| 41. |
- Greiff, Lennart, et al.
(författare)
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Effects of topical platelet activating factor on the guinea-pig tracheobronchial mucosa in vivo
- 1997
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 160:4, s. 387-391
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Tidskriftsartikel (refereegranskat)abstract
- Platelet activating factor (PAF) has been reported to produce a variety of airway effects including epithelial damage and increased airway-lung absorption of hydrophilic tracers. The present study examines effects of PAF on the guinea-pig tracheobronchial mucosa in vivo. Vehicle with and without PAF (4.0 and 8.0 nmol) was superfused onto the tracheobronchial mucosa. The levels of 125I-albumin, previously given intravenously, were determined in tracheobronchial lavage fluids as an index of mucosal exudation of plasma. The mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA (a low molecular weight, 492 Da, hydrophilic tracer) was superfused onto the mucosal surface through an oro-tracheal catheter, together with vehicle or PAF (8.0 nmol). A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of mucosal absorption. PAF produced dose-dependent mucosal exudation of plasma up to 20-fold greater than control (P < 0.001). However, PAF did not damage the epithelium and the absorption ability of the airway mucosa was unaffected. The results, in contrast to previous reports, suggest that PAF may not readily damage the airway mucosa even at large exudative doses of the agent. The present finding support the view that the plasticity of the epithelial junctions allows the creation of valve-like paracellular pathways for unidirectional clearance of extravasated plasma into the airway lumen. We suggest that endogenous PAF may participate in first line respiratory defence reactions by causing lumenal entry of bulk plasma without harming the epithelium.
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| 42. |
- Greiff, Lennart, et al.
(författare)
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Generation of clusters of free eosinophil granules (Cfegs) in seasonal allergic rhinitis
- 1998
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Ingår i: Allergy. - 1398-9995. ; 53:2, s. 200-203
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Tidskriftsartikel (refereegranskat)abstract
- Generation of clusters of free eosinophil granules (Cfegs), through lysis of eosinophils, has recently been proposed as a major paradigm for ultimate activation of airway mucosal eosinophils. In the present study involving patients with seasonal allergic rhinitis, we have investigated whether generation of Cfegs in the nasal mucosa is a feature of allergic rhinitis. Nasal mucosal biopsies were obtained before and late in a birch-pollen season, and were subjected to histochemical staining of eosinophil peroxidase. In biopsies obtained before the pollen season, a few, intact eosinophils were observed, and Cfegs were scarce. In biopsies taken during the pollen season, the numbers of eosinophils were increased about 10-fold (P < 0.05) and the Cfegs about 25-fold (P < 0.05). We conclude that generation of Cfegs is a significant feature of seasonal allergic rhinitis and that this process represents the ultimate activation of mucosal eosinophils in this disease.
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| 43. |
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| 44. |
- Greiff, Lennart, et al.
(författare)
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Loss of size-selectivity at histamine-induced exudation of plasma proteins in atopic nasal airways.
- 2002
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Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961. ; 22:1, s. 28-31
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Tidskriftsartikel (refereegranskat)abstract
- Plasma proteins occur in the airway lumen in inflammatory airway diseases. This study tests the hypothesis that airway microvascular-epithelial exudation of plasma proteins, as induced by a non-injurious inflammatory mediator, is characterized by loss of size-selectivity. Using a nasal pool-device, the nasal mucosa of 10 allergic individuals, without current disease, was sequentially exposed to saline and histamine (40 and 400 microg ml(-1)). Nasal lavage fluid and blood-levels of albumin (69 kD) and alpha2-macroglobulin (720 kD) were determined. Histamine produced concentration-dependent exudation of albumin and alpha2-macroglobulin. The albumin/alpha2-macroglobulin concentration ratio of the saline lavage fluid (baseline) was 40+/-19. However, at the histamine challenges the ratios were 25+/-3 and 22+/-2, respectively, which did not differ from that of circulating plasma (22+/-2). We conclude that there is minor and size-selective luminal entry of plasma proteins at baseline. However, at concentration-dependent exudative responses to histamine, plasma proteins enter the airway lumen without being sieved. These data indicate that inflammatory stimulus-induced extravasation, lamina propria distribution and paracellular epithelial passage of plasma occur with minimal size-selectivity. Inferentially, the full immunological capacity of plasma proteins may readily be made available at the surface of human intact airway mucosa.
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| 45. |
- Greiff, Lennart, et al.
(författare)
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Mucosal output of eotaxin in allergic rhinitis and its attenuation by topical glucocorticosteroid treatment
- 2001
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 1365-2222 .- 0954-7894. ; 31:8, s. 1321-1327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Eotaxin is a chemokine that attracts and activates eosinophils. The present study examines the occurrence of eotaxin in nasal mucosal surface liquids in patients with seasonal allergic rhinitis without allergen exposure and during repeat allergen challenge with and without topical glucocorticosteroid treatment. The number of subepithelial eosinophils and mucosal outputs of bulk plasma (alpha2-macroglobulin) and eosinophil cationic protein (ECP) are also examined. METHODS: Twelve patients underwent daily allergen challenges for 6 days. Separately, 14 patients, who were receiving budesonide and placebo in a parallel group design, also underwent allergen challenge for 6 days. Nasal biopsies were obtained before and 24 h after the allergen challenge series, and lavages were carried out before and 15 min after selected allergen challenges. RESULTS: At baseline nasal lavage fluid levels of eotaxin correlated to levels of alpha2-macroglobulin and ECP. After the first allergen challenge there was a correlation between nasal lavage fluid levels of eotaxin and ECP. Repeat allergen exposure increased the mucosal output of eotaxin (P <0.05) and ECP (P <0.01) as well as eosinophil numbers (P <0.01), but no correlation was found between increased eosinophil numbers and eotaxin. Budesonide reduced eotaxin levels during repeat allergen challenge (P <0.05). CONCLUSIONS: Repeat allergen exposure in allergic rhinitis is associated with increased mucosal output of eotaxin. Topical budesonide attenuates this effect, suggesting the possibility that inhibitory effects on mucosal eotaxin may contribute to anti-eosinophilic actions of topical glucocorticosteroids.
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| 46. |
- Greiff, Lennart, et al.
(författare)
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Non-radical primary diagnostic biopsies affect survival in cutaneous head and neck melanoma
- 2021
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 141:3, s. 309-319
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is unclear if a non-radical diagnostic biopsy entails a higher risk for metastasis and poorer survival for patients with cutaneous head and neck melanoma (cHNM). Aims/objectives: To assess whether or not initial diagnostic biopsy modality and radicality (clear, positive, or narrow histopathological margins) influence recurrence and survival in patients with cHNM. Materials and methods: Histopathological radicality of initial diagnostic biopsies and outcome for 368 consecutive cHNM patients, clinically asymptomatic of metastatic disease and referred to a tertiary care academic center for sentinel lymph node staging from 2004 through 2018, were retrospectively analyzed. Results: Patients with positive (n = 133) or narrow (0.1–0.5 mm) (n = 34) histopathological margins had significantly worse loco-regional (p=.004) and distant control (p=.004) as well as lower overall (p=.017) and melanoma specific (p=.0002) survival than 201 patients with clear margins. Multivariate analysis indicated positive or narrow histopathological margins as independent negative prognostic factors for melanoma specific survival (HR 2.16, p=.015), together with deeper Breslow (HR 1.17, p=.00001) and ulceration (HR 2.49, p=.003). Conclusions and significance: Non-radical primary diagnostic biopsies increase the risk for metastatic disease and impair survival in cHNM. Accordingly, radical melanoma diagnostic procedures should be encouraged in the head and neck region when possible.
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| 47. |
- Greiff, Lennart, et al.
(författare)
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Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis
- 2012
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. Objective: To evaluate the efficacy and safety of intranasal AZD8848. Methods: In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 mu g) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 mu g) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and alpha(2)-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30100 mu g produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and a2-macroglobulin were also reduced by AZD8848. Conclusions: Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.
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| 48. |
- Greiff, Lennart, et al.
(författare)
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Topical nitroprusside may reduce histamine-induced plasma exudation in human nasal airways
- 1995
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 50:7, s. 593-597
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal exudation of nonsieved bulk plasma is a key feature of airway defense and inflammation. We have previously observed in guinea pig tracheobronchial airways that endogenous nitric oxide (NO) of the mucosa may tonically suppress the permeability of the subepithelial microcirculation, and that topical administration of the NO donor nitroprusside may reduce plasma exudation responses. The present study examines whether nitroprusside affects histamine-induced mucosal exudation of plasma in the human nasal airway. In a dose-finding tolerability experiment, using changes in nasal patency as response, placebo and nitroprusside (1.2 and 3.6 mg per nasal cavity) were applied on the mucosal surface with a nasal-spray device. Nasal peak expiratory flow (PEF) rates were measured before the application and thereafter every third minute for 15 min. Nitroprusside produced a dose-dependent decrease in nasal PEF rates compared to placebo. Placebo or nitroprusside (7.2 mg) was then given to the right nasal cavity, followed 3 min later by challenge with saline or histamine (600 micrograms). The drug and the challenge were both applied with a nasal-spray device. With a nasal pool-device, the same large part of the nasal mucosal surface was lavaged before and after the treatment/challenge. The lavage fluid levels of alpha 2-macroglobulin were measured as an index of mucosal exudation of bulk plasma. The histamine-induced lavage fluid level of alpha 2-macroglobulin was significantly higher after treatment with placebo than with nitroprusside. The present data indicate that nitroprusside may have antiexudative effects in human airways. Hence, unlike other microvascular permeability active agents, this pharmacologic principle may be active in both guinea pig and human airways.
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| 49. |
- Gretarsson, Sigurdur, et al.
(författare)
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Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines
- 2020
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 140:4, s. 337-343
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Tidskriftsartikel (refereegranskat)abstract
- Background: Well characterized human cell lines are needed for preclinical treatment studies of anaplastic thyroid cancer (ATC).Aims/Objectives: The aim was to establish, verify and characterize a panel of ATC cell lines.Material and methods: Cell lines were established from ATC fine-needle aspiration biopsies and characterized genetically and functionally regarding treatment sensitivities.Results: Eight cell lines were established in vitro and the anaplastic thyroid origin was verified. Seven of the cell lines were also grown as xenografts. The cell lines harboured complex karyotypes with modal numbers in hyperdiploid to near-pentaploid range. Five were TP53 mutated and three carried the BRAFV600E mutation. None had rearrangements of RET. For doxorubicin, IC50 ranged from 0.42 to 46 nmol/L and for paclitaxel from 1.6 to 196 nmol/L. Radiation sensitivity varied between 2.6 and 6.3 Gy. Two of the BRAF mutated cell lines displayed high sensitivity to vemurafenib, while the third was similar to the wild-type ones.Conclusions and significance: We describe a series of new ATC cell lines demonstrating large heterogeneity in the response to cytostatic drugs and the BRAF inhibitor vemurafenib. The observations are relevant to future attempts to optimize treatment combinations for ATC.
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| 50. |
- Hafström, Anna, et al.
(författare)
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Outcome for sinonasal malignancies : a population-based survey
- 2022
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Ingår i: European Archives of Oto-Rhino-Laryngology. - : Springer Science and Business Media LLC. - 0937-4477 .- 1434-4726. ; 279:5, s. 2611-2622
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Sinonasal malignancies (SNM) represent a rare and complex group of cancers that includes a wide range of histopathological subtypes. Data from population-based cohorts are scarce but warranted as a basis for randomized controlled treatment trials (RCTs). Our aim was to assess overall and histology subset-specific outcomes for SNM patients treated at a tertiary referral centre. Methods: A retrospective, population-based, consecutive cohort of patients with SNMs diagnosed from 2001 through 2019 was examined. Outcome was analysed in relation to age, gender, site, stage, histopathology, and treatment. Results: Two-hundred and twenty-six patients were identified, whereof 61% presented with stage IV disease. 80% completed treatment with curative intent, which comprised surgery with neoadjuvant (29%) or adjuvant (37%) radiotherapy, monotherapy with surgery (22%), definitive chemoradiotherapy (7%), or radiotherapy (5%). Median follow-up was 106 months. The 5- and 10-year overall survival rates were 57% and 35%, respectively. Median overall survival was 76 months (esthesioneuroblastoma: 147 months; adenocarcinoma: 117; salivary carcinoma: 88; mucosal melanoma: 69; squamous cell carcinoma: 51, undifferentiated carcinoma: 42; neuroendocrine carcinoma: 9; and NUT-carcinoma 5). The 5- and 10-year disease-free survival rates were 63% and 54%, respectively, and disease-specific survival 83% and 66%. Increasing age, stage IVB, melanoma histopathology, and treatment with definitive chemoradiotherapy emerged as significant independent prognostic risk factors for disease-specific mortality (p ≤ 0.001). Conclusion: The results indicate a seemingly good outcome in comparison to previous reports, particularly for mucosal melanoma, adenocarcinoma, and undifferentiated carcinoma. The study provides additional background for future RCTs focusing on histology subset-specific treatment for SNM.
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