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- Düringer, Caroline, et al.
(författare)
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Agonist-specific patterns of beta(2)-adrenoceptor responses in human airway cells during prolonged exposure.
- 2009
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 158, s. 169-179
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: beta(2)-Adrenoceptor agonists (beta(2)-agonists) are important bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease. At the molecular level, beta(2)-adrenergic agonist stimulation induces desensitization of the beta(2)-adrenoceptor. In this study, we have examined the relationships between initial effect and subsequent reduction of responsiveness to restimulation for a panel of beta(2)-agonists in cellular and in vitro tissue models. Experimental approach: beta(2)-Adrenoceptor-induced responses and subsequent loss of receptor responsiveness were studied in primary human airway smooth muscle cells and bronchial epithelial cells by measuring cAMP production. Receptor responsiveness was compared at equi-effective concentrations, either after continuous incubation for 24 h or after a 1 h pulse exposure followed by a 23 h washout. Key findings were confirmed in guinea pig tracheal preparations in vitro. Key results: There were differences in the reduction of receptor responsiveness in human airway cells and in vitro guinea pig trachea by a panel of beta(2)-agonists. When restimulation occurred immediately after continuous incubation, loss of responsiveness correlated with initial effect for all agonists. After the 1 h pulse exposure, differences between agonists emerged, for example isoprenaline and formoterol induced the least reduction of responsiveness. High lipophilicity was, to some extent, predictive of loss of responsiveness, but other factors appeared to be involved in determining the relationships between effect and subsequent loss of responsiveness for individual agonists. Conclusions and implications: There were clear differences in the ability of different beta(2) agonists to induce loss of receptor responsiveness at equi-effective concentrations.
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| 4. |
- Glader, Pernilla, et al.
(författare)
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Cigarette smoke extract modulates respiratory defence mechanisms through effects on T-cells and airway epithelial cells.
- 2006
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 100:5, s. 818-827
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (CCPD) is a disease primarily caused by cigarette smoking, which in turn has been shown to affect the susceptibility to and progression of airway infections. The question addressed in this study was how components from cigarette smoke could affect the defence mechanisms of T-cells and epithelial cells, and thereby contribute to the development of the COPD pathology. T-cells and monocytes were isolated from buffycoats from healthy donors and T-cell responses studied in response to cigarette smoke extract (CSE). Activation level (CD25 expression), proliferation (BrdU incorporation) and intracellular expression of the cytotoxic markers granzyme-b and TIA-1 were determined using flowcytometry. Normal human bronchial epithelial cells were obtained from Cambrex and differentiated in air-liquid interface cultures. After exposure to CSE barrier function (trans-epithelial electric resistance, TEER), MUC5AC and interleukin-8 production were measured. T-cell activation, proliferation and expression of the cytotoxic proteins granzyme-b and TIA-1 were significantly reduced in response to 0.5-1% of CSE. The epithelial cells were more resistant to CSE and responded at doses 20 times higher than T-cells. The expression of interteukin-8 and MUC5AC was significantly increased after exposure to 15% and 30% CSE and TEER was largely unaffected at 30% CSE but clearly reduced at 40% CSE. This study shows that mechanisms, in both T-cells and airway epithelial cells, involved in the defence against infectious agents are modulated by CSE. (c) 2005 Elsevier Ltd. All rights reserved.
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| 5. |
- Hallgren, Oskar, et al.
(författare)
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Enhanced ROCK1 dependent contractility in fibroblast from chronic obstructive pulmonary disease patients
- 2012
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: During wound healing processes fibroblasts account for wound closure by adopting a contractile phenotype. One disease manifestation of COPD is emphysema which is characterized by destruction of alveolar walls and our hypothesis is that fibroblasts in the COPD lungs differentiate into a more contractile phenotype as a response to the deteriorating environment. Methods: Bronchial (central) and parenchymal (distal) fibroblasts were isolated from lung explants from COPD patients (n = 9) (GOLD stage IV) and from biopsies from control subjects and from donor lungs (n = 12). Tissue-derived fibroblasts were assessed for expression of proteins involved in fibroblast contraction by western blotting whereas contraction capacity was measured in three-dimensional collagen gels. Results: The basal expression of rho-associated coiled-coil protein kinase 1 (ROCK1) was increased in both centrally and distally derived fibroblasts from COPD patients compared to fibroblasts from control subjects (p < 0.001) and (p < 0.01), respectively. Distally derived fibroblasts from COPD patients had increased contractile capacity compared to control fibroblasts (p < 0.01). The contraction was dependent on ROCK1 activity as the ROCK inhibitor Y27632 dose-dependently blocked contraction in fibroblasts from COPD patients. ROCK1-positive fibroblasts were also identified by immunohistochemistry in the alveolar parenchyma in lung tissue sections from COPD patients. Conclusions: Distally derived fibroblasts from COPD patients have an enhanced contractile phenotype that is dependent on ROCK1 activity. This feature may be of importance for the elastic dynamics of small airways and the parenchyma in late stages of COPD.
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| 6. |
- Löfdahl, Elisabet, et al.
(författare)
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Compromised quality of life in adult patients who have received a radiation dose towards the basal part of the brain. A case-control study in long-term survivors from cancer in the head and neck region.
- 2012
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Ingår i: Radiation oncology (London, England). - 1748-717X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Adult patients with hypothalamic-pituitary disorders have compromised quality of life (QoL). Whether this is due to their endocrine consequences (hypopituitarism), their underlying hypothalamic-pituitary disorder or both is still under debate. The aim of this trial was to measure quality of life (QoL) in long-term cancer survivors who have received a radiation dose to the basal part of the brain and the pituitary. METHODS: Consecutive patients (n=101) treated for oropharyngeal or epipharyngeal cancer with radiotherapy followed free of cancer for a period of 4 to10 years were identified. Fifteen patients (median age 56 years) with no concomitant illness and no hypopituitarism after careful endocrine evaluation were included in a case-control study with matched healthy controls. Doses to the hypothalamic-pituitary region were calculated. QoL was assessed using the Symptom check list (SCL)-90, Nottingham Health Profile (NHP), and Psychological Well Being (PGWB) questionnaires. Level of physical activity was assessed using the Baecke questionnaire. RESULTS: The median accumulated dose was 1.9 Gy (1.5--2.2 Gy) to the hypothalamus and 2.4 Gy (1.8--3.3 Gy) to the pituitary gland in patients with oropharyngeal cancer and 6.0--9.3 Gy and 33.5--46.1 Gy, respectively in patients with epipharyngeal cancer (n=2). The patients showed significantly more anxiety and depressiveness, and lower vitality, than their matched controls. CONCLUSION: In a group of long time survivors of head and neck cancer who hade received a low radiation dose to the hypothalamic-pituitary region and who had no endocrine consequences of disease or its treatment QoL was compromised as compared with well matched healthy controls.
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| 7. |
- Löfdahl, Hedvig Elisabet
(författare)
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Risk factors and prevention of esophageal cancer
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Esophageal cancer is the eighth most common cancer in the world, consisting of two major histological types: squamous cell carcinoma (dominant globally) and adenocarcinoma (rapidly increasing in incidence in the Western world during the last decades). Established risk factors for adenocarcinoma are gastroesophageal reflux symptoms, obesity and tobacco smoking, whereas squamous cell carcinoma is mainly associated with tobacco smoking and excessive alcohol intake. Esophageal cancer predominantly affects men; the gender difference in squamous cell carcinoma cases is entirely explained by the higher prevalence of risk factors in men, but the striking 7:1 sex ratio in adenocarcinoma remains unexplained. Esophageal cancer carries a very poor prognosis and despite efforts to improve survival the overall 5-year survival rate is still less than 10%, emphasizing the need for preventive factors. This thesis focuses on the etiology of esophageal cancer and the unexplained male predominance in esophageal adenocarcinoma. The first paper investigates differences in risk factor profiles between women and men as a possible explanation for the male predominance in esophageal and cardiac adenocarcinoma. The paper was based on a nationwide population-based case-control study of all newly diagnosed cases of adenocarcinoma (n=451) and corresponding controls (n=816) in Sweden between 1994-1997. Contradictory to the hypothesis, the point odds ratios (OR) did not indicate any weaker association of the established risk factors reflux, obesity and tobacco smoking with risk of esophageal adenocarcinoma in women (4.6, 10.3, and 5.3, respectively) compared to men (3.4, 5.4, and 2.8, respectively). Protective factors such as a high intake of fruit and vegetables or infection with Helicobacter pylori showed no stronger protective effect in women. Thus, gender differences in the exposure to known risk factors do not seem to explain the male predominance in esophageal or cardia adenocarcinoma. The second paper investigated if the higher incidence rate of esophageal adenocarcinoma in the United Kingdom compared to Sweden is explained by a higher population prevalence of established risk factors. Investigations were based on identical questionnaires filled out by a random sample of the English (n=3633) and Swedish (n=1483) populations. The prevalence of gastroesophageal reflux symptoms and obesity were significantly higher in the English population (OR 2.0, 95% CI 1.6-2.4 and OR 1.8, 95% CI 1.5-2.1), suggesting that the higher incidence of esophageal adenocarcinoma in the United Kingdom is at least partly due to the higher population prevalence of well-established risk factors. The third paper investigates why surgical intervention of reflux does not provide protection against esophageal adenocarcinoma. All esophageal or cardia adenocarcinoma cases among antireflux operated patients in Sweden in 1965-2006 were identified and compared with matched controls from the same antireflux cohort. Recurrence of reflux after surgery was a risk factor for esophageal adenocarcinoma (OR 3.1, 95% CI 1.5-6.3), while BMI, tobacco smoking and type of antireflux surgery appeared to be of lesser importance. Recurrent reflux can explain the lack of a cancer protective effect of antireflux surgery and endoscopic surveillance might be an option for these patients. The fourth paper investigates the association between infection with human papillomavirus (HPV) and tumor location in the esophagus. The hypothesis is based on an oral route of transmission and an association between HPV and oropharyngeal squamous cell carcinoma. Available tumor material from esophageal squamous cell carcinomas in the Stockholm County in 1999-2006 was collected and examined for presence of HPV using multiplex polymerase chain reaction (PCR) with Luminex. No increased occurrence of HPV DNA was observed in esophageal squamous cell carcinomas located in the proximal compared to a more distal part of the esophagus. The prevalence of HPV DNA (10%) was low, and the identified HPV did not seem to be biologically active, based on p16INK4a data.
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| 10. |
- Nyblom, Stina, et al.
(författare)
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Pandemic impact on patients with advanced non-COVID-19 illness and their family carers receiving specialised palliative home care: a qualitative study.
- 2022
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the experiential impact of the COVID-19 pandemic on patients with non-COVID, life-threatening disease and their family carers.An interpretative qualitative design informed by phenomenological hermeneutics and based on data from in-depth interviews, performed between June and September 2020.Patients receiving specialised palliative home care and their family carers living in Sweden.22 patients (male/female 11/11) and 17 carers (male/female 5/12) aged 50 years and older. All the patients received specialised palliative home care and most were diagnosed with cancer.aged 18 years or older, diagnosed with an incurable life-threatening, non-COVID disease, sufficient strength to participate and capacity to provide informed consent. Participants were selected through a combination of convenient and consecutive sampling.The significance of the pandemic for both patients and carers showed a continuum from being minimally affected in comparison to the severe underlying disease to living in isolation with constant fear of becoming infected and falling ill with COVID-19, which some likened to torture.The imposed restrictions on social contact due to the pandemic were particularly palpable for this group of people with a non-COVID-19, life-limiting condition, as it was said to steal valuable moments of time that had already been measured.Most patients and carers found access to specialised palliative home care was maintained despite the pandemic. This care was of paramount importance for their sense of security and was often their sole visiting social contact.In the pandemic situation, highly accessible support from healthcare and social care at home is particularly important to create security for both patients and carers. Thus, to provide appropriate support, it is important for healthcare and social care personnel to be aware of the great diversity of reactions patients in palliative care and their carers may have to a pandemic threat.
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