Is There a Link Between Obesity and Asthma?

Increasing epidemiological data identify a link between obesity and asthma incidence and severity. Based on experimental data, it is possible that shared inflammatory mechanisms play a role in determining this linkage. Although controversial, the role of adipokines may be central to this association and the maintenance of the asthma phenotype. While leptin and adiponectin have a causal link to experimental asthma in mice, data in humans are less conclusive. Recent studies demonstrate that adipokines can regulate the survival and function of eosinophils and that these factors can affect eosinophil trafficking from the bone marrow to the airways. In addition, efferocytosis, the clearance of dead cells, by airway macrophages or blood monocytes appears impaired in obese asthmatics and is inversely correlated with glucocorticoid responsiveness. This review examines the potential mechanisms linking obesity to asthma.     

Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies.     

Modelling of Longitudinal Elastic Wave Propagation in a Steel Rod Using the Discrete Element Method

The paper deals with the issue of modelling elastic wave propagation using the discrete element method (DEM). The case of a longitudinal wave in a rod with a circular cross-section was considered. A novel, complex algorithm consisting of the preparation of models and simulation of elastic waves was developed. A series of DEM models were prepared for simulations, differing in discretisation and material parameters. Additional calculations with the finite element method (FEM) were performed. Numerical wave signals were obtained from each simulation and compared with experimental results to choose the best DEM model based on the correlation between the waveforms. Moreover, dispersion curves were prepared for each model to verify the agreement with the Pochhammer-Chree wave propagation theory. Both experimental and theoretical approaches indicated the same model as the most suitable. The analysis results allowed stating that DEM can be successfully used for modelling wave propagation in structural rods.     

Thrust joint manipulation utilization by U.S. physical therapists*

Study Design: Online survey study.

Objective: To determine physical therapists’ utilization of thrust joint manipulation (TJM) and their comfort level in using TJM between the cervical, thoracic, and lumbar regions of the spine. We hypothesized that physical therapists who use TJM would report regular use and comfort providing it to the thoracic and lumbar spines, but not so much for the cervical spine.

Background: Recent surveys of first professional physical therapy degree programs have found that TJM to the cervical spine is not taught to the same degree as to the thoracic and lumbar spines.

Methods: We developed a survey to capture the required information and had a Delphi panel of 15 expert orthopedic physical therapists review it and provide constructive feedback. A revised version of the survey was sent to the same Delphi panel and consensus was obtained on the final survey instrument. The revised survey was made available to any licensed physical therapists in the U.S.A. using an online survey system, from October 2014 through June 2015.

Results: Of 1014 responses collected, 1000 completed surveys were included for analysis. There were 478 (48%) males; the mean age of respondents was 39.7 ± 10.81 years (range 24–92); and mean years of clinical experience was 13.6 ± 10.62. A majority of respondents felt that TJM was safe and effective when applied to lumbar (90.5%) and thoracic (91.1%) spines; however, a smaller percentage (68.9%) felt that about the cervical spine. More therapists reported they would perform additional screening prior to providing TJM to the cervical spine than they would for the lumbar and thoracic spines. Therapists agreed they were less likely to provide and feel comfortable with TJM in the cervical spine compared to the thoracic and lumbar spines. Finally, therapists who are male; practice in orthopedic spine setting; are aware of manipulation clinical prediction rules; and have manual therapy certification, are more likely to use TJM and be comfortable with it in all three regions.

Conclusion: Results indicate that respondents do not believe TJM for the cervical spine to be as safe and efficacious as that for the lumbar and thoracic spines. Further, they are more likely to perform additional screening, abstain from and do not feel comfortable performing TJM for the cervical spine.

Clinical Relevance: Our research reveals there is a discrepancy between utilization of TJM at different spinal levels. This research provides an opportunity to address variability in clinical practice among physical therapists utilizing TJM.     

Effect of air filtration on house dust mite,cat and dog allergens and particulate matter in homes

BackgroundIndoor allergens (i.e. from mite, cat and dog) are carried by airborne particulate matter. Thus, removal of particles would reduce allergen exposure. This work aims to assess the performance of air filtration on particulate matter and thus allergen removal in 22 bedrooms.MethodsIndoor air was sampled (with and without air filtration) with a cascade impactor and allergens were measured using enzyme‐linked immunosorbent assay (ELISA). Particulate matter (including ultrafine particles) was also monitored.ResultsThe median of allergen reduction was 75.2% for Der f 1 (p < 0.001, n = 20), 65.5% for Der p 1 (p = 0.066, n = 4), 76.6% for Fel d 1 (p < 0.01, n = 21) and 89.3% for Can f 1 (p < 0.01, n = 10). For size fractions, reductions were statistically significant for Der f 1 (all p < 0.001), Can f 1 (PM_>10 and PM_2.5–10, p < 0.01) and Fel d 1 (PM_2.5–10, p < 0.01), but not for Der p 1 (all p > 0.05). PM was reduced in all fractions (p < 0.001). The allergens were found in all particle size fractions, higher mite allergens in the PM_>10 and for pet allergens in the PM_2.5–10.ConclusionsAir filtration was effective in removing mites, cat and dog allergens and also particulate matter from ambient indoor air, offering a fast and simple solution to mitigate allergen exposome.     

Understanding Social Media: Opportunities for Cardiovascular Medicine

Cardiology professionals have used social media platforms such as Twitter to gain exposure to new research, network with experts, share opinions, and engage in scientific debates. The power of social media to communicate openly, with wide-reaching access worldwide, and at a rate faster than ever before makes it a formidable force and voice. However, evolving individual and institutional use has resulted in uncertainty for all parties on how to optimally advance this newer digital frontier. Thus, the purpose of this paper is to: 1) introduce the basics of social media usage (with the focus on Twitter); 2) provide perspective on best social media practices in academic and clinical cardiovascular medicine; and 3) present a vision for social media and the future of cardiovascular medicine.     

Histidine-Rich Glycoprotein Modulates the Anti-Angiogenic Effects of Vasculostatin

Brain angiogenesis inhibitor 1 (BAI1) is a transmembrane protein expressed on glial cells within the brain. Its expression is dramatically down-regulated in many glioblastomas, consistent with its functional ability to inhibit angiogenesis and tumor growth in vivo. We have shown that the soluble anti-angiogenic domain of BAI1 (termed Vstat120) requires CD36, a cell surface glycoprotein expressed on microvascular endothelial cells (MVECs), for it to elicit an anti-angiogenic response. We now report that Vstat120 binding to CD36 on MVECs activates a caspase-mediated pro-apoptotic pathway, and this effect is abrogated by histidine-rich glycoprotein (HRGP). HRGP is a circulating glycoprotein previously shown to function as a CD36 decoy to promote angiogenesis in the presence of thrombospondin-1 or −2. Data here show that Vstat120 specifically binds HRGP. Under favorable MVEC growth conditions this interaction allows chemotactic-directed migration as well as endothelial tube formation to persist in in vitro cellular systems, and increased tumor growth in vivo as demonstrated in both subcutaneous and orthotopic brain tumor models, concomitant with an increase in tumor vascularity. Finally, we show that HRGP expression is increased in human brain cancers, with the protein heavily localized to the basement membrane of the tumors. These data help define a novel angiogenic axis that could be exploited for the treatment of human cancers and other diseases where excess angiogenesis occurs.Angiogenesis is the process through which new blood vessels are formed from pre-existing capillaries. In adulthood the vasculature is normally quiescent, a homeostatic state that is maintained by a precise balance of pro-angiogenic inducers such as vascular endothelial growth factor and anti-angiogenic inhibitors such as thrombospondin (TSP)−1 and −2. This angiostatic balance can be physiologically regulated in favor of new blood vessel formation during processes such as menstruation and wound healing allowing normal tissue regeneration; while pathological disruption of this balance is associated with many disease states, including diabetic retinopathy, atherosclerosis-induced tissue ischemia, chronic inflammation, tumor growth and metastasis, obesity, asthma, and several autoimmune diseases.¹ Therefore, it is extremely important to identify and dissect the pathways involved in vessel growth in both normal and aberrant conditions.Neovascularization is a major component of malignant tumor growth and many therapeutic strategies have been developed to inhibit tumor angiogenesis, including antibodies or decoys that bind and neutralize vascular endothelial growth factor,^2,3 small molecule inhibitors of growth factor signaling pathways,⁴ and peptides based on the anti-angiogenic type I repeat domains (TSR) of TSP-1.^5,6,7 Studies on the mechanisms of TSP-mediated anti-angiogenesis revealed that the TSR domains play an essential role⁸ and that the type B scavenger receptor CD36 functions as the critical endothelial cell surface receptor.^9,10 Using mouse corneal pocket angiogenesis assays we recently demonstrated that CD36 also functions as the receptor for a 120 kDa anti-angiogenic fragment derived from an unrelated TSR-containing protein, Brain Angiogenesis Inhibitor 1 (BAI1). This fragment, known as vasculostatin or Vstat120, suppressed neovessel formation in corneas from wild-type mice yet no effect was observed in CD36 null animals, showing for the first time that a TSR-containing protein distinct from TSP-1 and −2 mediates its anti-angiogenic functions through interactions with CD36.¹¹BAI1 is a 1584-aa brain-specific protein predicted to have seven transmembrane segments and a large extracellular domain. The extracellular domain contains an RGD integrin recognition motif, a putative hormone receptor (HomR) domain, and five TSR domains. Its expression is down-regulated in glioblastomas¹² and inversely correlated with vascularity and metastasis in colorectal cancer,¹³ consistent with an anti-angiogenic role. Kaur et al¹⁴ have shown that the TSR-containing fragment, Vstat120, was released from the cell membrane via proteolytic cleavage at a G protein–coupled receptor cleavage site and that this fragment inhibited microvascular endothelial cell (MVEC) proliferation, migration, and tube formation equivalent to that seen with full-length BAI1. Strikingly, restoration of Vstat120 expression in human glioma cells suppressed tumorigenicity and vascularity and enhanced animal survival in subcutaneous and orthotopic tumor implantation models in nude mice.¹¹The binding site on CD36 for the TSR domains of TSP-1 and −2 and Vstat120 has been localized to amino acids 93 to 120^11,15,16 within a highly conserved region termed the CLESH domain (CD36, LIMP2, EMP structural homology – see Figure 1A). CLESH domains are also found in proteins genetically distinct from the CD36 family,¹⁷ including some, such as HIV gp120 and histidine-rich glycoprotein (HRGP) which are known to bind TSP-1. HRGP, a 75-kDa glycoprotein synthesized in the liver, circulates in the blood at moderately high concentrations (approximately 100 to 150 μg/ml), and is secreted from activated platelets. In addition to TSP-1 and −2, it binds a wide range of ligands including divalent metal cations and several components of the provisional matrix laid down by healing wounds and tumors where angiogenesis is prevalent (for review see¹⁸). It has been implicated in the coagulation and fibrinolytic systems, and high levels have been associated with thrombotic disorders.^19,20 Work in our lab has shown that HRGP acts as a CD36 decoy to promote angiogenesis by binding TSP-1 and −2 and thereby preventing them from binding to CD36 on the endothelial cell surface.^21,22 Because both HRGP and CD36 compete for the identical binding region in TSP-1 and −2, we hypothesized that the relative concentrations of ligands, receptor, and decoy within a given microenvironment would ultimately determine the degree of angiogenesis. Within tumors and other areas of chronic inflammation, HRGP can be released from activated platelets as well as deposited from plasma that gained access via poorly organized hyperpermeable vessels. The angiogenic balance would then be tipped to favor angiogenesis by HRGP binding to TSPs as well as potentially other TSR containing anti-angiogenic proteins.Open in a separate windowFigure 1HRGP CLESH domain fusion protein specifically precipitates Vstat120 from tumor cell postculture media. A: HRGP/GST fusion proteins. Three recombinant GST fusion proteins were designed using fragments of the HRGP protein spanning amino acids 155 to 213 (within the second cystatin domain), amino acids 330 to 389 (the HRR), and amino acids 428 to 502 (CLESH domain). The linear structure of CD36 with the CLESH domain highlighted is shown below for reference. B: Coomassie stained gel (top panel) showing the purified GST-HRGP protein fragments after glutathione sepharose chromatography. The bottom panel shows Western blot analysis of each fusion protein probed with anti-GST antibody. C: Western blot analysis of a GST pull-down assay. The three GST-HRGP fusion proteins and GST alone were bound to glutathione sepharose beads, and CM from LN229V120 glioma cells were added to each sample. Each precipitate was then probed using the Vstat120/BAI1-specific antibody. Vstat120 was only detected when the CLESH domain (HRGP 428 to 502) was used in the pull-down and not the cystatin (HRGP 155 to 213) or the HRR (HRGP 330 to 389) domains. HRGP 428 to 502 only precipitated Vstat120 when CM from Vstat120-transfected LN229 cells (+ lanes) was used. No protein was detected when CM from the nontransfected parent cells (− lane) was used. This is a representative image from n = 3 experiments.In this article we show that the CLESH domain of HRGP binds Vstat120 and suppresses its anti-angiogenic activity by reversing inhibition of endothelial cell migration and tube formation. Furthermore, we show in both subcutaneous and orthotopic brain tumor models that HRGP exacerbates glioblastoma tumor growth and enhances tumor vascularity. We also show that the amount of HRGP present in human brain is increased in patients with primary tumors with the protein localized predominantly within the basement membrane. Finally, we offer some insight into the mechanism of action of Vstat120 by showing caspase-3 activation and endothelial cell apoptosis on Vstat120 addition. Together these results suggest that deposition of HRGP into angiogenic microenvironments, perhaps as the result of the inherent “leakiness” of the neo-vasculature and/or of platelet granule release, can modulate the anti-angiogenic processes mediated by the general family of TSR-containing proteins, and may shed light on the mechanism of angiogenesis regulation in the brain.     

Antioxidative and antiinflammatory potential of different functional drink concepts in vitro

The present study was undertaken to investigate the antioxidative effects of three different functional drink concepts especially designed to improve the body's performance and function and to possess high antioxidant activities. The concepts based on the mixture of various plant ingredients were: (1) eQ - equalize your nutrient balance, brain line [acerola-dragon fruit], (2) eQ - equalize your nutrient balance, beauty line [honey-pepper] and (3) Let's get red [intense]. By using a cell-based test assay, the study investigated the potential of the functional drinks to inactivate reactive superoxide anion radicals generated by inflammation-mediating cells as well as the effect on basal metabolism of these cells (antioxidant and antiinflammatory potential). In addition, by using a cell-free test assay the potential of the drinks to inactivate free exogenous superoxide anion radicals (scavenger effect) was investigated. The data presented here demonstrate the different radical scavenging, antioxidant and anti-inflammatory potential of the functional drink concepts. In particular Let's get red [intense] turned out to be the most potent drink in this respect and demonstrated marked efficacy in scavenging, antioxidant and antiinflammatory action.