Ruth Sepper - Academia.edu (original) (raw)

Papers by Ruth Sepper

Studies in health technology and informatics

Objective: The aim of this paper is to evaluate the costs and benefits of the Estonian interopera... more Objective: The aim of this paper is to evaluate the costs and benefits of the Estonian interoperable health information exchange system. In addition, a framework will be built for follow-up monitoring and analysis of a nationwide HIE system. Methods: PENG evaluation tool was used to map and quantify the costs and benefits arising from type II diabetic patient management for patients, providers and the society. The analysis concludes with a quantification based on real costs and potential benefits identified by a panel of experts. Results: Setting up a countrywide interoperable eHealth system incurs a large initial investment. However, if the system is working seamlessly, benefits will surpass costs within three years. The results show that while the society stands to benefit the most, the costs will be mainly borne by the healthcare providers. Therefore, new government policies should be devised to encourage providers to invest to ensure society wide benefits.

Laboratory investigation; a journal of technical methods and pathology, 2002

Matrix metalloproteinases (MMPs) contribute to extracellular matrix and basement membrane degrada... more Matrix metalloproteinases (MMPs) contribute to extracellular matrix and basement membrane degradation in asthma. The present study analyzed molecular forms and degree of activation and expression of MMP-8 in bronchoalveolar lavage fluid (BALF), BALF cells, and bronchial tissue specimens from 14 steroid-naive asthma patients, 13 uncontrolled severe asthma patients, 13 controlled asthma patients, and 14 healthy subjects by Western immunoblotting, immunohistochemistry, and in situ hybridization. Immunohistochemistry and in situ hybridization revealed a prominent MMP-8 immunoreactivity in submucosal inflammatory, glandular, and shed, but not in intact bronchial epithelial cells of asthma patients. In BALF cytospins, both MMP-8 protein and mRNA expression were observed in epithelial cells, macrophages, and polymorphonuclear leukocytes (PMNs). MMP-8 was present in BALFs asthma patients in complex, pro- and active PMN-type, and pro- and active non-PMN-type forms. BALF MMP-8 was significant...

The European respiratory journal, 1995

Our aim was to study histopathological changes in lung tissue at the light microscopic and ultras... more Our aim was to study histopathological changes in lung tissue at the light microscopic and ultrastructural level during recovery from immunosuppression and Pneumocystis carinii pneumonia. Male Wistar rats were immunosuppressed by per oral dexamethasone for 12 weeks to induce P. carinii pneumonia, after which dexamethasone was stopped. Recovery was monitored 1, 2 and 4 weeks after cessation of the immunosuppression. In immunosuppressed animals, CD4+ and CD8+ lymphocytes were both decreased in situ. CD8+ lymphocytes increased above control level at week one. Like CD8+ cells, the ED1+ macrophages increased rapidly in situ. This was accompanied by a progressively increasing migration (more transient for lymphocytes) of macrophages into bronchoalveolar fluid, associated with morphological signs of activation and phagocytosis and proliferation of type II pneumocytes. Bronchoalveolar lavage (BAL) fluid tumour necrosis factor-alpha (TNF-alpha) increased from subnormal levels to a 4 week pea...

C102. WHAT'S NEW IN INTERVENTIONAL PULMONARY: EBUS AND MORE, 2010

D101. NEW ASPECTS OF INTERVENTIONAL PULMONOLOGY/BRONCHOSCOPY, 2009

Journal of Proteome Research, 2011

The nation-wide electronic health record database acts as an interoperable repository of health d... more The nation-wide electronic health record database acts as an interoperable repository of health data obtained throughout citizen contacts with health care providers. This system improves accessibility for citizens and researchers to health data with the ability to assign context to disease development. In that system, individual patients who are members of the large population-based health database can be assessed as individuals or as a population in prospective studies of prospective diseases.

Journal of Clinical Immunology, 1995

The presence, activities, and molecular forms of the serine proteinases, elastase, and cathepsin ... more The presence, activities, and molecular forms of the serine proteinases, elastase, and cathepsin G, and their endogenous inhibitors, alpha 1-antitrypsin and alpha 1-antichymotrypsin, were investigated in bronchoalveolar lavage (BAL) fluid of bronchiectasis patients divided into mild, moderate, and severe disease subgroups and compared to BAL fluid from healthy controls. Immunochemical characterization and quantitation were performed by Western immunoblot. The activities of elastase and cathepsin G were recorded spectrophotometrically using synthetic substrates. The results showed a significant difference in elastase and cathepsin G activities in BAL fluid of the three subgroups, revealing the following data--mild subgroup, 0.21 +/- 0.09 mU/g and 57.35 +/- 20.9 U/g; moderate subgroup, 1.87 +/- 1.12 mU/g and 89.24 +/- 31.4 U/g; and severe subgroup, 2.64 +/- 1.63 mU/g and 139.18 +/- 58.3 U/g, respectively--compared to those of the healthy control group, 0.09 +/- 0.03 mU/g and 50.96 +/- 16.5 U/g. Evidently, the protective shield of plasma-derived antiproteinases was sufficient in healthy subjects and, also, in mild cases of bronchiectasis, but not in cases of severe and moderate forms of bronchiectasis, in which free and catalytically active elastase and cathepsin G were detected. The serine proteinases inhibitors (serpins), alpha 1-antitrypsin and alpha 1-antichymotrypsin, have evidently been oxidized and/or proteolytically cleaved in the cases of moderate and severe bronchiectasis. The results indicate that insufficient endogenous downregulation of catalytically active elastase and cathepsin G in BALF leads to tissue injury, resulting in alterative and deformative processes in the bronchiectasis lung.

European Respiratory Journal, 1997

We attempted to study the possible relationships between neutrophil-type procollagenase/pro-matri... more We attempted to study the possible relationships between neutrophil-type procollagenase/pro-matrix metalloproteinase (MMP-8) and the serine proteinases plasmin, cathepsin G and tryptase in bronchiectasis. The presence of the plasmin/plasminogen system and plasmin-, cathepsin G- and tryptase-like activities were compared to the activity of endogenously activated MMP-8 in bronchoalveolar lavage (BAL) fluid in 38 bronchiectasis patients and in 14 healthy controls by means of immunohistochemistry, Western-blot and substrate-based functional assays. In contrast to cathepsin G- and tryptase-like activities, the plasmin/plasminogen activator system in BAL fluid was observed to have a relatively weak activation stage and no correlation with disease severity. Neither plasmin-like activities nor concentrations of plasminogen activators from the bronchiectatic patients differed significantly from the values of healthy controls. Immunolocation of plasminogen activator inhibitor-1 showed a marked, but not significant, increase in bronchiectatic lung as compared to controls. In contrast to cathepsin G- and tryptase-like activities, with their strong and significant correlation with endogenously activated collagenase (r=0.9; p=0.0001; and r=0.6; p=0.03, respectively), no correlations were observed between plasmin-like and endogenously activated collagenase (r=0.3; p=0.2) in bronchiectasis. These findings suggest that cathepsin G- and tryptase-like activities may act as potent pro-matrix metalloproteinase-8 activators in patients with bronchiectasis, whereas the plasminogen activator/plasmin cascade was shown to be down-regulated.

European Journal of Radiology, 2010

Teleradiology aims to even radiologists&amp;amp;amp;amp;amp;amp;amp;#39; workload, ensure... more Teleradiology aims to even radiologists&amp;amp;amp;amp;amp;amp;amp;#39; workload, ensure on-call services, reduce waiting lists, consult other specialists and cut costs. Cross-border teleradiology widens this scope beyond the country borders. However, the new service should not reduce the quality of radiology. Quality and trust are key factors in establishment of teleradiology. Additionally there are organizational, technical, legal, security and linguistic issues influencing the service. Herein, we have used experiences from two partially European Union funded telemedicine projects to evaluate factors affecting cross-border teleradiology. Clinical partners from Czech Republic, Denmark, Estonia, Finland, Lithuania and the Netherlands went through 649 radiology test cases in two different teleradiology projects to build trust and agree about the report structure. Technical set-up was established using secure Internet data transfer, streaming technology, integration of workflows and creating structured reporting tool to overcome language barriers. The biggest barrier to overcome in cross-border teleradiology was the language issue. Establishment of the service was technically and semantically successful but limited to knee and hip X-ray examinations only because the structured reporting tool did not cover any other anatomical regions yet. Special attention has to be paid to clinical quality and trust between partners in cross-border teleradiology. Our experience shows that it is achievable. Legal, security and financial aspects are not covered in this paper because today they differ country by country. There is however an European Union level harmonization process started to enable cross-border eHealth in general.

CHEST Journal, 1994

To evaluate the extracellular matrix (ECM) degradation in bronchiectasis (BE), the level of gelat... more To evaluate the extracellular matrix (ECM) degradation in bronchiectasis (BE), the level of gelatinolytic and type IV collagenolytic activity was analyzed in bronchoalveolar lavage fluid (BALF) by using zymographies. The BALF of patients with bronchiectasis revealed a high gelatinolytic and type IV collagenolytic activity whereas no such activities were detected in BALF of the healthy controls. Furthermore, the level of degradative activity correlated with the severity of disease with a spectrum varying from patients characterized by frequent pneumonia and bronchitis, mucopurulent and purulent sputum production, and saccular changes of bronchi having high activities of both 92-kd and 72-kd gelatinases type IV collagenases (corresponding to the neutrophil type MMP-9 and fibroblast type MMP-2 activities, respectively) to patients having few clinical symptoms and displaying only a weak activity at the 92-kd area. These findings suggest a role for the matrix metalloproteinases MMP-2 (72-kd gelatinase/type IV collagenase) and MMP-9 (92-kd gelatinase/type IV collagenase) in the degradation of ECM of bronchial wall and lung tissue. In addition, severe bronchiectasis was associated with the presence of low-molecular weight gelatinases reflecting in vivo metalloproteinase activation and/or the presence of microbial-derived gelatinolytic proteinases.

CHEST Journal, 1995

Collagenases in bronchoalveolar lavage fluid (BALF) of patients with bronchiectasis and healthy s... more Collagenases in bronchoalveolar lavage fluid (BALF) of patients with bronchiectasis and healthy subjects were characterized using specific functional and immunologic assays. The BAL fluid contained interstitial collagenase and collagenolytic proteinases of bacterial origin. Collagenase activities, obtained after organomercurial activation, correlated with the severity of bronchiectasis. In severe cases, collagenase activities were 3.5 x 10(-7) IU/L/48 h or 4.8 x 10(-6) IU/g/48 h (p < 0.01), in moderate ones 1.74 x 10(-7) IU/L/48 h or 3.35 x 10(-6) IU/g/48 h (p < 0.05), and in mild cases 0.32 x 10(-7) IU/L/48 h or 0.7 x 10(-6) IU/g/48 h (p < 0.05). The corresponding activities in healthy control subjects were 0.08 x 10(-7) IU/L/48 h or 0.13 x 10(-6) IU/g/48 h. The cellular origin of interstitial collagenase was assessed with doxycycline inhibition test utilizing the differential sensitivity of fibroblast-type collagenase/MMP-1 (IC50 = 280 microM) and neutrophil-type collagenase/MMP-8 (IC50 = 26 microM) to the anticollagenolytic, nonantimicrobial doxycycline action. Interstitial collagenase, contained in BALF, was totally inhibited by 100 microM of doxycycline. It can therefore be concluded that most of mammalian collagenase presented in inflamed fluid of bronchiectasis originated from neutrophils. The molecular forms of neutrophil-type collagenase/MMP-8 were confirmed and analyzed by Western-blot, which showed evidence of the proteolytic conversion of the latent 85-kD MMP-8 proenzyme species into active 65-kD molecular weight species. These findings strongly suggest involvement of proteolytic activation pathway of proMMP-8, especially in severe and moderate forms of bronchiectasis. Furthermore, collagenolytic proteases of bacterial origins may also participate in tissue destruction of the lung.

Annals of the New York Academy of Sciences, 1994

Annals of Medicine, 1998

Bronchiectasis (BE) is a chronic severe inflammatory lung disease characterized by frequent bacte... more Bronchiectasis (BE) is a chronic severe inflammatory lung disease characterized by frequent bacterial infections and polymorphonuclear neutrophil-dominated inflammatory reaction. We have attempted to elucidate the role of mast cells (MCs) in BE lung inflammation by measuring in the bronchoalveolar lavage fluid (BALF) the MC-derived tryptase levels by radioimmunoassay and immunoblotting and also by measuring the tryptase-like activities in 36 BE patients and in 14 healthy controls. The amount of MC in the lung tissue was assessed by immunohistochemical staining of resected lung tissue samples. Based on the clinical and radiological parameters the patients were divided into subgroups according to the severity of the disease. The MC tryptase concentrations (microg/L; median (range)) in BALF of BE patients were higher compared to healthy controls (4.7(1.4-20.1) and 2.0 (0.1-3.5), respectively, P < 0.01). Tryptase concentrations in the groups of mild, moderate and severe BE were 3.8 (0.9-10.8), 4.3 (3.0-12.6) and 9.6 (1.2-20.1), respectively. All the values differed significantly from those observed in the healthy controls. The tryptase-like activities (nmol/sec/L) in BE patients were also markedly increased (174 (31-2874)) compared to healthy controls (28 (9-45) P < 0.0001). The tryptase-like activities in the patient subgroups were 45 (36-598) in mild, 91 (31-1437) in moderate and 1336 (37-2874) in severe BE. Again, all values differed significantly from those observed in the healthy controls. Moreover, immunoblot experiments disclosed the most intensive immunoreactivity of the 27.5 kD tryptase monomer in BALF of patients with severe BE followed by weaker immunoreactivity in groups of moderate and mild BE and in healthy controls. No significant difference could be observed in the amount of tryptase-positive cells between BE patients and controls. However, the presence of degranulated MCs was more evident in BE lung tissue. Significant correlation could also be observed between the degree of activation of latent procollagenase and tryptase concentration (r = 0.8, P = 0.0004) in BALF of individual BE patients. The observed strong correlation between tryptase levels and disease severity suggests that MCs may be involved in the inflammatory reaction in the BE lung. Importantly, the high levels of tryptase, observed also in patients with mild BE, suggests that activation of and proteinase release from MCs may be one of the reasons for the perpetuation of tissue injury even during the clinically quiescent periods in BE.

Analytical Chemistry, 2011

Drug therapy is often directed to specific organ and tissue compartments where the mode of action... more Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound affects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 μm) and small (30 μm) raster sizes. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in four out of five subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3 and 80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings.

AJP: Lung Cellular and Molecular Physiology, 2004

The expression profile of a panel of 15 cAMP phosphodiesterase isoforms was determined for inflam... more The expression profile of a panel of 15 cAMP phosphodiesterase isoforms was determined for inflammatory cell types of relevance to chronic obstructive pulmonary disease (COPD). In particular, the expression profiles for bronchoalveolar macrophages, peripheral blood monocytes, T lymphocytes, and neutrophils from smokers with and without COPD were compared. The phosphodiesterase expression profile was also analyzed for peripheral blood monocytes, T lymphocytes, and neutrophils from nonsmokers and compared with smokers. Qualitative RT-PCR identified transcripts for PDE4A10, PDE4A7, PDE4B1, PDE4B2, PDE4D1, and PDE4D2 isoforms as well as transcripts for both PDE3B and PDE7A in T cells, monocytes, and macrophages in all subjects. Transcripts for PDE4B3 and PDE4D4 were not observed in any of the cell types investigated. PDE4C was detected in all cells analyzed except for T cells. The long PDE4A4, PDE4D3, and PDE4D5 isoforms exhibited cell type-specific expression patterns. Semiquantitative and real-time quantitative RT-PCR were used to analyze differential expression between disease states and between cell types. PDE4A4 was found significantly upregulated in lung macrophages from smokers with COPD when compared with control smokers. Furthermore, PDE4A4 as well as PDE4B2 transcripts were detected in higher amounts in peripheral blood monocytes of smokers when compared with nonsmokers. Finally, PDE4D5 and PDE4C were differentially regulated in lung macrophages when compared with monocytes of the same subjects, irrespective of the disease state. The data obtained suggest that PDE4A4 may be relevant as a macrophage-specific anti-inflammatory target for COPD.

APMIS, 2002

Maisi P, Prikk K, Sepper R, Pirilä E, Salo T, Hietanen J, Sorsa T. Soluble membrane-type 1 matrix... more Maisi P, Prikk K, Sepper R, Pirilä E, Salo T, Hietanen J, Sorsa T. Soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) and gelatinase A (MMP-2) in induced sputum and bronchoalveolar lavage fluid of human bronchial asthma and bronchiectasis. APMIS 2002;110:771-82.

The Journal of Pathology, 2001

The purpose of this study was to determine whether other cellular sources than neutrophils can ex... more The purpose of this study was to determine whether other cellular sources than neutrophils can express matrix metalloproteinase (MMP)-8 protein and mRNA in bronchiectatic (BE) lung. The molecular forms of MMP-8 in the BE bronchoalveolar lavage fluid (BALF) and healthy control BALF were analysed by western immunoblotting. MMP-8 expression was demonstrated by immunohistochemistry and in situ hybridization in BE lung tissue and by immunohistochemistry in control lung tissue. In the BE BALF, different MMP-8 species were detected: 70-80 kD MMP-8 apparently of polymorphonuclear leukocyte (PMN) origin and also 40-60 kD MMP-8 from non-PMN cellular sources, such as bronchial epithelial cells, glandular cells or monocytes/ macrophages. Both of these MMP-8 species were elevated and converted to a significant extent to activated forms in BE BALF compared with healthy control BALF. The levels of high molecular weight (>80 kD) MMP-8 complexes, evidently representing MMP-8 trapped by endogenous MMP inhibitors and/or MMP-8 dimers, were significantly elevated in BE BALF compared with healthy control BALF. In BE lung tissue, the MMP-8 protein and mRNA expression was found in bronchial ciliated epithelial cells, glandular cells, neutrophils, and monocytes/macrophages infiltrating the bronchial epithelial area. Minimal MMP-8 expression was observed in neutrophils, monocytes/macrophages, and epithelial cells in control lung tissues. In this study, new potential cellular sources have been demonstrated for MMP-8 in the inflamed lung. MMP-8 from multiple cellular sources, including inflamed lung epithelium, was activated to a significant extent in the BE BALF, indicating a major role for MMP-8 in the destruction of lung and bronchial tissues.