| 1. |
- Mirabelli, Pierfrancesco
(författare)
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Inhibitors of corneal inflammation and angiogenesis : Prospectives and challenges
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pathologic angiogenesis is involved in cancer and several blinding conditions such as wet age-related macular degeneration, proliferative retinopathies and corneal neovascularization.In these dieseases, the angiogenic triggers are hypoxia and inflammation, and both involve the main angiogenic mediator, which is Vascular Endothelial Growth Factor (VEGF). Among available treatments, anti-VEGF often shows limited or temporary efficacy, while steroids are potentially responsible for many side-effects. This thesis presents a series of linked studies aimed at elucidating the early pathologic changes leading to inflammation and corneal neovascularization, and how various treatments affect this process. In this thesis, anti-inflammatory and anti-angiogenic treatments are applied in corneal neovascularization models, to identify VEGF-independent pathways and other novel factors as future therapy targets, as well as to investigate the endogenous modulation of angiogenesis.A model of experimental neovascularization in the rat cornea was used as main model, where the neovascular response is triggered by a surgical suture placed into the cornea. Investigational treatments (anti-Vegf, dexamethasone, IMD0354, Gap27, or control substances) were then given topically, with the exception of IMD0354, which was given systemically. The effects in the cornea were studied in vivo with slit lamp photography to assess and quantify macroscopic vessel growth and using in vivo confocal microscopy (IVCM) to study cell infiltration and limbal vessel dilation and detect microscopic vessel sprouts; these examinations were performed longitudinally. Genomic analysis with RNA microarray, selected gene expression with q-RT-PCR, and selected protein expression in tissue (immunohistochemistry, immunofluorescence, Western blot) were performed at different time-points. Moreover, other experiments on cell cultures (HUVEC and HCEC), organ cultures (human corneas), ex vivo models (aortic rings) and in vivo studies (zebrafish vasculogenesis) were performed.Dexamethasone suppressed limbal vasodilation and corneal neovascularization more than anti-Vegf, despite no difference in inflammatory cell infiltration into the cornea. Five-hundred eleven fewer genes were differentially expressed in dexamethasone-treated corneas relative to naïve corneas, compared to anti-Vegf. Among them, several major pro-angiogenic and pro-inflammatory factors and chemokines were suppressed only by dexamethasone and represent novel candidate factors to target in order to improve anti-VEGF treatment. On the other hand, selective inhibition of a single inflammatory pathway (NF-κB), despite showing similar early effects as dexamethasone in suppressing tissue inflammation, was not effective enough to suppress new vessel growth. The same factors suppressed by dexamethasone are also inhibited in endogenous modulation of angiogenesis. Surprisingly, dexamethasone activated several complement factors, which could possibly be beneficial in the anti-angiogenic response.In a different therapeutic approach, promoting cell migration to accelerate epithelial wound closure similarly was not sufficient to avoid inflammation and angiogenesis in the cornea.In conclusion, new and more effective treatments are needed for corneal inflammation and neovascularization with fewer side-effects. In this thesis, several novel factors and mechanisms related to inflammation are identified, factors that are not addressed by anti-Vegf therapy, and therefore represent interesting objects for further study, as they have the potential to be targets for adjuvant therapy. Specific anti-inflammatory treatment as well as therapeutic activation of endogenous regulatory pathways, and potentially complement modulation, might represent new strategies to improve anti-angiogenic therapy, but when used alone they do not seem to avoid corneal neovascularization.
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| 2. |
- Henneberger, P K, et al.
(författare)
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The occupational contribution to severe exacerbation of asthma.
- 2010
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Ingår i: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 36:4, s. 743-50
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Tidskriftsartikel (refereegranskat)abstract
- The goal of this study was to identify occupational risk factors for severe exacerbation of asthma and estimate the extent to which occupation contributes to these events. The 966 participants were working adults with current asthma who participated in the follow-up phase of the European Community Respiratory Health Survey. Severe exacerbation of asthma was defined as self-reported unplanned care for asthma in the past 12 months. Occupations held in the same period were combined with a general population job-exposure matrix to assess occupational exposures. 74 participants reported having had at least one severe exacerbation event, for a 1-yr cumulative incidence of 7.7%. From regression models that controlled for confounders, the relative risk (RR) was statistically significant for low (RR 1.7, 95% CI 1.1-2.6) and high (RR 3.6, 95% CI 2.2-5.8) biological dust exposure, high mineral dust exposure (RR 1.8, 95% CI 1.02-3.2), and high gas and fumes exposure (RR 2.5, 95% CI 1.2-5.5). The summary category of high dust, gas, or fumes exposure had RR 3.1 (95% CI 1.9-5.1). Based on this RR, the population attributable risk was 14.7% among workers with current asthma. These results suggest occupation contributes to approximately one in seven cases of severe exacerbation of asthma in a working population, and various agents play a role.
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| 3. |
- Le Moual, Nicole, et al.
(författare)
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Occupational exposures and uncontrolled adult-onset asthma in the European Community Respiratory Health Survey II
- 2014
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 43:2, s. 374-386
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Tidskriftsartikel (refereegranskat)abstract
- Occupational exposure is a well-recognised modifiable risk factor for asthma, but the relationship between occupational exposure and asthma control has not been studied. We aimed to study this association among working-age adults from the European Community Respiratory Health Survey (ECRHS). Data were available for 7077 participants (mean age 43 years, 45% never-smokers, 5867 without asthma and 1210 with current asthma). Associations between occupational exposure to specific asthmagens and asthma control status (33% with uncontrolled asthma, based on the Global Initiative for Asthma guidelines) were evaluated using logistic and multinomial regressions, adjusted for age, sex and smoking status, with study areas included as a random effect. Statistically significant positive associations were observed between uncontrolled adult-onset asthma and both past 12-month and 10-year exposure to any occupational asthmagens (OR (95% CI) 1.6 (1.0-2.40) and 1.7 (1.2-2.5), respectively); high (1.7 (1.0-2.8) and 1.9 (1.3-2.9), respectively) and low (1.6 (1.0-2.7) and 1.8 (1.2-2.7), respectively) molecular weight agents; and cleaning agents (2.0 (1.1-3.6) and 2.3 (1.4-3.6), respectively), with stronger associations for long-term exposures. These associations were mainly explained by the exacerbation domain of asthma control and no associations were observed between asthmagens and partly controlled asthma. These findings suggest that occupational exposure to asthmagens is associated with uncontrolled adult-onset asthma. Occupational risk factors should be quickly identified to prevent uncontrolled asthma.
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| 4. |
- Kogevinas, Manolis, et al.
(författare)
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Exposure to substances in the workplace and new-onset asthma : an international prospective population-based study (ECRHS-II)
- 2007
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 370:9584, s. 336-341
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Tidskriftsartikel (refereegranskat)abstract
- Background The role of exposure to substances in the workplace in new-onset asthma is not well characterised in population-based studies. We therefore aimed to estimate the relative and attributable risks of new-onset asthma in relation to occupations, work-related exposures, and inhalation accidents. Methods We studied prospectively 6837 participants from 13 countries who previously took part in the European Community Respiratory Health Survey (1990-95) and did not report respiratory symptoms or a history of asthma at the time of the first study. Asthma was assessed by methacholine challenge test and by questionnaire data on asthma symptoms. Exposures were defined by high-risk occupations, an asthma-specific job exposure matrix with additional expert judgment, and through self-report of acute inhalation events. Relative risks for new onset asthma were calculated with log-binomial models adjusted for age, sex, smoking, and study Centre. Findings A significant excess asthma risk was seen after exposure to substances known to cause occupational asthma (Relative risk=1.6, 95% CI 1.1-2.3, p=0.017). Risks were highest for asthma defined by bronchial hyper-reactivity in addition to symptoms (2.4,1.3-4.6, p=0.008). Of common occupations, a significant excess risk of asthma was seen for nursing (2.2,1.3-4.0, p=0.007). Asthma risk was also increased in participants who reported an acute symptomatic inhalation event such as fire, mixing cleaning products, or chemical spills (RR=3.3, 95% CI 1.0-11.1, p=0.051). The population-attributable risk for adult asthma due to occupational exposures ranged from 10% to 25%, equivalent to an incidence of new-onset occupational asthma of 250-300 cases per million people per year. Interpretation Occupational exposures account for a substantial proportion of adult asthma incidence. The increased risk of asthma after inhalation accidents suggests that workers who have such accidents should be monitored closely.
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| 5. |
- Mirabelli, Maria C, et al.
(författare)
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Occupational risk factors for asthma among nurses and related healthcare professionals in an international study
- 2007
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Ingår i: Occupational and Environmental Medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 64:7, s. 474-479
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The authors examined the relations between self-reported work tasks, use of cleaning products and latex glove use with new-onset asthma among nurses and other healthcare workers in the European Community Respiratory Health Survey (ECRHS II). Methods: In a random population sample of adults from 22 European sites, 332 participants reported working in nursing and other related healthcare jobs during the nine-year ECRHS II follow-up period and responded to a supplemental questionnaire about their principal work settings, occupational tasks, products used at work and respiratory symptoms. Poisson regression models with robust error variances were used to compare the risk of new-onset asthma among healthcare workers with each exposure to that of respondents who reported professional or administrative occupations during the entire follow-up period (n=2481). Results: Twenty (6%) healthcare workers and 131 (5%) members of the referent population reported new-onset asthma. Compared to the referent group, the authors observed increased risks among hospital technicians (RR 4.63; 95% Cl 1.87 to 11.5) and among those using ammonia and/or bleach at work (RR 2.16; 95% Cl 1.03 to 4.53). Conclusions: In the ECRHS II cohort, hospital technicians and other healthcare workers experience increased risks of new-onset current asthma, possibly due to specific products used at work.
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| 6. |
- Tognon, M. S., et al.
(författare)
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Tuberculosis of the eye in Italy: a forgotten extrapulmonary localization
- 2014
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Ingår i: Infection. Zeitschrift für Klinik und Therapie der Infektionen. - : Springer Verlag (Germany). - 0300-8126 .- 1439-0973. ; 42:2, s. 335-342
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Tuberculosis (TB) of the eye is a well-known extrapulmonary localization in high-incidence countries. Data on its relevance in developed countries are scanty. We aim to study the epidemiological and clinical pattern of ocular TB in a tertiary care institution of a western country. Methods From 2007 to 2010, consecutive patients with a diagnosis of isolated ocular TB or associated to extraocular TB were recruited. Patients with ophthalmological and clinical features of TB were treated with standard antitubercular therapy (ATT) and steroids in case of concomitant severe ocular inflammation. Results Seventeen cases of ocular and extraocular TB and 45 cases of isolated ocular TB were identified. The proportion of patients with ocular and extraocular TB in our local district was 8.1 %, with a proportion of 10.6 % for the isolated cases. In Cohort 1, only one patient was symptomatic for ocular impairment, and uveitis without inflammation was the most common presentation. On the contrary, in Cohort 2, all patients had visual impairment, mainly with bilateral involvement. 77.8 % of the patients showed an inflammatory pattern. ATT was administered for at least 9 months, in four cases with a short course of systemic corticosteroids. Eight cases in Cohort 2 showed recurrence after 1 year from diagnosis. Conclusions TB of the eye should not be forgotten, even in geographical areas not considered among endemic countries. Ocular evaluation is advisable in patients with pulmonary and extrapulmonary TB, as early detection may allow ATT to preserve visual acuity.
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| 7. |
- Zock, Jan-Paul, et al.
(författare)
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Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults
- 2009
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 124:4, s. 731-738
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Professional use of hypochlorite (bleach) has been associated with respiratory symptoms. Bleach is capable of inactivating allergens, and there are indications that its domestic use may reduce the risk of allergies in children. OBJECTIVE: To study the associations between household use of bleach and atopic sensitization, allergic diseases, and respiratory health status in adults. METHODS: We identified 3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes and for whom data on specific serum IgE to 4 environmental allergens were available. Frequency of bleach use and information on respiratory symptoms were obtained in face-to-face interviews. House dust mite and cat allergens in mattress dust were measured in a subsample. Associations between the frequency of bleach use and health outcomes were evaluated by using multivariable mixed logistic regression analyses. RESULTS: The use of bleach was associated with less atopic sensitization (odds ratio [OR], 0.75; 95% CI, 0.63-0.89). This association was apparent for specific IgE to both indoor (cat) and outdoor (grass) allergens, and was consistent in various subgroups, including those without any history of respiratory problems (OR, 0.85). Dose-response relationships (P < .05) were apparent for the frequency of bleach use and sensitization rates. Lower respiratory tract symptoms, but not allergic symptoms, were more prevalent among those using bleach 4 or more days per week (OR, 1.24-1.49). The use of bleach was not associated with indoor allergen concentrations. CONCLUSION: People who clean their homes with hypochlorite bleach are less likely to be atopic but more likely to have respiratory symptoms.
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