Does flutter prevent drag reduction by reconfiguration?

The static reconfiguration of flexible beams exposed to transverse flows is classically known to reduce the drag these structures have to withstand. But the more a structure bends, the more parallel to the flow it becomes, and flexible beams in axial flows are prone to a flutter instability that is responsible for large inertial forces that drastically increase their drag. It is, therefore, unclear whether flexibility would still alleviate, or on the contrary enhance, the drag when flapping occurs on a reconfiguring structure. In this article, we perform numerical simulations based on reduced-order models to demonstrate that the additional drag induced by the flapping motion is almost never significant enough to offset the drag reduction due to reconfiguration. Isolated and brief snapping events may transiently raise the drag above that of a rigid structure in the particular case of heavy, moderately slender beams. But apart from these short peak events, the drag force remains otherwise always significantly reduced in comparison with a rigid structure.

C-type natriuretic peptide signalling drives homeostatic effects in human chondrocytes.

Signals induced by mechanical loading and C-type natriuretic peptide (CNP) represent chondroprotective routes that may potentially prevent osteoarthritis (OA). We examined whether CNP will reduce hyaluronan production and export via members of the multidrug resistance protein (MRP) and diminish pro-inflammatory effects in human chondrocytes. The presence of interleukin-1ß (IL-1ß) increased HA production and export via MRP5 that was reduced with CNP and/or loading. Treatment with IL-1ß conditioned medium increased production of catabolic mediators and the response was reduced with the hyaluronan inhibitor, Pep-1. The induction of pro-inflammatory cytokines by the conditioned medium was reduced by CNP and/or Pep-1, αCD44 or αTLR4 in a cytokine-dependent manner, suggesting that the CNP pathway is protective and should be exploited further.

miR-19-Mediated Inhibition of Transglutaminase-2 Leads to Enhanced Invasion and Metastasis in Colorectal Cancer.

UNLABELLED: Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome-13 amplification events, leading to altered invasive behavior in colorectal cancer cells. IMPLICATIONS: Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2.

Role of C-type natriuretic peptide signalling in maintaining cartilage and bone function.

C-type natriuretic peptide (CNP) has been demonstrated in human and mouse models to play critical roles in cartilage homeostasis and endochondral bone formation. Indeed, targeted inactivation of the genes encoding CNP results in severe dwarfism and skeletal defects with a reduction in growth plate chondrocytes. Conversely, cartilage-specific overexpression of CNP was observed to rescue the phenotype of CNP deficient mice and significantly enhanced bone growth caused by growth plate expansion. In vitro studies reported that exogenous CNP influenced chondrocyte differentiation, proliferation and matrix synthesis with the response dependent on CNP concentration. The chondroprotective effects were shown to be mediated by natriuretic peptide receptor (Npr)2 and enhanced synthesis of cyclic guanosine-3',5'-monophosphate (cGMP) production. Recent studies also showed certain homeostatic effects of CNP are mediated by the clearance inactivation receptor, Npr3, highlighting several mechanisms in maintaining tissue homeostasis. However, the CNP signalling systems are complex and influenced by multiple factors that will lead to altered signalling and tissue dysfunction. This review will discuss the differential role of CNP signalling in regulating cartilage and bone homeostasis and how the pathways are influenced by age, inflammation or sex. Evidence indicates that enhanced CNP signalling may prevent growth retardation and protect cartilage in patients with inflammatory joint disease.

Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: implications for cartilage degradation in arthritis.

OBJECTIVE: We have previously reported the up-regulation of matrix metalloproteinase 10 (MMP-10) following treatment with the procatabolic stimulus of interleukin-1 (IL-1) and oncostatin M (OSM) in chondrocytes. Although MMP-10 is closely related to MMP-3, little is known about the role of MMP-10 in cartilage catabolism. The purpose of this study was to determine whether MMP-10 is expressed in connective tissue cells and to assess how it may contribute to cartilage collagenolysis. METHODS: MMP gene expression was assessed by real-time polymerase chain reaction using RNA from human articular chondrocytes and synovial fibroblasts stimulated with IL-1 plus OSM or tumor necrosis factor alpha (TNFalpha) plus OSM. Synovial fluid levels of MMP-10 were determined by specific immunoassay. Recombinant procollagenases were used in activation studies. Immunohistochemistry assessed MMP-10 expression in diseased joint tissues. RESULTS: MMP-10 expression was confirmed in both chondrocytes and synovial fibroblasts following stimulation with either IL-1 plus OSM or TNFalpha plus OSM, and MMP-10 was detected in synovial fluid samples from patients with various arthropathies. Exogenous MMP-10 significantly enhanced collagenolysis from IL-1 plus OSM-stimulated cartilage, and MMP-10 activated proMMP-1, proMMP-8, and proMMP-13. Immunohistochemistry revealed the presence of MMP-10 in the synovium and cartilage of an IL-1 plus OSM-induced model of arthritis as well as in samples of diseased human tissues. CONCLUSION: We confirm that both synovial fibroblasts and articular chondrocytes express MMP-10 following treatment with procatabolic stimuli. Furthermore, the detectable levels of synovial fluid MMP-10 and the histologic detection of this proteinase in diseased joint tissues strongly implicate MMP-10 in the cartilage degradome during arthritis. The ability of MMP-10 to superactivate procollagenases that are relevant to cartilage degradation suggests that this activation represents an important mechanism by which this MMP contributes to tissue destruction in arthritis.

Interleukin-6 signalling in juvenile idiopathic arthritis is limited by proteolytically cleaved soluble interleukin-6 receptor.

OBJECTIVES: Interleukin-6 (IL-6) exerts multiple effects on chondrocytes and fibroblasts within the joint and is associated with disease activity in juvenile idiopathic arthritis (JIA). Although these cells express the ubiquitous signalling receptor for all IL-6-related cytokines, gp130, they do not express a cognate IL-6 receptor. Consequently, IL-6 responses within these cells occur via IL-6 trans-signalling relying on the presence of a soluble receptor (sIL-6R). Levels of sIL-6R in vivo are governed by either proteolytic cleavage (PC) of cognate receptor or by differential sIL-6R mRNA splicing (DS). The aim of this study was to evaluate the contribution of both isoforms to clinical parameters associated with IL-6 signalling in JIA. METHODS: IL-6, sIL-6R and DS-sIL-6R were measured by ELISA in serum and synovial fluid (SF) samples from 86 JIA patients. These data were related to indicators of inflammation-erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and compared between patients stratified by subtype, age and disease duration. RESULTS: SF IL-6 significantly correlated with general indicators of activity (ESR and CRP) and SF PC-sIL-6R to a lesser degree with CRP. When the IL-6:sIL-6R ratio was calculated as an indicator of the potential for IL-6 signalling within the joint, 33% of SF samples showed a ratio >1 indicating saturation of sIL-6R by IL-6. Mean DS-sIL-6R levels were 0.71 ng/ml, whereas PC-sIL-6R levels constituted the majority of sIL-6R at 20.89 ng/ml. CONCLUSIONS: IL-6 trans-signalling within the joints of JIA patients is predominantly governed by the presence of PC-sIL-6R, and the data provided suggest that synovial levels of IL-6 and sIL-6R would be sufficient to drive IL-6 responses in chondrocytes and synovial fibroblasts.

Assessment of the clinical significance of gelatinase activity in patients with juvenile idiopathic arthritis using quantitative protein substrate zymography.

OBJECTIVE: To measure gelatinase activities in paired synovial fluid (SF) and serum of patients with juvenile idiopathic arthritis (JIA), and to assess how these activities relate to clinical and laboratory measures of disease activity. METHODS: A quantitative protein substrate zymography method was adapted and validated for use with serum and SF. Bands of activity were measured by densitometry and correlated with standard laboratory indicators of inflammation: erythrocyte sedimentation rate and platelet count. RESULTS: Gelatinase activity was found consistently in patients with JIA, with reproducible, quantified bands of activity corresponding to pro-matrix metalloproteinase-9 (pro-MMP-9), including the neutrophil associated lipocalin complex, and pro- and active forms of MMP-2. Both active MMP-2 and pro-MMP-9 were higher in JIA serum than in controls, though no differences were seen between patients grouped according to age, disease duration, or JIA subtype. However, SF MMP-9 correlated significantly with the laboratory indicators of inflammation, as did the relative level of active MMP-2. CONCLUSIONS: Both MMP-2 and MMP-9 gelatinolytic activities are raised during active JIA and associated with inflammatory activity regardless of age and disease duration, supporting a role for MMPs in the breakdown of joint components from early in disease. These MMPs may be specific markers of active joint destruction linked to inflammatory JIA, MMP-9 as a product of infiltrating cells, and the activation of MMP-2 produced within the joint.

Levels of matrix metalloproteinase (MMP)-1 in paired sera and synovial fluids of juvenile idiopathic arthritis patients: relationship to inflammatory activity, MMP-3 and tissue inhibitor of metalloproteinases-1 in a longitudinal study.

OBJECTIVES: To measure levels of the collagenases matrix metalloproteinase (MMP)-1 and -13 in the synovial fluid (SF) and serum of patients with juvenile idiopathic arthritis (JIA), and to correlate these measurements with inflammatory activity, levels of the collagenase activator MMP-3 and the tissue inhibitor of metalloproteinases-1 (TIMP-1). METHODS: Levels of MMP-1, -3, -13 and TIMP-1 were measured in paired SF and serum from 82 JIA patients using enzyme-linked immunsorbent assay and compared between subtypes and patients of different ages and disease durations. These levels were also correlated to the active joint count (AJC) and standard measures of inflammatory activity and therapeutic response, including erythrocyte sedimentation rate (ESR) and platelet count (PLT). RESULTS: MMP-1 was detected in JIA SF and correlated with PLT. MMP-3 levels were high in SF and detectable in serum where they correlated with PLT, ESR and AJC. MMP-13, however, was not detected in SF or serum. No differences were observed between patients grouped by subtype, age or disease duration. MMP-3 contributed the majority of total MMP in SF samples resulting in excess MMP levels over TIMP-1. CONCLUSIONS: MMP-1 is up-regulated in SF concordant with inflammatory activity in JIA. This was true for patients in all JIA subtypes and age groups, suggesting that the capability for degradation of type II collagen is present in early disease, and throughout the disease course. MMP-3 may be important in the activation of collagenases and the saturation of exogenous inhibitors. Serum MMP-3 may therefore be a useful, measurable and specific marker of active disease in JIA.

On applications of high-frequency asymptotics in aeroacoustics.

The aim of this paper is to survey a range of applications of high-frequency asymptotic methods in aeroacoustics. Specifically, we are concerned with problems associated with noise generation, propagation and scattering as found in large modern aeroengines. With regard to noise generation, we consider the interaction between high-frequency vortical waves and thin aerofoils, with particular emphasis being placed on the way in which the vortical waves act on the non-uniform mean flow around the aerofoil. A ray-theoretic description of the resulting sound as it propagates along the engine intake is then presented, followed by consideration of the diffraction of these rays by the (possibly asymmetric) intake lip to produce sound in the far field. A range of more detailed possible extensions is also presented.

Genotyping of Enterocytozoon bieneusi in AIDS patients from the north west of England.

OBJECTIVES: In this study Enterocytozoon bieneusi -positive faeces samples from AIDS patients in the north west of England were investigated by polymerase chain reaction (PCR) and DNA sequencing for potential zoonotic origins. METHODS: The ITS and flanking regions of the rDNA was amplified by PCR and product sequenced. Sequences were compared with those held on GenBank to ascribe known genotypes. RESULTS: Of 13 E. bieneusi -positive samples tested, all gave a 508 bp amplification product by PCR. The samples yielded the following: genotypes B (n=11; so far only been found in humans), D (n=1; has been reported from humans and a laboratory macaque) and K (n=1; previously identified only from a cat). CONCLUSIONS: A possible zoonotic link with cats has been demonstrated for one human case. The origin of the majority of cases in the north west of England is unknown and may indicate that genotype B is solely a human pathogen.

Comparison of antibody kinetics following meningococcal serogroup C conjugate vaccine between healthy adults previously vaccinated with meningococcal A/C polysaccharide vaccine and vaccine-naïve controls.

Few data are available on the kinetics of meningococcal serogroup C-specific antibody production following meningococcal serogroup C conjugate (MCC) vaccination, particularly in those who have received prior meningococcal A/C polysaccharide (MACP) vaccination(s). Laboratory staff who had previously received either one dose (n = 35), two doses (n = 18) of MACP vaccine or who were naïve to previous meningococcal vaccination (n = 42) were vaccinated with MCC. Bloods were taken pre-vaccination, on the subsequent 4 days and on days 10 and 28. Serogroup C serum bactericidal antibody (SBA), and anti-serogroup C-specific IgG, IgM and IgA were measured. There were no significant differences between the groups who had received either 2 or 1 prior dose(s) of MACP, therefore, these results were combined. Up to day 4 there was no evidence of a significant increase or decrease in the median levels of SBA, IgG, IgM or IgA in either the naïve or MACP groups, although about 20% of individuals did have 4-fold SBA rises by day 4. By day 10 there were large significant increases in the levels of SBA, IgG, IgM and IgA with respective fold increases from pre-vaccination levels of 4.6, 1.9, 1.2 and 2.1 in the MACP group and 270, 13.4, 4.8 and 33.8 in the naïve group. Further significant increases were seen between day 10 and 28 for SBA, IgG and IgM (naïve group only). By day 28, 4-fold SBA rises had occurred in 63.5% of the MACP group and 97.6% of the naïve group. The SBA GMT on day 28 significantly differed between the naïve and MACP groups with GMTs 2.8-fold higher in the naïve group (P = 0.021). In conclusion, no decline in serogroup C-specific antibody levels was demonstrated immediately post-MCC vaccination whilst these levels had risen significantly by day 10. Putative protective SBA titres (> or =8, 32 or 128) were observed by day 10 following MCC vaccination regardless of MACP history.

Reduced antibody response to revaccination with meningococcal serogroup A polysaccharide vaccine in adults.

Widespread use of meningococcal A and C polysaccharide (MACP) vaccines has raised concerns about induction of hyporesponsiveness to these polysaccharides. Immunological hyporesponsiveness to C polysaccharide has been clearly documented in infants, children and adults but only limited data from Gambian children are available for A polysaccharide. We investigated whether a second dose of MACP, given 6 months after an initial dose affected the immunological response as measured by the serum bactericidal assay (SBA) and enzyme-linked immunosorbent assay (ELISA), to serogroup A meningococci in young adults (university students, n=36). Serogroup A SBA responses 1 month following the second dose of MACP (geometric mean titre (GMT) 103.6, 95% CI 45.6-235.1) were approximately one third of the levels observed 1 month post first dose (GMT 281.9, 95% CI 134.9-581.4). The serogroup A-specific IgG levels post second dose (GMC 21.2, 95% CI 15.3-29.4) were also significantly lower at an average of three-quarters the level post first dose (GMC 28.7, 95% CI 20.8-39.7). This confirms that revaccination with MACP vaccine, 6 months following the initial dose, results in a reduced immunological response to A polysaccharide in adults. Repeated vaccination with MACP vaccine may be ineffective and development and use of meningococcal serogroup A conjugate vaccines should be encouraged.