A review of the tolerability and safety of levocabastine eye drops and nasal spray. Implications for patient management

Levocabastine is a highly potent and selective H1-receptor antagonist specifically developed for topical administration by ocular and nasal routes. The clinical effects of levocabastine occur rapidly and are predominantly due to local antihistaminic effects at the site of application. Clinically, levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate and placebo. As might be expected from the route of drug administration, local irritation is the most frequent adverse event seen with levocabastine eye drops and nasal spray with an incidence comparable with that in placebo-treated controls. Intranasal application of levocabastine has been shown to have no adverse effect on ciliary activity both in vitro and in vivo, while ocular administration has not been shown to have any significant or consistent adverse effect in both animal and human studies. At therapeutic doses, levocabastine appears to be devoid of significant systemic activity producing no apparent effects on cardiovascular, psychomotor and cognitive function. Since levocabastine undergoes little hepatic metabolism, and only low plasma levels of the drug are attained following topical administration, drug interactions are unlikely

Transforming growth factor-beta promotes rhinovirus replication in bronchial epithelial cells by suppressing the innate immune response

Rhinovirus (RV) infection is a major cause of asthma exacerbations which may be due to a deficient innate immune response in the bronchial epithelium. We hypothesized that the pleiotropic cytokine, TGF-?, influences interferon (IFN) production by primary bronchial epithelial cells (PBECs) following RV infection. Exogenous TGF-?(2) increased RV replication and decreased IFN protein secretion in response to RV or double-stranded RNA (dsRNA). Conversely, neutralizing TGF-? antibodies decreased RV replication and increased IFN expression in response to RV or dsRNA. Endogenous TGF-?(2) levels were higher in conditioned media of PBECs from asthmatic donors and the suppressive effect of anti-TGF-? on RV replication was significantly greater in these cells. Basal SMAD-2 activation was reduced when asthmatic PBECs were treated with anti-TGF-? and this was accompanied by suppression of SOCS-1 and SOCS-3 expression. Our results suggest that endogenous TGF-? contributes to a suppressed IFN response to RV infection possibly via SOCS-1 and SOCS-3

Expression of CD44 and integrins in bronchial mucosa of normal and mildly asthmatic subjects

We have investigated the expression of cell surface markers and leucocyte cell adhesion molecules by immunohistochemistry in bronchial biopsies from 10 mild atopic asthmatics and 8 normal, nonatopic subjects. Significantly increased numbers of eosinophils (p<0.01) were evident in the bronchial submucosa of asthmatic subjects. In epithelium there were more CD44+ (p<0.02) and lymphocyte function-associated antigen-1 (LFA-1)+ (p<0.06) leucocytes in asthmatics than in normal subjects. Bronchial epithelial cells stained positively with anti-CD44 monoclonal antibodies (moAb) in both groups; however, when the staining was expressed as percentage of the total basement membrane, a considerable and highly significant increase was observed in the asthmatics (median 80 vs 22%, p=0.003). Few leucocytes were positive for very late activation antigen (VLA)-1, VLA-2 and VLA-4. The moAb for VLA-6 stained the basement membrane of the bronchial epithelium; while intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were constitutively expressed in endothelium. A positive correlation was found between LFA-1+ cells and activated eosinophils (EG2+) in the submucosa (p<0.005; r(s)=0.80). We conclude that even in mild asthma there is evidence of increased expression of cell surface ligands, and suggest that adhesive mechanisms play a role both in cell recruitment and disease activity.peer-reviewe

Eddy correlation measurements of oxygen fluxes in permeable sediments exposed to varying current flow and light

Author Posting. © Association for the Sciences of Limnology and Oceanography, 2013. This article is posted here by permission of Association for the Sciences of Limnology and Oceanography for personal use, not for redistribution. The definitive version was published in Limnology and Oceanography 58 (2013): 1329–1343, doi:10.4319/lo.2013.58.4.1329.Based on noninvasive eddy correlation measurements at a marine and a freshwater site, this study documents the control that current flow and light have on sediment–water oxygen fluxes in permeable sediments. The marine sediment was exposed to tidal-driven current and light, and the oxygen flux varied from night to day between −29 and 78 mmol m−2 d−1. A fitting model, assuming a linear increase in oxygen respiration with current flow, and a photosynthesis–irradiance curve for light-controlled production reproduced measured fluxes well (R2 = 0.992) and revealed a 4-fold increase in oxygen uptake when current velocity increased from ∼ 0 to 20 cm s−1. Application of the model to a week-long measured record of current velocity and light showed that net ecosystem metabolism varied substantially among days, between −27 and 31 mmol m−2 d−1, due to variations in light and current flow. This variation is likely typical of many shallow-water systems and highlights the need for long-term flux integrations to determine system metabolism accurately. At the freshwater river site, the sediment–water oxygen flux ranged from −360 to 137 mmol m−2 d−1. A direct comparison during nighttime with concurrent benthic chamber incubations revealed a 4.1 times larger eddy flux than that obtained with chambers. The current velocity during this comparison was 31 cm s−1, and the large discrepancy was likely caused by poor imitation by the chambers of the natural pore-water flushing at this high current velocity. These results emphasize the need for more noninvasive oxygen flux measurements in permeable sediments to accurately assess their role in local and global carbon budgets.Support for this study was provided by the following National Science Foundation grants: OCE-0420575, OCE- 0536431, and OCE-1061364

Results from the Global Allergy and Asthma Network of Excellence (GA2LEN) Survey

Background Fruits and vegetables are rich in compounds with proposed antioxidant, anti-allergic and anti-inflammatory properties, which could contribute to reduce the prevalence of asthma and allergic diseases. Objective We investigated the association between asthma, and chronic rhino-sinusitis (CRS) with intake of fruits and vegetables in European adults. Methods A stratified random sample was drawn from the Global Allergy and Asthma Network of Excellence (GA2LEN) screening survey, in which 55,000 adults aged 15–75 answered a questionnaire on respiratory symptoms. Asthma score (derived from self-reported asthma symptoms) and CRS were the outcomes of interest. Dietary intake of 22 subgroups of fruits and vegetables was ascertained using the internationally validated GA2LEN Food Frequency Questionnaire. Adjusted associations were examined with negative binomial and multiple regressions. Simes procedure was used to control for multiple testing. Results A total of 3206 individuals had valid data on asthma and dietary exposures of interest. 22.8% reported having at least 1 asthma symptom (asthma score ≥1), whilst 19.5% had CRS. After adjustment for potential confounders, asthma score was negatively associated with intake of dried fruits (β-coefficient −2.34; 95% confidence interval [CI] −4.09, −0.59), whilst CRS was statistically negatively associated with total intake of fruits (OR 0.73; 95% CI 0.55, 0.97). Conversely, a positive association was observed between asthma score and alliums vegetables (adjusted β-coefficient 0.23; 95% CI 0.06, 0.40). None of these associations remained statistically significant after controlling for multiple testing. Conclusion and clinical relevance There was no consistent evidence for an association of asthma or CRS with fruit and vegetable intake in this representative sample of European adults

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene A Disintegrin and Metalloprotease (ADAM)33, acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble (s)ADAM33 is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33 null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances post-natal airway eosinophilia and bronchial hyperresponsiveness following sub-threshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma

The reintroduction of large carnivores to the Eastern Cape, South Africa: an assessment

Recently, conservation estate in South Africa's Eastern Cape Province has increased 10-fold resulting in large predators being increasingly reintroduced to restore ecological integrity and maximize tourism. We describe the reintroductions of large carnivores (>10 kg) that have occurred in the Eastern Cape and use various criteria to assess their success. Lion Panthera leo reintroduction has been highly successful with a population of 56 currently extant in the region and problems of overpopulation arising. The African wild dog Lycaon pictus population has increased to 24 from a founder population of 11. Preliminary results for spotted hyaenas Crocuta crocuta also indicate success. Wild populations of leopards Panthera pardus exist on several reserves and have been supplemented by translocated individuals, although deaths of known individuals have occurred and no estimate of reproduction is available. Cheetah Acinonyx jubatus reintroduction has also been less successful with 36 individuals reintroduced and 23 cubs being born but only 41 individuals surviving in 2005. Criteria for assessing the success of reintroductions of species that naturally occur in low densities, such as top predators, generally have limited value. Carrying capacity for large predators is unknown and continued monitoring and intensive management will be necessary in enclosed, and possibly all, conservation areas in the Eastern Cape to ensure conservation success

Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3–like protein 1

BackgroundDisease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood.ObjectiveWe aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients.MethodsOne hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis.ResultsSevere asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3–like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels.ConclusionIn 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma

Liquefaction features produced by the 2010-2011 Canterbury earthquake sequence in southwest Christchurch, New Zealand, and preliminary assessment of Paleoliquefaction features

Liquefaction features and the geologic environment in which they formed were carefully studied at two sites near Lincoln in southwest Christchurch. We undertook geomorphic mapping, excavated trenches, and obtained hand cores in areas with surficial evidence for liquefaction and areas where no surficial evidence for liquefaction was present at two sites (Hardwick and Marchand). The liquefaction features identified include (1) sand blows (singular and aligned along linear fissures), (2) blisters or injections of subhorizontal dikes into the topsoil, (3) dikes related to the blows and blisters, and (4) a collapse structure. The spatial distribution of these surface liquefaction features correlates strongly with the ridges of scroll bars in meander settings. In addition, we discovered paleoliquefaction features, including several dikes and a sand blow, in excavations at the sites of modern liquefaction. The paleoliquefaction event at the Hardwick site is dated at A.D. 908-1336, and the one at the Marchand site is dated at A.D. 1017-1840 (95% confidence intervals of probability density functions obtained by Bayesian analysis). If both events are the same, given proximity of the sites, the time of the event is A.D. 1019-1337. If they are not, the one at the Marchand site could have been much younger. Taking into account a preliminary liquefaction-triggering threshold of equivalent peak ground acceleration for an Mw 7.5 event (PGA7:5) of 0:07g, existing magnitude-bounded relations for paleoliquefaction, and the timing of the paleoearthquakes and the potential PGA7:5 estimated for regional faults, we propose that the Porters Pass fault, Alpine fault, or the subduction zone faults are the most likely sources that could have triggered liquefaction at the study sites. There are other nearby regional faults that may have been the source, but there is no paleoseismic data with which to make the temporal link

Innate and adaptive T cells in asthmatic patients: relationship to severity and disease mechanisms

BackgroundAsthma is a chronic inflammatory disease involving diverse cells and mediators whose interconnectivity and relationships to asthma severity are unclear.ObjectiveWe performed a comprehensive assessment of TH17 cells, regulatory T cells, mucosal-associated invariant T (MAIT) cells, other T-cell subsets, and granulocyte mediators in asthmatic patients.MethodsSixty patients with mild-to-severe asthma and 24 control subjects underwent detailed clinical assessment and provided induced sputum, endobronchial biopsy, bronchoalveolar lavage, and blood samples. Adaptive and invariant T-cell subsets, cytokines, mast cells, and basophil mediators were analyzed.ResultsSignificant heterogeneity of T-cell phenotypes was observed, with levels of IL-13–secreting T cells and type 2 cytokines increased at some, but not all, asthma severities. TH17 cells and ??-17 cells, proposed drivers of neutrophilic inflammation, were not strongly associated with asthma, even in severe neutrophilic forms. MAIT cell frequencies were strikingly reduced in both blood and lung tissue in relation to corticosteroid therapy and vitamin D levels, especially in patients with severe asthma in whom bronchoalveolar lavage regulatory T-cell numbers were also reduced. Bayesian network analysis identified complex relationships between pathobiologic and clinical parameters. Topological data analysis identified 6 novel clusters that are associated with diverse underlying disease mechanisms, with increased mast cell mediator levels in patients with severe asthma both in its atopic (type 2 cytokine–high) and nonatopic forms.ConclusionThe evidence for a role for TH17 cells in patients with severe asthma is limited. Severe asthma is associated with a striking deficiency of MAIT cells and high mast cell mediator levels. This study provides proof of concept for disease mechanistic networks in asthmatic patients with clusters that could inform the development of new therapies