In a previous work, we derived optimum conditions for the design of finite-size 1-D unidirectional leaky-wave antennas (LWAs) in the general case. The bandwidth and the gain-bandwidth figure of merit ...are, however, structure-specific and have not been discussed yet. A practical case that is widely investigated in the literature is that of 1-D unidirectional LWAs based on partially reflecting surfaces (PRSs). In this work, we not only evaluate these features for this specific class of antennas, but we also derive design rules for optimizing the PRS impedance and cavity height to get maximum gain. Numerical results and full-wave simulations are finally proposed for a realistic example based on a metal strip-grating structure, to validate the theoretical findings.
The lymphatic system is best known for draining interstitial fluid from the tissues and returning it to the blood circulation. However, the lymphatic system also provides the means for immune ...surveillance in the immune system, acting as conduits that convey soluble antigens and antigen‐presenting cells from the tissues to the lymph nodes, where primary lymphocyte responses are generated. One macromolecule that potentially unites these two functions is the large extracellular matrix glycosaminoglycan hyaluronan (HA), a chemically simple copolymer of GlcNAc and GlcUA that fulfills a diversity of functions from danger signal to adhesive substratum, depending upon chain length and particular interaction with its many different binding proteins and a small but important group of receptors. The two most abundant of these receptors are CD44, which is expressed on leukocytes that traffic through the lymphatics, and LYVE‐1, which is expressed almost exclusively on lymphatic endothelium. Curiously, much of the HA within the tissues is turned over and degraded in lymph nodes, by a poorly understood process that occurs in the medullary sinuses. Indeed there are several mysterious aspects to HA in the lymphatics. Here we cover some of these by reviewing recent findings in the biology of lymphatic endothelial cells and their possible roles in HA homeostasis together with fresh insights into the complex and enigmatic nature of LYVE‐1, its regulation of HA binding by sialylation and self‐association, and its potential function in leukocyte trafficking.
Asthma exacerbations: Origin, effect, and prevention Jackson, David J., MRCP; Sykes, Annemarie, MRCP, PhD; Mallia, Patrick, MRCP, PhD ...
Journal of allergy and clinical immunology,
12/2011, Letnik:
128, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children in the Western world. Despite advances in asthma management, acute exacerbations continue to ...occur and impose considerable morbidity on patients and constitute a major burden on health care resources. Respiratory tract viruses have emerged as the most frequent triggers for exacerbations in both children and adults; however, the mechanisms underlying these remain poorly understood. More recently, it has become increasingly clear that interactions might exist between viruses and other triggers, increasing the likelihood of an exacerbation. In this article we begin with an overview of the health, economic, and social burden that exacerbations of asthma carry with them. This is followed by a review of the pathogenesis of asthma exacerbations, highlighting the various triggers responsible and multiple interactions that exist between them. The final section first addresses what preventative measures are currently available for asthma exacerbations and subsequently examines which of the new treatments in development might lessen the burden of exacerbations in the future.
Mepolizumab was the first licensed anti-IL5 monoclonal antibody for severe eosinophilic asthma (SEA). To date there are few data to confirm its efficacy in the real-world setting or assessment of ...baseline characteristics associated with response.
How do patients with severe eosinophilic asthma respond to mepolizumab in the real world setting and which characteristics are associated with a super-response to this therapy?
We conducted a retrospective review of all patients who received at least 16 weeks of treatment with mepolizumab (100 mg subcutaneously) for SEA at our regional asthma center in the United Kingdom. Clinical data were collected at each 4-week visit. At 16, 24, and 52 weeks, patients were classified as “responders” or “nonresponders.” A response was defined as ≥50% reduction in exacerbations; for patients whose condition requires maintenance oral corticosteroids (mOCS), a response was defined as ≥50% reduction in prednisolone dose. Super responders were defined as exacerbation-free and off mOCS at one year.
Ninety-nine patients were included in the analysis. Asthma exacerbations decreased from a baseline of 4.04 ± 2.57 to 1.86 ± 2.17 per year at one year (54% reduction; P < .001). Sixty-eight patients were receiving mOCS at the time of commencing mepolizumab. By one year, the daily median dose fell from 10 mg (interquartile range, 10 to 15) to 0 mg (interquartile range, 0 to 10; P < .001). Fifty-seven percent of them were able to discontinue mOCS; 72.7% (95% CI, 63.0 to 80.7) of the patients were classified as responders, and 28.3% (95% CI, 20.2 to 38.0) of the patients were classified as super responders. Baseline characteristics associated with responder and super responder status included the presence of nasal polyposis (P = .012), lower baseline Asthma Control Questionnaire 6 (P = .006), a lower BMI (P = .014), and, in those patients receiving mOCS, a significantly lower prednisolone dose at baseline (P = .005). At 16 weeks, the one-year responder status was correctly identified in 80.8% patients; by 24 weeks, this status rose to 92.9%.
In a real-world SEA cohort, treatment with mepolizumab reduced exacerbation frequency and mOCS requirements. Nasal polyposis, a lower BMI, and a lower maintenance prednisolone requirement at baseline were associated with better outcomes. Twelve-month response was identifiable in >90% of patients by week 24.
Like all organisms, plants require energy for growth. They achieve this by absorbing light and fixing it into a usable, chemical form via photosynthesis. The resulting carbohydrate (sugar) energy is ...then utilized as substrates for growth, or stored as reserves. It is therefore not surprising that modulation of carbohydrate metabolism can have profound effects on plant growth, particularly cell division and expansion. However, recent studies on mutants such asstimpyorramosa3have also suggested that sugars can act as signalling molecules that control distinct aspects of plant development. This review will focus on these more specific roles of sugars in development, and will concentrate on two major areas: (i) cross-talk between sugar and hormonal signalling; and (ii) potential direct developmental effects of sugars. In the latter, developmental mutant phenotypes that are modulated by sugars as well as a putative role for trehalose-6-phosphate in inflorescence development are discussed. Because plant growth and development are plastic, and are greatly affected by environmental and nutritional conditions, the distinction between purely metabolic and specific developmental effects is somewhat blurred, but the focus will be on clear examples where sugar-related processes or molecules have been linked to known developmental mechanisms.
Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation ...rates and maintenance oral corticosteroids (mOCSs).
What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy?
We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma.
One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 56.9%), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV1. Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients.
In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation.
A novel slotted substrate integrated waveguide (SIW) leaky-wave antenna is proposed. This antenna works in the TE 10 mode of the SIW. Leakage is obtained by introducing a periodic set of transverse ...slots on the top of the SIW, which interrupt the current flow on the top wall. It is seen that three modes (a leaky mode, a proper waveguide mode, and a surface-wave-like mode) can all propagate on this structure. The wavenumbers of the modes are calculated theoretically and are numerically evaluated by HFSS simulation. The leakage loss, dielectric loss, and conductor loss are also analyzed. A uniform slotted SIW leaky-wave antenna is designed that has good beam scanning from near broadside (though not exactly at broadside) to forward endfire. This type of SIW leaky-wave antenna has a wide impedance bandwidth and a narrow beam that scans with frequency. Measured results are consistent with the simulation and the theoretical analysis.
Shoot meristems are maintained by pluripotent stem cells that are controlled by CLAVATA-WUSCHEL feedback signaling. This pathway, which coordinates stem cell proliferation with differentiation, was ...first identified in Arabidopsis, but appears to be conserved in diverse higher plant species. In this Review, we highlight the commonalities and differences between CLAVATA-WUSCHEL pathways in different species, with an emphasis on Arabidopsis, maize, rice and tomato. We focus on stem cell control in shoot meristems, but also briefly discuss the role of these signaling components in root meristems.
Tissue inflammation induces rapid mobilization of antigen-charged dendritic cells (DCs), which migrate to draining lymph nodes via afferent lymphatics to elicit the immune response. This increase in ...DC trafficking has been shown to require integrin-dependent adhesion to ICAM-1 and VCAM-1, expressed on inflamed lymphatic endothelium. In addition, both constitutive- and inflammation-induced DC migration involves the chemokine CCL21, which most likely triggers integrin activation on DC via its receptor CCR7. Recently, however, conflicting evidence has suggested that DC entry occurs independently of integrins, implying that the role of CCL21 in lymphatics is purely chemotactic. Hence, while CCL21 is reported to be inducible during inflammation, the details of this induction and the role of CCL21 during initial DC trafficking are unclear. Here, we have characterized both the production of CCL21 and the mechanism of its action in DC transmigration using primary human dermal lymphatic endothelial cells (HDLECs) and a mouse model of skin contact hypersensitivity. We showed that CCL21 is constitutively expressed intracellularly but rapidly secreted after exposure to the inflammatory cytokine tumour necrosis factor (TNF) α following de novo RNA and protein synthesis. Furthermore, using in vitro transmigration assays, we showed that endogenous HDLEC-derived CCL21 stimulates DC translymphatic migration by a predominantly chemotactic mechanism in resting HDLEC and by a β2 integrin-mediated mechanism in TNFα-stimulated HDLEC. These results imply a direct role for CCL21 in lymphatic transmigration that involves the selective use of integrin activation in inflammation.
Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological ...remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal. In the mammalian adult heart, however, the persistent influx of immune cells, coupled with the lack of an inherent regenerative capacity, results in cardiac fibrosis. Here, we reveal that stimulation of cardiac lymphangiogenesis with VEGF-C improves clearance of the acute inflammatory response after MI by trafficking immune cells to draining mediastinal lymph nodes (MLNs) in a process dependent on lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1 in mice, preventing docking and transit of leukocytes through the lymphatic endothelium, results in exacerbation of chronic inflammation and long-term deterioration of cardiac function. Our findings support targeting of the lymphatic/immune cell axis as a therapeutic paradigm to promote immune modulation and heart repair.
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