality is uncertain. We used systematic review methodology to identify the methods employed to develop PGs in CYMH and assess whether they align with international quality standards. Methods We used prespecified inclusion criteria to search for CYMH PGs (2009–2014) in journals of professional associations or websites of organizations who produce or house PGs. Eligible PGs and organization websites were screened to identify PG development methods. Two reviewers assessed the alignment of the PG development methods with PG quality criteria using the Appraisal of Guidelines for Research and Evaluation (AGREE II) domains and Institute of Medicine (IOM) standards. Results Five sets of eligible development methods were identified in 70 eligible PGs. Three sets adhered to all (National Institute for Health and Care Excellence; Scottish Intercollegiate Guidelines Network) or most (U.S. Preventive Services Task Force) AGREE II domains and IOM standards, and were used to develop 31.4% of PGs. The two remaining sets of development methods had important weaknesses (e.g. lack of mandatory rigorous systematic reviews, multidisciplinary development groups, or transparent conflict of interest methods) and were associated with 21.4% of PGs. No development methods could be identified in 40.0% of PGs; ineligible development methods were referenced in 7.1% of PGs. Conclusions Up to 69% of available CYMH PGs may have been developed using methods that do not align with AGREE II quality criteria or IOM standards. The quality of available CYMH PGs needs to be assessed, and strategies designed to guide practitioners to high quality PGs and facilitate adherence by PG developers to international quality standards are needed.

Objective: Children with attention-deficit hyperactivity disorder (ADHD) may have oppositional behaviour, conduct problems, and aggression. These symptoms vary in severity, and may be related to a comorbid diagnosis of oppositional defiant disorder (ODD) or conduct disorder (CD). Critical evaluation of the efficacy of ADHD medications may guide the clinician regarding the usefulness of medications for these symptoms. Method: We performed a systematic review and meta-analysis of psychostimulants, alpha-2 agonists, and atomoxetine for oppositional behaviour, conduct problems, and aggression in youth with ADHD, ODD, and CD. The quality of evidence for medications was rated using the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Two systematic reviews and 20 randomized controlled trials were included. There is high-quality evidence that psychostimulants have a moderate-to-large effect on oppositional behaviour, conduct problems, and aggression in youth with ADHD, with and without ODD or CD. There is very-low-quality evidence that clonidine has a small effect on oppositional behaviour and conduct problems in youth with ADHD, with and without ODD or CD. There is moderate-quality evidence that guanfacine has a small-to-moderate effect on oppositional behaviour in youth with ADHD, with and without ODD. There is high-quality evidence that atomoxetine has a small effect on oppositional behaviour in youth with ADHD, with and without ODD or CD. Conclusions: Evidence indicates that psychostimulants, alpha-2 agonists, and atomoxetine can be beneficial for disruptive and aggressive behaviours in addition to core ADHD symptoms; however, psychostimulants generally provide the most benefit.

Objective:To develop evidence-based guidelines on pharmacotherapy for severe disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), or conduct disorder (CD). The guidelines assume that psychosocial interventions have been pursued but did not achieve sufficient improvement.Method:A multidisciplinary consensus group used the Grading of Recommendations Assessment, Development and Evaluation approach for rating evidence quality and for grading recommendations. We conducted a systematic review of medications studied in placebo-controlled trials for treating disruptive and aggressive behaviour in children and adolescents with ADHD, ODD, or CD. We followed consensus procedures to make 1 of 4 recommendations for each medication: strong, in favour (↑↑); conditional, in favour (↑?); conditional, against (↓?); and strong, against (↓↓).Results:For children and adolescents with disruptive or aggressive behaviour associated with ADHD, psychostimulants received a strong recommendation in favour of use, while atomoxetine and alpha-2 agonists received a conditional recommendation in favour of use. If these patients do poorly with ADHD medications, the medication with the most evidence is risperidone. Risperidone also has the most evidence for treating disruptive or aggressive behaviour in the absence of ADHD. However, given risperidone's major adverse effects, it received only a conditional recommendation in favour of use. We recommended against using quetiapine, haloperidol, lithium, or carbamazepine because of the poor quality of evidence and their major adverse effects.Conclusion:When severe disruptive or aggressive behaviour occurs with ADHD, medications for ADHD should be used first. Other medications have major adverse effects and, with the exception of risperidone, very limited evidence to support their use.

RATIONALE Human genetics studies in African Americans have shown a strong correlation between polymorphisms in the ApoL1 gene and chronic kidney disease (CKD). To gain further insight into the etiology of ApoL1-associated kidney diseases, the determination of circulating levels of both wild type as well as ApoL1 variants could be of significant use. To date, antibodies that discriminate between all three ApoL1variant forms (wild type, G1 and G2) are not available. We aimed to develop a rapid method for detecting and quantifying ApoL1 variants and total levels in plasma. METHODS Ultra-performance liquid chromatography (UPLC) and tandem mass spectrometry (MS/MS) in multiple-reaction monitoring acquisition mode was used to quantify ApoL1. RESULTS We demonstrated that it is feasible to detect and quantify ApoL1 variants (wild type, G1 and G2), and total ApoL1 concentrations in plasma. ApoL1 genotypes determined by LC/MS agreed perfectly with the traditional method DNA sequencing for 74 human subjects. The method exhibited at least three orders of linearity with a lower limit of quantification of 10 nM. Moreover, the method can readily be multiplexed for the quantification of a panel of protein markers in a single sample. CONCLUSIONS The method reported herein obviates the need to perform DNA genotyping of ApoL1 variants, which is of significant value in cases where stored samples are unsuitable for DNA analysis. More importantly, the method could potentially be of use in the early identification of individuals at risk of developing CKD, and for the stratification of patients for treatment with future ApoL1-modifying therapies. Copyright © 2013 John Wiley & Sons, Ltd.

The aim of this study was to describe the frequency and trends in prescriptions and recommendations for selective serotonin reuptake inhibitors (SSRIs) for mental health disorders in children and adolescents in Canada from 2005 to 2009. Data were extracted from databases supplied by IMS Brogan (IMS), a proprietary source of pharmacoepidemiologic data. Analyses were performed to obtain descriptive statistics on SSRI prescriptions dispensed, SSRI drug recommendation frequency, reasons for drug recommendations (therapeutic indication), and median duration of use of SSRIs in Canadian children. Canadian census data were used to assess whether changes in SSRI use were related to changes in the number of children in Canada over the time period studied. SSRI prescriptions written by pediatricians increased by 39 %, while SSRI drug recommendations by all specialists for children and adolescents increased by 44 % over the 5-year interval. Over the 5-year period studied, fluoxetine was the most commonly recommended and dispensed SSRI. The use of escitalopram has increased while the use of paroxetine has declined. Between 2005 and 2009, the two most common therapeutic indications for SSRI recommendations were mood disorder (50 %) and anxiety disorder (25 %). Median treatment duration was less than 1 year, with duration generally increasing with patient age. The increase in use of SSRIs in Canadian children and adolescents from 2005 to 2009 suggests that the effects of public health warnings concerning suicidal thinking and behavior associated with these drugs are now dissipating. This may be attributable to the FDA’s pediatric approvals for fluoxetine and escitalopram, the growing comfort of clinicians with using SSRIs in children, limited availability of psychosocial treatments, and the influence of marketing. The use of paroxetine has continued to decline, likely because of specific warnings directed toward this agent and limited evidence supporting its efficacy.

Objective: The use of second-generation antipsychotics (SGAs) in youth has increased considerably. Increases are mainly attributable to treatment of disruptive behaviour disorders (DBDs). Our objective was to review the evidence regarding the efficacy of SGAs for DBDs in youth. Method: We performed a systematic review of all randomized controlled trials (RCTs) of SGAs and placebo for the treatment of DBDs in youth, focusing on efficacy data. Results: Eight RCTs in youth with DBDs were included. Five RCTs evaluated the use of risperidone in youth with the combination of subaverage-borderline IQ and disruptive behaviour-aggression. Single RCTs evaluated the use of risperidone for treatment-resistant aggression in attention-deficit hyperactivity disorder and for the treatment of conduct disorder (CD), and a single RCT evaluated the use of quetiapine for adolescent CD. The efficacy results of each of these studies are described. Conclusion: Four placebo-controlled studies support the short-term efficacy of low-dose risperidone in youth with a subaverage IQ. Placebo-controlled evidence is weak or nonexistent for SGAs other than risperidone, and is weak in youth with an average IQ. Multiple factors likely account for the disconnect between this limited evidence base and the frequent use of SGAs for DBDs in clinical practice. These include extrapolation from studies in youth with autism or a subaverage IQ to normally developing youth; ease of SGA titration and the mistaken perception that little monitoring is required; unavailability of psychosocial treatments; limited familiarity with other pharmacological options; clinical and cultural norms; and the influence of the pharmaceutical industry.

These are commentaries on a Cochrane review, published in this issue of EBCH, first published as: Pringsheim T, Steeves T. Cochrane Database of Systematic Reviews 2011, Issue 4. Art. No.: CD007990. DOI: 10.1002/ 14651858.CD007990.pub2 Further information for this Cochrane review is available in this issue of EBCH in the accompanying Summary article. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The Cochrane Collaboration

This clinical guideline provides recommendations for nonpharmacological treatments for tic disorders. We conducted a systematic literature search for clinical trials on the treatment of tics. One evidence-based review (including 30 studies) and 3 studies on behavioural interventions, 3 studies on deep brain stimulation (DBS), and 3 studies on transcranial magnetic stimulation (TMS) met our inclusion criteria. Based on this evidence, we have made strong recommendations for the use of habit reversal therapy and exposure and response prevention, preferably embedded within a supportive, psychoeducational program, and with the option to combine either of these approaches with pharmacotherapy. Although evidence exists for the effcacy of DBS, the quality of this evidence is poor and the risks and burdens of the procedure are fnely balanced with the perceived benefts. Our recommendation is that this intervention continues to be considered an experimental treatment for severe, medically refractory tics that have imposed severe limitations on quality of life. We recommend that the procedure should only be performed within the context of research studies and by physicians expert in DBS programming and in the management of tics. There is no evidence to support the use of TMS in the treatment of tics. However, the procedure is associated with a low rate of known complications and could continue to be evaluated within research protocols. The recommendations we provide are based on current knowledge, and further studies may result in their revision in future.

The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4+ T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23–induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19−/− mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19−/− mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides.

Background Tourette syndrome and chronic tic disorder are heritable but aetiologically complex. Although environment plays a role in their development, existing studies of non-genetic risk factors are inconsistent. Aims To examine the association between pre- and perinatal exposures and Tourette syndrome/chronic tic disorder in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective longitudinal pre-birth cohort. Method Relationships between exposures and Tourette syndrome/chronic tic disorder were examined in 6090 children using logistic regression. Results Maternal alcohol and cannabis use, inadequate maternal weight gain and parity were associated with Tourette syndrome or Tourette syndrome/chronic tic disorder. Other previously reported exposures, including birth weight and prenatal maternal smoking, were not associated with Tourette syndrome/chronic tic disorder. Conclusions This study supports previously reported relationships between Tourette syndrome/chronic tic disorder and prenatal alcohol exposure, and identifies additional previously unexplored potential prenatal risk factors.

Stochastic resonance has seen wide application in the physical sciences as a tool to understand weak signal ampliflcation by noise. However, this apparently counterintuitive phenomenon does not appear to have been exploited as a tool to enhance vibrational energy harvesting. In this note we demonstrate that by adding periodic forcing to a vibrationally excited energy harvesting mechanism, the power available from the device is apparently enhanced over a mechanism without periodic forcing. In order to illustrate this novel efiect, a conceptually simple, but plausible model of such a device is proposed to explore the use of stochastic resonance to enhance vibrational energy harvesting.

When carrying out vibration health monitoring (VHM) of a structure it is usually assumed that the structure is in the absence of fluid interaction and that any environmental effects which can cause changes in natural frequency either remain constant or are negligible. In certain cases, this condition cannot be assumed and therefore it is necessary to extract values of natural frequencies of the structure for the condition with no fluid interaction from those values measured. This paper considers the case of a thin circular plate in contact with a fluid cavity giving rise to strong structural/fluid vibration interaction. The paper details the free vibration analysis of the coupled system and through consideration of modal energy, illustrates how the affined modes of vibration of the plate and the fluid can be qualitatively described. The paper then introduces a method by which the natural frequencies of the plate in the absence of fluid interaction can be obtained from those of the plate in interaction with the fluid.

When carrying out vibration health monitoring (VHM) of a structure it is usually assumed that the structure is in the absence of fluid interaction and/or that any environmental effects which can cause changes in the vibration response of the structure either remain constant or are negligible. In general, the natural frequencies of a structure are the first candidates to be considered for damage features. But the natural frequencies would also change as a result of the interaction of the structure with a fluid/gas environment. For the purpose of VHM, one needs the pure structural natural frequencies corresponding to conditions when the structure does not interact with the environment. Therefore, in certain cases when the above assumptions cannot be made it becomes necessary to extract values of natural frequencies of the structure if it were in the absence of fluid interaction from those values measured. This paper considers the case of a cantilever beam in contact with a fluid cavity giving rise to strong structural/fluid vibration interaction and develops a method by which the natural frequencies of the beam in the absence of fluid interaction can be obtained from those of the beam in interaction.

Interleukin (IL)-25 is a member of the IL-17 family of cytokines. However, unlike the other members of this family, IL-25 promotes T helper (Th) 2 responses. We now show that IL-25 also regulates the development of autoimmune inflammation mediated by IL-17–producing T cells. We have generated IL-25–deficient (il25−/−) mice and found that they are highly susceptible to experimental autoimmune encephalomyelitis (EAE). The accelerated disease in the il25−/− mice is associated with an increase of IL-23 in the periphery and a subsequent increase in the number of inflammatory IL-17–, IFNγ-, and TNF-producing T cells that invade the central nervous system. Neutralization of IL-17 but not IFNγ in il25−/− mice prevented EAE, suggesting that IL-17 is a major disease-promoting factor. IL-25 treatment at several time points during a relapse-remitting model or chronic model of EAE completely suppressed disease. IL-25 treatment induced elevated production of IL-13, which is required for suppression of Th17 responses by direct inhibition of IL-23, IL-1β, and IL-6 expression in activated dendritic cells. Thus, IL-25 and IL-17, being members of the same cytokine family, play opposing roles in the pathogenesis of organ-specific autoimmunity.

BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory disease characterised by clinical features that include bone loss and epidermal hyperplasia. Aberrant cytokine expression has been linked to joint and skin pathology; however, it is unclear which cytokines are critical for disease initiation. Interleukin 17A (IL-17A) participates in many pathological immune responses; however, its role in PsA has not been fully elucidated.ObjectiveTo determine the role of IL-17A in epidermal hyperplasia and bone destruction associated with psoriatic arthritis.DesignAn in vivo gene transfer approach was used to investigate the role of IL-17A in animal models of inflammatory (collagen-induced arthritis) and non-inflammatory (receptor activator of NF-κB ligand (RANKL)-gene transfer) bone loss.ResultsIL-17A gene transfer induced the expansion of IL-17RA+CD11b+Gr1low osteoclast precursors and a concomitant elevation of biomarkers indicative of bone resorption. This occurred at a time preceding noticeable joint inflammation, suggesting that IL-17A is critical for the induction of pathological bone resorption through direct activation of osteoclast precursors. Moreover, IL-17A induced a second myeloid population CD11b+Gr1high neutrophil-like cells, which was associated with cutaneous pathology including epidermal hyperplasia, parakeratosis and Munro's microabscesses formation.ConclusionsCollectively, these data support that IL-17A can play a key role in the pathogenesis of inflammation-associated arthritis and/or skin disease, as observed in PsA.

A previous small study showed lower serum ferritin levels in subjects with Tourette's syndrome than in healthy subjects. The authors measured peripheral iron indices in a large group of Tourette's syndrome and comparison subjects and explored associations of ferritin levels with regional brain volumes.Ferritin was measured in 107 children and adults (63 Tourette's syndrome, 44 comparison); serum iron was measured in 73 (41 Tourette's syndrome, 32 comparison). Magnetic resonance imaging scans were used to measure volumes of the basal ganglia and cortical gray matter.Ferritin and serum iron were significantly lower in the Tourette's syndrome subjects, although still within the normal range. No association was found between tic severity and either iron index. In the Tourette's syndrome subjects, ferritin did not correlate significantly with caudate volume but did correlate positively with putamen volume. In the comparison subjects, ferritin correlated inversely with caudate volume but did not correlate significantly with putamen volume. Irrespective of diagnosis, ferritin correlated positively with volumes of the sensorimotor, midtemporal, and subgenual cortices.The lower peripheral ferritin and iron levels in persons with Tourette's syndrome are consistent with findings in other movement disorders and suggest that lower iron availability may have a causal role in the pathophysiology of tic disorders. Lower iron stores may contribute to hypoplasia of the caudate and putamen, increasing vulnerability to developing tics or to having more severe tics. Lower iron stores may also contribute to smaller cortical volumes and consequently to reduced inhibitory control of tics.

Aberrant cytokine expression has been proposed as an underlying cause of psoriasis, although it is unclear which cytokines play critical roles. Interleukin (IL)-23 is expressed in human psoriasis and may be a master regulator cytokine. Direct intradermal administration of IL-23 in mouse skin, but not IL-12, initiates a tumor necrosis factor–dependent, but IL-17A–independent, cascade of events resulting in erythema, mixed dermal infiltrate, and epidermal hyperplasia associated with parakeratosis. IL-23 induced IL-19 and IL-24 expression in mouse skin, and both genes were also elevated in human psoriasis. IL-23–dependent epidermal hyperplasia was observed in IL-19−/− and IL-24−/− mice, but was inhibited in IL-20R2−/− mice. These data implicate IL-23 in the pathogenesis of psoriasis and support IL-20R2 as a novel therapeutic target.

Cytokines of the interleukin-1 (IL-1) family, such as IL-1 alpha/beta and IL-18, have important functions in host defense, immune regulation, and inflammation. Insight into their biological functions has led to novel therapeutic approaches to treat human inflammatory diseases. Within the IL-1 family, IL-1 alpha/beta, IL-1Ra, and IL-18 have been matched to their respective receptor complexes and have been shown to have distinct biological functions. The most prominent orphan IL-1 receptor is ST 2. This receptor has been described as a negative regulator of Toll-like receptor-IL-1 receptor signaling, but it also functions as an important effector molecule of T helper type 2 responses. We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.

This paper describes the free vibration analysis of a cylindrical gas cavity axially bounded at one end by a liquid interface and a thin elastic disc at the other end. Natural frequencies of the complete liquid/gas/structural coupled system are calculated and compared with values obtained when simplifying assumptions are made with respect to the boundaries between the liquid, gas and structure. The analysis includes examination of the interaction between liquid and gas when the disc is assumed rigid. In selected cases the natural frequencies are compared with corresponding values obtained experimentally and from a commercial finite element code.

A general approach to modelling the vibration of prestressed thin cylindrical shells conveying fluid is presented. The steady flow of fluid is described by the classical potential flow theory, and the motion of the shell is represented by Sanders' theory of thin shells. A strain-displacement relationship is deployed to derive the geometric stiffness matrix due to the initial stresses caused by hydrostatic pressure. Hydrodynamic pressure acting on the shell is developed through dynamic interfacial coupling conditions. The resulting equations governing the motion of the shell and fluid are solved by a finite element method. This model is subsequently used to investigate the small-vibration dynamic behaviour of prestressed thin cylindrical shells conveying fluid. It is validated by comparing the computed natural frequencies, within the linear region, with existing reported experimental results. The influence of initial tension, internal pressure, fluid flow velocity and the various geometric properties is also examined.

This paper describes the free vibration analysis of a cylindrical gas cavity axially bounded at one end by a liquid interface and a thin elastic disc at the other end. Natural frequencies of the complete liquid/gas/structural coupled system are calculated for pre-set degrees of uncoupling.

CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a structurally related receptor (CD200R) expressed on rodent myeloid cells and is involved in regulation of macrophage function. We report the first characterization of human CD200R (hCD200R) and define its binding characteristics to hCD200. We also report the identification of a closely related gene to hCD200R, designated hCD200RLa, and four mouse CD200R-related genes (termed mCD200RLa-d). CD200, CD200R, and CD200R-related genes were closely linked in humans and mice, suggesting that these genes arose by gene duplication. The distributions of the receptor genes were determined by quantitative RT-PCR, and protein expression was confirmed by a set of novel mAbs. The distribution of mouse and human CD200R was similar, with strongest labeling of macrophages and neutrophils, but also other leukocytes, including monocytes, mast cells, and T lymphocytes. Two mCD200 receptor-like family members, designated mCD200RLa and mCD200RLb, were shown to pair with the activatory adaptor protein, DAP12, suggesting that these receptors would transmit strong activating signals in contrast to the apparent inhibitory signal delivered by triggering the CD200R. Despite substantial sequence homology with mCD200R, mCD200RLa and mCD200RLb did not bind mCD200, and presently have unknown ligands. The CD200 receptor gene family resembles the signal regulatory proteins and killer Ig-related receptors in having receptor family members with potential activatory and inhibitory functions that may play important roles in immune regulation and balance. Because manipulation of the CD200-CD200R interaction affects the outcome of rodent disease models, targeting of this pathway may have therapeutic utility.

The results of an experimental study on both pulsating and steady Newtonian fluid flow in an initially stretched rubber tube subjected to external vibration are reported. A circulating loop system was designed to maintain constant hydrostatic pressure throughout the tests so that the influence of external excitation on the fluid flow could be properly distinguished. The effects of fluid flow velocity and initial stretch rates on the dynamic response and damping of the tube conveying fluid were examined, and it was observed that damping ratios increase with increasing flow velocities, and generally decrease with increasing initial stretch rates for the tube conveying fluid. It was also noted that dynamic responses increase with increasing initial stretch rates, and decrease with increasing flow velocities. The effect of external vibration on fluid flow rates is small in a tube with a thickness-to-radius ratio (Dout−Din)/Din=0.617. Fluid pressures vary, in terms of frequency and amplitude, with external vibration as well as Womersley number.

IFN-κ belongs to a recently identified subclass of type I IFNs. In this study, we report the cloning and preliminary characterization of the murine homologue of IFN-κ. The gene encodes a 200-aa protein which is 38.5% homologous to human IFN-κ. Murine IFN-κ contains four cysteines in analogous positions to those observed in the IFN-α and an additional fifth unique cysteine, C174. The murine gene is located on chromosome 4, where other type I murine IFN genes, IFN-α and IFN-β, are clustered. This region is syntenic with human chromosome 9 where the gene encoding IFN-κ and the type I IFN gene cluster are found. Mouse IFN-κ is expressed at low levels in peritoneal macrophages and its expression is up-regulated by dsRNA and IFN-γ. Similar to previously reported transgenic mice carrying type I and type II IFNs, transgenic mice overexpressing murine IFN-κ in the β cells of the pancreas develop overt diabetes with hyperglycemia. Histological characterization of pancreatic islets from these transgenic mice showed inflammatory infiltrates with corresponding destruction of β cells.

A finite element formulation is developed to predict the vibration of cylindrical shells conveying fluid. The method is based on the three-dimensional theory of elasticity and the linearised Eulerian equations. The hydrodynamic pressure is derived from the condition for dynamic coupling of the fluid-structure and the Eulerian equation. The influence of initial stresses within the shell due to fluid pressure is taken into account. Predicted natural frequencies for fluid-shell systems in the radius-to-thickness ratio range of R/h=38.96-1624 are compared with published experimental results to validate the model, and are also compared with results obtained using other finite element models (based on the classical shell theory and potential flow theory) to demonstrate advantages and disadvantages in terms of accuracy. The effect of variation in flow velocities and hydrostatic pressures on the dynamic behaviour of fluid-conveying shells is examined, and the influence of supported conditions on the free vibration is also discussed.

We have biologically characterized two new members of the IL-17 cytokine family: IL-17F and IL-25. In contrast to conventional in vitro screening approaches, we have characterized the activity of these new molecules by direct in vivo analysis and have compared their function to that of other IL-17 family members. Intranasal administration of adenovirus expressing IL-17, IL-17C, or IL-17F resulted in bronchoalveolar lavage neutrophilia and inflammatory gene expression in the lung. In contrast, intranasal administration of IL-25-expressing adenovirus or IL-25 protein resulted in the production of IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia in the bronchoalveolar lavage and lung tissue. Mice given intranasal IL-25 also developed epithelial cell hyperplasia, increased mucus secretion, and airway hyperreactivity. IL-25 gene expression was detected following Aspergillus and Nippostrongylus infection in the lung and gut, respectively. IL-25-induced eosinophilia required IL-5 and IL-13, but not IL-4 or T cells. Following IL-25 administration, the IL-5+ staining cells were CD45R/B220+, Thy-1+/−, but were NK1.1-, Ly-6G(GR-1)-, CD4-, CD3-, and c-kit-negative. γ-common knockout mice did not develop eosinophilia in response to IL-25, nor were IL-5+ cells detected. These findings suggest the existence of a previously unrecognized cell population that may initiate Th2-like responses by responding to IL-25 in vivo. Further, these data demonstrate the heterogeneity of function within the IL-17 cytokine family and suggest that IL-25 may be an important mediator of allergic disease via production of IL-4, IL-5, IL-13, and eotaxin.

A linear analysis of the vibratory behaviour of initially tensioned orthotropic circular cylindrical shells conveying a compressible inviscid fluid is presented. The model is based on the three-dimensional nonlinear theory of elasticity and the Eulerian equations. A nonlinear strain-displacement relationship is employed to derive the geometric stiffness matrix due to initial stresses and hydrostatic pressures. Frequency-dependent fluid mass, damping and stiffness matrices associated with inertia, Coriolis and centrifugal forces, respectively, are derived through the fluid-structure coupling condition. The resulting equation governing the vibration of fluid-conveying shells is solved by the finite element method. The free vibration of initially tensioned orthotropic cylindrical shells conveying fluid is investigated; numerical examples are given and discussed.

A comparative study of the relative performance of several different axisymmetric finite elements, when applied to the dynamic problem of thin cylindrical shells conveying fluid, is presented. The methods used are based on (1) the Sanders' theory of thin shells and the potential flow theory, and (2) the theory of elasticity and the Euler equations. The elements studied are: linear, paralinear, parabolic and cubilinear. Extensive comparison with experiment is carried out for the free vibration of cylindrical shells in the absence of, and containing, quiescent and flowing fluid. The analysis of the relative competence of these elements is presented for shell length-to-radius ratios 1.95≤L/R≤32, shell radius-to-thickness ratios 10≤R/h≤375 and boundary conditions: clamped–clamped, clamped–free and simply supported. We show that natural frequencies of thin cylindrical shells in the absence of, and containing, quiescent and flowing fluid can be assessed accurately when using two- and eight-noded elements, and the latter are also applicable to the dynamic problem of thick cylindrical shells. Copyright © 2002 John Wiley & Sons, Ltd.

A hybrid method for investigating pulsatile fluid flow in a long, thin, artery-like tube subjected to external excitations is presented. The non-linear partial differential equations governing the motion of the system, which incorporate the influence of circumferential strains, are solved by a combination of a finite element method, a finite difference method and a method of characteristics with interpolation. An initially axially stretched elastic tube conveying pulsating fluid, simply supported at both ends, is modelled to assess the effect of external harmonic excitation on the dynamic responses of the tube and the fluid flow. The results agree well with new experimental data. Comparison of the predicted results with those of a decoupled model demonstrates that it is necessary to consider the mechanism of fluid-structure interaction fully in the study of initially stretched cylindrical tubes conveying pulsatile fluid flow. An analysis of these coupling effects is presented for Womersley numbers α = 2.81 and 3.97 and a mean flow Reynolds number Re = 875.

In order to model pharmacokinetics and pharmacodynamics of pegylated IFNalpha, we utilized hydrodynamic delivery technology using minicircle DNA vectors encoding universal IFNalpha as a rapid and cost-effective method to obtain sustained levels of serum IFNalpha2alpha1. This approach is particularly useful for delivering secreted molecules, such as cytokines, as transfected hepatocytes secrete the transgene product in a paracrine manner providing a serum exposure profile resembling that reported in PEG-intron-treated patients. We found that sustained exposure of IFNalpha2alpha1 induced inhibition of metastasis. Primary 4T1 tumor growth was partially inhibited, while significant decreases in pulmonary metastatic burden were consistently observed. Further evidence that the observed inhibition of metastasis was independent of potential effects on the primary tumor was tested by resecting the primary tumor prior to treatment, which did not alter the outcome. Importantly, sustained IFNalpha2alpha1 treatment correlated with a significant increase in the survival of tumor-bearing animals. IFNalpha effects are plieotropic resulting in potential activation of numerous immune cell types associated with both innate and adaptive immunity. However, the mechanisms associated with IFNalpha-induced inhibition of lung metastasis were largely engendered by innate immune cells since treatment in BALB/c mice deficient for T and B cells did not affect the capacity of IFNalpha to inhibit pulmonary metastasis when compared to wild-type animals. The importance of NK cells has recently been reported as an important innate component for IFNalpha induced reduction of metastatic burden. However, little is known about IFNalpha-regulation of other innate cell types that may contribute to the inhibition of tumor metastasis. Here we report IFNalpha2alpha1 treatment induced marked decreases in 4T1-induced expansion and activation of immature CD11b+ Gr-1+ myeloid cells (aka: MDSC), which have been reported to contribute to metastatic potential. These results correlated with similar decreases in metastatic burden in mice following chlodronate-liposome depletion of CD11b+ Gr-1+ myeloid cells. Citation Format: Christina Kochel, Kalyan Pande, Roanna Ueda, Dan Gorman, Drake Laface. Sustained IFNalpha treatment inhibits metastasis in 4T1 mammary carcinoma and correlates with decreasing myeloid-derived suppressor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B49.

Obsessions are recurrent thoughts, images or urges that are generally unwanted (ego-dystonic). Compulsions are repetitive behaviours or mental acts performed to relieve anxiety related to obsessions or according to rigid rules. Typical obsessive–compulsive themes include contamination or cleaning

In a search for genes expressed by dendritic cells (DC), we have cloned cDNAs encoding different forms of an asialoglycoprotein receptor (ASGPR). The DC-ASGPR represents long and short isoforms of human macrophage lectin, a Ca2+-dependent type II transmembrane lectin displaying considerable homology with the H1 and H2 subunits of the hepatic ASGPR. Immunoprecipitation from DC using an anti-DC-ASGPR mAb yielded a major 40-kDa protein with an isoelectric point of 8.2. DC-ASGPR mRNA was observed predominantly in immune tissues. Both isoforms were detected in DC and granulocytes, but not in T, B, or NK cells, or monocytes. DC-ASGPR species were restricted to the CD14-derived DC obtained from CD34+ progenitors, while absent from the CD1a-derived subset. Accordingly, both monocyte-derived DC and tonsillar interstitial-type DC expressed DC-ASGPR protein, while Langerhans-type cells did not. Furthermore, DC-ASGPR is a feature of immaturity, as expression was lost upon CD40 activation. In agreement with the presence of tyrosine-based and dileucine motifs in the intracytoplasmic domain, mAb against DC-ASGPR was rapidly internalized by DC at 37°C. Finally, intracellular DC-ASGPR was localized to early endosomes, suggesting that the receptor recycles to the cell surface following internalization of ligand. Our findings identify DC-ASGPR/human macrophage lectin as a feature of immature DC, and as another lectin important for the specialized Ag-capture function of DC.

This paper describes the free vibration analysis of a thin disc vibrating and interacting with an acoustic medium contained in a cylindrical duct. The effects of structural-acoustic coupling are studied by means of an analytical-numerical method that is based upon classical theory and the Galerkin method. The coupling effects are discussed, and results obtained from the analysis are compared with corresponding values obtained both experimentally and from a finite element analysis. There is good agreement between the three sets of results.

This paper presents a method for the dynamic analysis of initially tensioned orthotropic thin-walled cylindrical tubes conveying steady fluid flow, based on Sanders' non-linear theory of thin shells and the classical potential flow theory. The method is relatively straightforward, using a hydrodynamic pressure formulation derived from the velocity potential, a dynamic coupling condition at the fluid-structure interface and two-noded frustum elements to assess the dynamic behaviour of these tube/fluid systems accurately. A non-linear strain-displacement relationship is also deployed to derive the geometric stiffness matrix due to the initial stresses and hydrostatic pressures. The equations of motion for the tube and fluid are solved by a finite element method, and this is validated by comparing the natural frequencies obtained with other published results. The influence of material properties, fluid flow velocities and initial axial tensions on the natural frequencies is then illustrated and discussed.

The sequence of a novel hemopoietic cytokine was discovered in a computational screen of genomic databases, and its homology to mouse thymic stromal lymphopoietin (TSLP) suggests that it is the human orthologue. Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R α-chain. Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5. Human TSLPR and IL-7Rα are principally coexpressed on monocytes and dendritic cell populations and to a much lesser extent on various lymphoid cells. In accord, we find that human TSLP functions mainly on myeloid cells; it induces the release of T cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c+ dendritic cells, as evidenced by the strong induction of the costimulatory molecules CD40 and CD80 and the enhanced capacity to elicit proliferation of naive T cells.

The non-linear equations of motion of a flexible pipe conveying unsteadily flowing fluid are derived from the continuity and momentum equations of unsteady flow. These partial differential equations are fully coupled through equilibrium of contact forces, the normal compatibility of velocity at the fluid– pipe interfaces, and the conservation of mass and momentum of the transient fluid. Poisson coupling between the pipe wall and fluid is also incorporated in the model. A combination of the finite difference method and the method of characteristics is employed to extract displacements, hydrodynamic pressure and flow velocities from the equations. A numerical example of a pipeline conveying fluid with a pulsating flow is given and discussed.

This paper presents a viscoelastic finite element approach to the vibration analysis of viscoelastic Timoshenko tubes conveying inviscid incompressible fluid, within which the temperature-dependent functions of material properties are assumed known. The derivation of a viscoelastic finite element model, applied to a time-domain solution, is detailed. The dynamic behaviour of viscoelastic tubes conveying fluid is investigated for several initial axial tensions and fluid velocities. Numerical results are presented and discussed