Gradual wavelet reconstruction of the velocity increments for turbulent wakes

This work explores the properties of the velocity increment distributions for wakes of contrasting local Reynolds number and nature of generation (a cylinder wake and a multiscale-forced case, respectively). It makes use of a technique called gradual wavelet reconstruction (GWR) to generate constrained randomizations of the original data, the nature of which is a function of a parameter, ϑ. This controls the proportion of the energy between the Markov-Einstein length (∼ 0.8 Taylor scales) and integral scale that is fixed in place in the synthetic data. The properties of the increments for these synthetic data are then compared to the original data as a function of ϑ. We write a Fokker-Planck equation for the evolution of the velocity increments as a function of spatial scale, r, and, in line with previous work, expand the drift and diffusion terms in terms up to fourth order in the increments and find no terms are relevant beyond the quadratic terms. Only the linear contribution to the expansion of the drift coefficient is non-zero and it exhibits a consistent scaling with ϑ for different flows above a low threshold. For the diffusion coefficient, we find a local Reynolds number independence in the relation between the constant term and ϑ for the multiscale-forced wakes. This term characterizes small scale structure and can be contrasted with the results for the Kolmogorov capacity of the zero-crossings of the velocity signals, which measures structure over all scales and clearly distinguishes between the types of forcing. Using GWR shows that results for the linear and quadratic terms in the expansion of the diffusion coefficient are significant, providing a new means for identifying intermittency and anomalous scaling in turbulence datasets. All our data showed a similar scaling behavior for these parameters irrespective of forcing type or Reynolds number, indicating a degree of universality to the anomalous scaling of turbulence. Hence, these terms are a useful metric for testing the efficacy of synthetic turbulence generation schemes used in large eddy simulation, and we also discuss the implications of our approach for reduced order modeling of the Navier-Stokes equations

Large eddy simulation of the velocity-intermittency structure for flow over a field of symmetric dunes

Owing to their frequent occurrence in the natural environment, there has been significant interest in refining our understanding of flow over dunes and other bedforms. Recent work in this area has focused, in particular, on their shear-layer characteristics and the manner by which flow structures are generated. However, field-based studies, are reliant on single-, or multi-point measurements, rather than delimiting flow structures from the velocity gradient tensor, as is possible in numerical work. Here, we extract pointwise time series from a well-resolved large eddy simulation as a means to connect these two approaches. The at-a-point analysis technique is termed the velocity-intermittency quadrant method and relates the fluctuating, longitudinal velocity, (Formula presented.), to its fluctuating pointwise Hölder regularity, (Formula presented.). Despite the difference in boundary conditions, our results agree very well with previous experiments that show the importance, in the region above the dunes, of a quadrant 3 ((Formula presented.), (Formula presented.)) flow configuration. Our higher density of sampling beneath the shear layer and close to the bedforms relative to experimental work reveals a negative correlation between (Formula presented.) and (Formula presented.) in this region. This consists of two distinct layers, with quadrant 4 ((Formula presented.), (Formula presented.)) dominant near the wall and quadrant 2 ((Formula presented.), (Formula presented.)) dominant close to the lower part of the separated shear layer. These results are consistent with a near-wall advection of vorticity into a region downstream of a temporarily foreshortened reattachment region, and the entrainment of slow moving and quiescent fluid into a faster, more turbulent shear layer. A comparison of instantaneous vorticity fields to the velocity-intermittency analysis shows how the pointwise results reflect larger-scale organisation of the flow. We illustrate this using results from two instantaneous datasets. In the former, extreme velocity-intermittency events corresponding to a foreshortened recirculation region (and high pressures on the stoss slope of the dune immediately downstream) arise, and the development of intense flow structures occurs as a consequence. In the other case, development of a ‘skimming flow’ with relatively little exchange between the inner and outer regions results in exceedances because of the coherence associated with this high velocity, high turbulence outer region. Thus, our results shed further light on the characteristics of dune flow in the near-wall region and, importantly for field-based research, show that useful information on flow structure can be obtained from single-point single velocity component measurements

The coupling between inner and outer scales in a zero pressure boundary layer evaluated using a Hölder exponent framework

This work considers the connectivity between large and small scales in boundary-layer turbulence by formalizing the modulation effect of the small scales by the large in terms of the pointwise Hölder condition for the small scales. We re-investigate a previously published dataset from this perspective and are able to characterize the coupling effectively using the (cross-)correlative relations between the large scale velocity and the small scale Hölder exponents. The nature of this coupling varies as a function of dimensionless distance from the wall based on inner-scaling, ${y}^{+}$, as well as on the boundary-layer height, δ. In terms of the fundamental change in the sign of the coupling between large and small scales, the critical height appears to be ${y}^{+}\sim 1000$. Below this height, small scale structures are associated with (and occur earlier than) maxima in the large scale velocity. Above this height, while the lag is similar in magnitude, the small scale structures are associated with minima in the large scale velocity. To consider these results further, we introduce a modified quadrant analysis and show that it is the coupling to the large scale low velocity state that is critical for the dynamics

Identification of Specific Language Impairment in Multilingual Contexts: Preliminary Validation of a Short Parental Bilingual Questionnaire in Lebanon

Assessing children with Specific language Impairment (SLI) in multilingual contexts is challenging for speech language therapists given that language patterns in bilinguals and in children with SLI are often reported to be remarkably similar and that screening language tests are not standardized on bilingual populations. The present study aims to validate the use of a parental questionnaire focusing on early language development, the languages spoken by the child, the use of languages in his/her environment, and information on linguistic difficulties within the family, as a complement to language assessment in multilingual contexts. Thirty-three Lebanese/French bilingual children (12 with SLI and 21 with typical development) and their parents participated in this study in Lebanon. The parents were interviewed via the questionnaire while the children were administered standardized language tests in each language. Data analysis showed that the parents’ answers to the questionnaire were coherent throughout and that some variables of the questionnaire strongly discriminated between the two groups of children, in particular the age of the first words and first sentences. Moreover, although significant correlations were found with language test scores, the answers to the questionnaire allowed us to refine the interpretation of the performance on the standardized tests, thus demonstrating the value of the parental questionnaire as a complementary tool to clinical evaluation

Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials

Purpose The addition of bisphosphonates to adjuvant therapy improves survival in postmenopausal breast cancer (BC) patients. We report a meta-analysis of four randomised trials of neoadjuvant chemotherapy (CT) +/– zoledronic acid (ZA) in stage II/III BC to investigate the potential for enhancing the pathological response. Methods Individual patient data from four prospective randomised clinical trials reporting the effect of the addition of ZA on the pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). Trial-level and individual patient data meta-analyses were done. Predefined subgroup-analyses were performed for postmenopausal women and patients with triple-negative BC. Results pCRb and pCR data were available in 735 and 552 patients respectively. In the total study population ZA addition to neoadjuvant CT did not increase pCRb or pCR rates. However, in postmenopausal patients, the addition of ZA resulted in a significant, near doubling of the pCRb rate (10.8% for CT only versus 17.7% with CT+ZA; odds ratio [OR] 2.14, 95% confidence interval [CI] 1.01–4.55) and a non-significant benefit of the pCR rate (7.8% for CT only versus 14.6% with CT+ZA; OR 2.62, 95% CI 0.90–7.62). In patients with triple-negative BC a trend was observed favouring CT+ZA. Conclusion This meta-analysis shows no impact from the addition of ZA to neoadjuvant CT on pCR. However, as has been seen in the adjuvant setting, the addition of ZA to neoadjuvant CT may augment the effects of CT in postmenopausal patients with BC

Severe Compromise of Preosteoblasts in a Surgical Mouse Model of Bisphosphonate-Associated Osteonecrosis of the Jaw.

Objectives: The effect of amino-bisphosphonates on osteoblastic lineage and its potential contribution to the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BONJ) remain controversial. We assessed the effects of zoledronic acid (ZOL) on bone and vascular cells of the alveolar socket using a mouse model of BONJ. Material and Methods: Thirty-two mice were treated twice a week with either 100 μg/kg of ZOL or saline for 12 weeks. The first left maxillary molar was extracted at the third week. Alveolar sockets were assessed at both 3 weeks (intermediate) and 9 weeks (long-term) after molar extraction by semi-quantitative histomorphometry for empty lacunae, preosteoblasts (Osterix), osteoclasts (TRAP), and pericyte-like cells (CD146). Also, the bone microarchitecture was assessed by micro-CT. Results: Osteonecrotic-like lesions were observed in 21% of mice. Moreover, a decreased number of preosteoblasts contrasted with the increased number of osteoclasts at both time points. In addition, osteoclasts display multinucleation and detachment from the endosteal surface. Furthermore, the number of pericyte-like cells increased at the intermediate time point. The alveolar bone mass increased exclusively with long-term ZOL treatment. Conclusion: The severe imbalance between bone-forming cells and bone-resorbing cells showed in this study could contribute to the pathogenesis of BONJ

Pharmacodynamics of bisphosphonates in arthritis.

Inflammatory arthritis is a group of autoimmune diseases characterized by chronic inflammation of the joints. Rheumatoid arthritis, the most common form of arthritis, is associated with local joint destruction and systemic bone loss. Osteoclasts, the only cells of the body able to resorbe bone, are key players in these two types of bone loss. Bisphosphonates are analogs of pyrophosphate that inhibit osteoclast action and bone resorption. They are indicated in pathology associated with excess resorption. Besides their effect on bone they also exhibit extra-osseous properties, acting on tumor cells, inflammation and angiogenesis. As a result, they have been trialed in the context of arthritis. It is now clear that they do not have any significant direct effect on disease activity or pain. If their indication in the prevention of glucocorticoid-induced osteoporosis is clear, any beneficial effects on bone erosions are still controversial but interesting preliminary results warrant further investigations

Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies

Cancer Treatment Dosing Regimens of Zoledronic Acid Result in Near-Complete Suppression of Mandible Intracortical Bone Remodeling in Beagle Dogs

Bisphosphonate doses used in cancer treatment are substantially higher than those used for osteoporosis. Little is known about the effects of these high doses on tissue-level remodeling suppression. The aim of this study was to assess the effects of cancer dosing regimens of zoledronic acid on tissue-level bone remodeling at different skeletal sites. Skeletally mature female beagle dogs were treated with monthly intravenous infusions of vehicle (VEH, saline) or zoledronic acid (ZOL, 0.067 mg/kg); an additional group of animals was treated daily with oral alendronate (ALN, 0.2 mg/kg/day). Doses of ZOL and ALN were, on a milligram per kilogram basis, consistent with those used for cancer and osteoporosis, respectively. Following either 3 or 6 months of treatment, animals were euthanized, and mandible, rib, and tibia were processed for dynamic bone histology. There was no evidence of oral lesions or bone matrix necrosis in the mandibles of any animals. After 3 months, the rate of intracortical bone remodeling in the mandible was significantly suppressed with ZOL (−95%) compared with VEH; by 6 months, ZOL had produced nearly complete suppression (−99%) compared with VEH. ZOL also significantly suppressed remodeling in the rib cortex at both 3 (−83%) and 6 (−85%) months compared with VEH; tibia cortex bone formation rate was nonsignificantly lower with ZOL treatment (−68% to −75%). Remodeling suppression in ZOL-treated animals was significantly greater than in ALN-treated animals at both the mandible and the rib; ALN and VEH were not different for any of the assessed parameters at any of the sites. Compared across skeletal sites, the absolute level of remodeling suppression with ZOL treatment was significantly greater at sites with higher remodeling, whereas the percent reduction was similar among the sites. These results document nearly complete intracortical remodeling suppression resulting from monthly intravenous zoledronic acid dosing, with changes being most dramatic at the mandible. Copyright © 2010 American Society for Bone and Mineral Researc

Tumour macrophages as potential targets of bisphosphonates

Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use