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- Birck, Malene M., et al.
(författare)
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Infection-induced coronary dysfunction and systemic inflammation in piglets are dampened in hypercholesterolemic milieu
- 2011
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Ingår i: American Journal of Physiology: Heart and Circulatory Physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 300:5, s. 1595-1601
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Tidskriftsartikel (refereegranskat)abstract
- Birck MM, Pesonen E, Odermarsky M, Hansen AK, Persson K, Frikke-Schmidt H, Heegaard PM, Liuba P. Infection-induced coronary dysfunction and systemic inflammation in piglets are dampened in hypercholesterolemic milieu. Am J Physiol Heart Circ Physiol 300: H1595-H1601, 2011. First published February 25, 2011; doi:10.1152/ajpheart.01253.2010.-The synergism of infection with conventional cardiovascular risk factors in atherosclerosis is much debated. We hypothesized that coronary arterial injury correlates with infection recurrence and pathogen burden and is further aggravated by hypercholesterolemia. Forty-two Gottingen minipigs were assigned to repeated intratracheal inoculation of PBS, Chlamydia pneumoniae (Cpn), or both Cpn and influenza virus at 8, 11, and 14 wk of age. Animals were fed either standard or 2% cholesterol diet (chol-diet.). At 19 wk of age coronary vasomotor responses to acetylcholine (ACh) and adenosine were assessed in vivo and blood and tissue samples were collected. Nonparametric tests were used to compare the groups. In cholesterol-fed animals, total cholesterol/HDL was significantly increased in infected animals compared with noninfected animals [3.13 (2.17-3.38) vs. 2.03 (1.53-2.41), respectively; P = 0.01]. C-reactive protein (CRP) rose in infected animals [10.60 (4.96-18.00) vs. 2.47 (1.44-3.01) mu g/ml in noninfected; P < 0.01] without significant difference between the mono- and coinfected groups. Among coinfected animals, both CRP and haptoglobin were lower in those fed chol-diet than in those fed standard diet (P < 0.05). The vasoconstricting response to ACh was most prominent in coinfected animals (769.3 (594-1,129) cm; P = 0.03 vs. noninfected [342 (309-455) cm] and P = 0.07 vs. monoinfected [415 (252.5-9711.8) cm]}. Among monoinfected animals, similar to CRP, a trend for less vasoconstriction was observed in those fed chol-diet (P = 0.08). Coinfection of piglets appears to be associated with more pronounced coronary muscarinic vasomotor dysfunction. In monoinfected animals, use of chol-diet seems to dampen both coronary dysfunction and systemic inflammation induced by infection.
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- Chubb, Henry, et al.
(författare)
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Long-Term Outcome Following Catheter Valvotomy for Pulmonary Atresia With Intact Ventricular Septum
- 2012
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 59:16, s. 1468-1476
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study investigated the outcome for all patients undergoing catheter valve perforation for pulmonary atresia with intact ventricular septum (PAIVS) 21 years after the first procedure at their center. Background Catheter perforation for PAIVS is now an established procedure. However, the management of the borderline right ventricle (RV) is controversial, and there may be a place for novel techniques such as stenting of the arterial duct. Methods There were 37 successful valve perforations (total 39 patients). Median length of follow-up was 9.2 years (range 2.2 to 21.0 years). Seventeen patients had stenting of the arterial duct. The mean (SD) initial z-score for the tricuspid valve was -5.1 (+/- 3.4), and a further 142 sets of measurements were taken to assess the growth of the RV of survivors. Results There were 8 deaths (21%), and no deaths after the first 35 days. There were no late arrhythmias or ischemic events. Twenty-five patients (83% of survivors) have a biventricular circulation. For patients who had stenting of the arterial duct, significant reductions in early reintervention (0 vs. 7 patients, p = 0.009) and hospital stay (17.4 +/- 18.1 days vs. 33.8 +/- 28.6 days, p = 0.012) occurred, with no increase in mortality or morbidity. There was no catch-up growth of the RV in patients who had a biventricular outcome (z-score increase +0.08/year, p = 0.26). Conclusions Long-term survival is good, and even small RVs may be amenable to this procedure. Multiple interventions may be required to achieve biventricular circulation, but stenting of the arterial duct may reduce hospital stay and repeat procedures. (J Am Coll Cardiol 2012;59:1468-76) (C) 2012 by the American College of Cardiology Foundation
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- Diaconu, Iulia, et al.
(författare)
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Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus
- 2012
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72:9, s. 2327-2338
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Tidskriftsartikel (refereegranskat)abstract
- Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (TH1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)–mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the TH1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8+ T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of TH1 cytokines.
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| 12. |
- Elming, Sten-åke, et al.
(författare)
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Drift history of Fennoscandia
- 2009
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Ingår i: A continent revealed. - Cambridge : Cambridge University Press.
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 13. |
- Elming, Sten-åke, et al.
(författare)
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The drift of the Fennoscandian and Ukrainian Shields during the Precambrian : a Palaeomagnetic analysis
- 1993
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Ingår i: Tectonophysics. - : Elsevier BV. - 0040-1951 .- 1879-3266. ; 223:3-4, s. 177-198
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Tidskriftsartikel (refereegranskat)abstract
- A revised Precambrian (2.85-0.6 Ga) Apparent Polar Wander Path (APWP) for the Fennoscandian Shield, based on a new compilation and analysis of data, is presented. In fitting the APW path to successive Grand Mean Palaeomagnetic poles (GMPs), we applied the spherical spline technique originally developed by Jupp and Kent in 1987. The position and orientation of the Fennoscandian Shield during 2.85-0.6 Ga was determined from the GMPs. Major palaeoclimatological findings are used to constrain the palaeomagnetic interpretation of palaeolatitudes. The general drift of Fennoscandia, from relatively high latitudes in the late Archaean-Early Proterozoic to nearly equatorial latitudes in the Middle Proterozoic, correlates with palaeoclimatological indications that a period of cold climate was followed by one of warm climate during this time interval. From the continuous APWP the APW velocities and latitudinal drift velocities of the shield were calculated. An accumulated APW curve was also calculated. The palaeomagnetic data are irregularly distributed and some periods are rather poorly represented. This means that the calculated velocities can sometimes be artifacts of sampling. Late Archaean and Early Proterozoic (2.85-1.90 Ga) data are too sparse to make these calculations meaningful and velocity calculations are therefore restricted to data of 1.90 Ga and younger ages. The accumulated APW curve shows a number of linear segments with varying slopes, indicating sudden changes in drift rate. During the Middle Proterozoic (1.90-1.35 Ga) there was a period when the rate of APW was constant and low and that of latitudinal drift also was low. This pattern changed at ca. 1.35 Ga, and the following Middle-Late Proterozoic period can be described by rapid APW and strongly fluctuating drift velocities. Jotnian rifting and the intrusion of numerous dyke swarms (at ca. 1.25 Ga) correlate with this shift in rate. These changes are attributed to changes in plate configuration. A new database for the Ukrainian Shield is also presented, and GMPs in the 2.32-1.20 Ga range are defined. The database is still inadequate and the comparison of the Ukrainian and Fennoscandian drift histories is therefore tentative. Similarities in position, latitudinal drift and rotation during the Early-Middle Proterozoic are, nevertheless, evident. A close relationship between the shields in this period is consistent with the low APW rate of Fennoscandia, indicating that Fennoscandia may have been part of a larger continent, including the Ukraine, at that time. At ca. 1.2 Ga, the latitudinal position of Ukraine differed significantly from that of Fennoscandia, suggesting that the large shield split up between ca. 1.35 and 1.2 Ga. This would explain the change in APW rate at 1.35 Ga. The subsequent increase in rate was due to a reduction in the size of the shield. The discrepancy in palaeopositions of Fennoscandia and Ukraine at 1.2 Ga led Mikhailova and Kravchenko to suggest a late Precambrian time (1.07-0.57 Ga) for the accreation of Fennoscandia to the East European Platform (EEP). This may be correct as the rate of APW for Fennoscandia decreased in the late Precambrian, reflecting such a consolidation.
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- Pesonen, I., et al.
(författare)
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Delay and inequalities in the treatment of idiopathic pulmonary fibrosis: the case of two Nordic countries
- 2018
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Ingår i: Multidisciplinary Respiratory Medicine. - : PAGEPress Publications. - 2049-6958 .- 1828-695X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of lung function with high mortality within the first 5 years from diagnosis. In 2011-2014, two drugs, pirfenidone and nintedanib, have been approved worldwide for prevention of IPF progression. National IPF-registries have been established in both Finland and Sweden. Our study explored potential differences in the care of IPF in these two countries. Methods: Patients included consecutively in the Finnish and Swedish IPF-registries from January 1, 2014 through December 31, 2016 were included in the study. Data on demographics and lung function at the time of inclusion were collected. Access to antifibrotic drugs and data on disease outcomes, mortality and the proportion of patients who underwent lung transplantation, was collected during a 3-year follow up. Results: One-hundred and fifty-two patients from the Finnish and 160 patients from the Swedish IPF-cohorts were included in the study. At inclusion, Finnish patients were significantly older than the Swedish patients (74.6 years vs 72.5 years, p = 0.017). The proportion of non-smokers was significantly higher in the Finnish cohort (41.7% vs 26.9%, p = 0.007). Forced vital capacity (FVC), % of predicted (78.2 vs 71.7 for Finnish and Swedish patients, respectively, p = 0.01) and diffusion capacity for carbon monoxide (DLCO), % of predicted (53.3 vs 48.2 for Finnish and Swedish patients, respectively, p = 0.002) were significantly higher in the Finnish cohort compared to the Swedish cohort at the time of inclusion. During the 3-year follow up period, 45 (29.6%) Finnish and 111 (69.4%) Swedish patients, respectively, were initiated on treatment with an antifibrotic drug (pirfenidone or nintedanib) (p < 0.001). When comparing possible determinants of treatment, patients with higher FVC % were less likely to start antifibrotic drugs (OR 0.96, 95% CI 0.93-1.00, p < 0.024). To be resident in Sweden was the main determinant for receiving antifibrotic drugs (OR 5.48, 95% CI 2.65-11.33, p < 0.0001). No significant difference in number of deaths and lung transplantation during the follow up period was found. Conclusions: This study highlights differences concerning how IPF patients are treated in Finland and Sweden. How these differences will influence the long-term outcome of these patients is unknown.
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- Turanlahti, M, et al.
(författare)
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Plasma cyclic guanosine monophosphate reflecting the severity of persistent pulmonary hypertension of the newborn
- 2001
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Ingår i: Biology of the Neonate. - : S. Karger AG. - 1421-9727. ; 80:2, s. 107-112
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to examine the relationship between the plasma concentration of cyclic guanosine monophosphate (cGMP) and pulmonary pressure and hypoxia defined by oxygenation index (OI) in newborn infants with severe persistent pulmonary hypertension (PPHN) on inhaled nitric oxide (NO). In this prospective study, 18 newborn infants having Doppler ultrasound-diagnosed PPHN and treated with NO were investigated. The ratio of pulmonary artery to systemic artery pressure (PAP/SAP) and OI was assessed before treatment and at 0.5, 1, 12, and 24 h from the beginning of NO. At these time points, plasma concentrations of cGMP could be determined in 11 patients. The association of birth asphyxia as assessed by Apgar 1 min and 5 min and plasma cGMP before the NO treatment was examined. The initial median plasma concentration of cGMP was 37.3 pmol/ml (IQR 13.3-79.6). After the start of NO, cGMP increased significantly within 60 min (p = 0.003) and peaked at 12 h. Initial plasma cGMP was associated with Apgar score (1 and 5 min). OI decreased within 30 min of NO and PAP/SAP within 60 min. Persistent high PAP/SAP after 1 h of NO was associated with low cGMP concentration (r = 0.70, p = 0.02). We conclude that a significant increase in plasma cGMP is already evident after 60 min of NO therapy. This effect is accompanied by changes in oxygenation index and in pulmonary artery pressure. Initial plasma concentrations of cGMP were associated with hypoxia assessed as Apgar score.
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- Bulanova, Daria, et al.
(författare)
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Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins
- 2017
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Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.
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- Dias, J D, et al.
(författare)
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Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4
- 2012
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Ingår i: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 19:10, s. 988-998
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Tidskriftsartikel (refereegranskat)abstract
- Promising clinical results have been achieved with monoclonal antibodies (mAbs) such as ipilimumab and tremelimumab that block cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152). However, systemic administration of these agents also has the potential for severe immune-related adverse events. Thus, local production might allow higher concentrations at the target while reducing systemic side effects. We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Δ24aCTLA4 expressing complete human mAb specific for CTLA-4 and tested it in vitro, in vivo and in peripheral blood mononuclear cells (PBMCs) of normal donors and patients with advanced solid tumors. mAb expression was confirmed by western blotting and immunohistochemistry. Biological functionality was determined in a T-cell line and in PBMCs from cancer patients. T cells of patients, but not those of healthy donors, were activated by an anti-CTLA4mAb produced by Ad5/3-Δ24aCTLA4. In addition to immunological effects, a direct anti-CTLA-4-mediated pro-apoptotic effect was observed in vitro and in vivo. Local production resulted in 43-fold higher (P<0.05) tumor versus plasma anti-CTLA4mAb concentration. Plasma levels in mice remained below what has been reported safe in humans. Replication-competent Ad5/3-Δ24aCTLA4 resulted in 81-fold higher (P<0.05) tumor mAb levels as compared with a replication-deficient control. This is the first report of an oncolytic adenovirus producing a full-length human mAb. High mAb concentrations were seen at tumors with lower systemic levels. Stimulation of T cells of cancer patients by Ad5/3-Δ24aCTLA4 suggests feasibility of testing the approach in clinical trials.
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