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- Stegmayr, Bernd, et al.
(författare)
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Low-dose atorvastatin in severe chronic kidney disease patients : a randomized, controlled endpoint study
- 2005
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Ingår i: Scandinavian Journal of Urology and Nephrology. - 0036-5599 .- 1651-2065. ; 39:6, s. 489-497
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Tidskriftsartikel (refereegranskat)abstract
- Objective. There have been no endpoint studies with statins for patients with severe renal failure. The purpose of this prospective, open, randomized, controlled study was to investigate whether atorvastatin (10 mg/day) would alter cardiovascular endpoints and the overall mortality rate of patients with chronic kidney disease stage 4 or 5 (creatinine clearance < 30 ml/min).Material and methods. The study subjects comprised 143 patients who were randomized either to placebo (controls; n=73; mean age 69.5 years) or to treatment with atorvastatin (n=70; mean age 67.9 years). The patients included were either non-dialysis (n=33), haemodialysis (n=97) or peritoneal dialysis (n=13) patients. Analysis focused on the primary endpoints of all-cause mortality, non-lethal acute myocardial infarction, coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. Statistical analysis for endpoint data was mainly by intention-to-treat.Results. Primary endpoints occurred in 74% of the subjects. There was no difference in outcome between the control and atorvastatin groups. The 5-year endpoint-free survival rate from study entry was 20%. Atorvastatin was withdrawn in 20% of patients due to unacceptable side-effects. In the atorvastatin group, low-density lipoprotein (LDL) cholesterol was reduced by 35% at 1 month and then sustained. The controls showed a progressive reduction in LDL cholesterol until 36 months.Conclusions. Although atorvastatin reduced total and LDL cholesterol effectively it was not beneficial regarding the long-term outcomes of cardiovascular endpoints or survival. In contrast to other patient groups, patients with severe chronic kidney disease, especially those on dialysis, seem to derive limited benefit from this lower dose of atorvastatin.
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- Söderström, K, et al.
(författare)
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High expression of V gamma 8 is a shared feature of human gamma delta T cells in the epithelium of the gut and in the inflamed synovial tissue.
- 1994
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 152:12, s. 6017-27
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Tidskriftsartikel (refereegranskat)abstract
- We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a new mAb (B18) specific for V gamma 8 of human TCR-gamma delta+ T cells. The B18+ population constituted a minor subset of the gamma delta T cells in peripheral blood (PB) of healthy persons (6 +/- 5%) and only 1 of 35 gamma delta T cell clones analyzed was positive. In contrast, the B18+ subset was a dominant gamma delta T cell population among intraepithelial lymphocytes (IEL) derived from the human intestine (74 +/- 29, p < 0.002), and two of three IEL clones from patients with coeliac disease were B18+. Interestingly, a higher proportion of B18+ gamma delta T cells was found in the synovial fluid of patients with rheumatoid arthritis (RA) (21 +/- 18%, 0.02 < p < 0.05) compared with normal PB. Furthermore, the B18+ subset was more frequent among IL-2-expanded gamma delta T cells (42 +/- 20%) derived from synovial tissue than among IL-2-expanded cells derived from synovial fluid (p < 0.002) and PB from RA patients (p < 0.02) as well as normal PB (p < 0.002). The V-gene usage of 13 gamma delta T cell clones from the synovial fluid of arthritic patients was analyzed. All B18+ clones (n = 7) expressed mRNA for V gamma 8 together with mRNA for V delta 1 (n = 5) or mRNA for V delta 3 (n = 2). None of the B18- clones expressed V gamma 8 (n = 6). We conclude that the gamma delta T cell that expresses V gamma 8, together with mainly V delta 1, is a major gamma delta T cell subset among the IEL of the gut and a highly frequent subset in the synovial tissue of patients with RA. This subset may correspond to the mouse V gamma 7+ IEL, which has a high degree of amino acid sequence homology with the human V gamma 8 protein.
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- BUCHT, A, et al.
(författare)
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Analysis of gamma delta V region usage in normal and diseased human intestinal biopsies and peripheral blood by polymerase chain reaction (PCR) and flow cytometry
- 1995
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Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 99:1, s. 57-64
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Tidskriftsartikel (refereegranskat)abstract
- The intestinal population of γδ T cell receptor (TCR)-bearing cells was characterized with regard to Vδ and Vγ subtype expression. For this purpose, we utilized V gene-specific PCR of mRNA prepared from intestinal biopsies. Predominant expression of the Vδ1 subtype was demonstrated in the small intestine of patients with coeliac disease and in the inflamed colon of patients with inflammatory bowel diseases (IBD: ulcerative colitis and Crohn's disease) as well as in colon biopsies taken from macroscopically normal areas of colon. Although intestinal γδ T cells preferentially expressed Vδ1, other Vδ transcripts could be detected, of which Vδ2 and Vδ5 were commonly expressed. Analysis of biopsies from mesenteric lymph nodes demonstrated a Vδ repertoire similar to the mucosa. In peripheral blood on the other hand, high expression of both Vδ2 and Vδ1 was found. The predominant expression of Vδ1 transcripts in the intestinal mucosa of IBD patients correlated well with protein cell surface expression as analysed by flow cytometry using Vδ1- and Vδ2-specific antibodies. Selective expansion of γδ T cells could not be demonstrated within the inflamed mucosa as shown by mRNA analysis and flow cytometry. Instead, IBD patients demonstrated a decreased proportion of TCR 76-carrying T cells in the inflamed mucosa compared with macroscopically normal area of colon. On the other hand, a significantly increased percentage of T cells bearing the γδ TCR was found in peripheral blood of patients with Crohn's disease compared with healthy individuals, indicating that local mucosal inflammation may influence the circulating γδ T cell population.
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| 21. |
- Bucht, A, et al.
(författare)
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Expression of interferon-gamma (IFN-gamma), IL-10, IL-12 and transforming growth factor-beta (TGF-beta) mRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA)
- 1996
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Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 103:3, s. 357-367
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Tidskriftsartikel (refereegranskat)abstract
- The expression of immunoregulatory cytokines was investigated in freshly isolated synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) from patients with RA, using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. IFN-γ, TGF-β, IL-10 and IL-12 (p40) transcripts were detected in SFMC of patients with early disease (<1 year duration) as well as in patients with long standing arthritis (>1 year). The expression of IFN-γ, IL-10 and IL-12 mRNA was increased in SFMC compared with RA PBMC. In addition, the expression was higher in RA SFMC than in PBMC from healthy control individuals. Immunoassay analysis of the secreted IL-12 heterodimer demonstrated increased levels in RA SF compared with levels found in serum from RA patients and control individuals. High levels of TGF-β mRNA were found in SFMC, but a significantly decreased TGF-β/β2-microglobulin (β2-M) ratio was found compared with PBMC from both patients and control individuals. IL-4 mRNA could not be detected, either in SFMC or in PBMC. Cytokine expression in RA PBMC did not differ from control PBMC, with the exception of a decreased TGF-β/β2-M ratio in RA patients with early disease. Our findings of IFN-7 mRNA and IL-12, but undetectable levels of IL-4 mRNA, suggest that the synovitis is characterized by a type 1 immune response. The presence of TGF-β and IL-10 mRNA indicates that immunosuppressive cytokines may also operate in the inflamed joint, although their level of expression may not be sufficient for down-modulation of immune activation.
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- Holt, Sandra, 1977-
(författare)
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Fatty acid amide hydrolase - A target for anti-inflammatory therapies?
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Anti-inflammatory drugs are a widely used class of therapeutic agents, but the use of non-steroidal anti-inflammatory drugs (NSAID) is hampered by their gastrointestinal side-effects. Recent reports that cyclooxygenase-2 inhibitors may cause cardiovascular events underline the importance of identifying new therapeutic strategies for the treatment of inflammation. One such target could be agents modifying the endogenous cannabinoid (endocannabinoid) system, since there is evidence that this system plays a role in our natural defence against inflammation. The levels of the endocannabinoid anandamide (arachidonoyl ethanolamide, AEA) are low under normal conditions, and stand under strict regulatory control of synthesising and degrading enzymes. Fatty acid amide hydrolase (FAAH) is the main enzyme degrading AEA, hydrolysing it to ethanolamine and arachidonic acid. The focus of this thesis lies in exploring the pharmacology of FAAH to evaluate its possibilities as a target for new anti-inflammatory drugs. In Papers I and II, the effects of the ambient pH on the properties of FAAH were investigated, since tissue pH is known to decrease under inflammatory conditions. In homogenates, it was found that the activity of FAAH decreased as the assay pH was decreased, consistent with the known pH profile of the enzyme. More importantly, the sensitivity of the enzyme to inhibition by FAAH inhibitors changed. In particular, the sensitivity of the enzyme to inhibition by the NSAID ibuprofen increased seventeen-fold as the assay pH decreased from 8.37 to 5.28. A similar pattern was found using intact C6 glioma cells when the extracellular, but not the intracellular pH was reduced. Thus, at an extracellular pH value of 6.2, (R)-ibuprofen, (S)-flurbiprofen and (R,S)-flurbiprofen inhibited the metabolism of AEA with IC50 values of 26, 14 and 15 µM, respectively. These values are in theory reachable upon normal dosing of the compounds. In Paper III, the effect of the selective FAAH inhibitor URB597 and the NSAID indomethacin were investigated in vivo upon the oedema response to carrageenan administration in the paw of anaesthetised mice. Both compounds reduced the oedema in a manner completely blocked by the CB2 receptor antagonist SR144528. In Paper IV, the effect of inflammation upon endocannabinoid synthesis was investigated in mice. Lipopolysaccharide-induced pulmonary inflammation was found not to affect the release of AEA to any obvious extent, and did not change the activities of the AEA synthesising enzymes N-acyl transferase or N-acyl phosphatidylethanolamine phospholipase D, or of FAAH in lung tissue. The results of this thesis would suggest that FAAH inhibitors can produce anti-inflammatory effects, and that the endocannabinoid system contributes to the actions of the NSAID indomethacin in the carrageenan model of inflammation, but that an increased endocannabinoid synthesis (a prerequisite for FAAH inhibition as a therapeutic strategy) is not an obligatory response to an inflammatory stimulus.
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- Muala, Ala, et al.
(författare)
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Assessment of the capacity of vehicle cabin air inlet filters to reduce diesel exhaust-induced symptoms in human volunteers
- 2014
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Ingår i: Environmental Health. - : BioMed Central (BMC). - 1476-069X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exposure to particulate matter (PM) air pollution especially derived from traffic is associated with increases in cardiorespiratory morbidity and mortality. In this study, we evaluated the ability of novel vehicle cabin air inlet filters to reduce diesel exhaust (DE)-induced symptoms and markers of inflammation in human subjects.METHODS: Thirty healthy subjects participated in a randomized double-blind controlled crossover study where they were exposed to filtered air, unfiltered DE and DE filtered through two selected particle filters, one with and one without active charcoal. Exposures lasted for one hour. Symptoms were assessed before and during exposures and lung function was measured before and after each exposure, with inflammation assessed in peripheral blood five hours after exposures. In parallel, PM were collected from unfiltered and filtered DE and assessed for their capacity to drive damaging oxidation reactions in a cell-free model, or promote inflammation in A549 cells.RESULTS: The standard particle filter employed in this study reduced PM10 mass concentrations within the exposure chamber by 46%, further reduced to 74% by the inclusion of an active charcoal component. In addition use of the active charcoal filter was associated by a 75% and 50% reduction in NO2 and hydrocarbon concentrations, respectively. As expected, subjects reported more subjective symptoms after exposure to unfiltered DE compared to filtered air, which was significantly reduced by the filter with an active charcoal component. There were no significant changes in lung function after exposures. Similarly diesel exhaust did not elicit significant increases in any of the inflammatory markers examined in the peripheral blood samples 5 hour post-exposure. Whilst the filters reduced chamber particle concentrations, the oxidative activity of the particles themselves, did not change following filtration with either filter. In contrast, diesel exhaust PM passed through the active charcoal combination filter appeared less inflammatory to A549 cells.CONCLUSIONS: A cabin air inlet particle filter including an active charcoal component was highly effective in reducing both DE particulate and gaseous components, with reduced exhaust-induced symptoms in healthy volunteers. These data demonstrate the effectiveness of cabin filters to protect subjects travelling in vehicles from diesel exhaust emissions.
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| 32. |
- Nilsson Ekdahl, Kristina, et al.
(författare)
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Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles
- 2018
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Ingår i: Nanomedicine. - : Elsevier. - 1549-9634 .- 1549-9642. ; 14:3, s. 735-744
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Tidskriftsartikel (refereegranskat)abstract
- Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine α-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The α-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikreinactivation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.
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- Pisa, P, et al.
(författare)
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Selective expression of interleukin 10, interferon gamma, and granulocyte-macrophage colony-stimulating factor in ovarian cancer biopsies.
- 1992
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 89:16, s. 7708-12
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Tidskriftsartikel (refereegranskat)abstract
- The variable clinical response seen with most cancer immunotherapy suggests that there is a large interindividual variation in immunologic response to tumors. One of the key functional parameters of an immune response is the local production of cytokines. As a method to survey the immune status of tumor-infiltrating cells, we have investigated the constitutive expression of cytokine mRNA in biopsies from epithelial ovarian carcinomas by using a PCR-assisted mRNA amplification assay. Using a set of cytokine-specific primers for 10 different cytokines, we have found selective expression of interleukin 10 (IL-10), granulocyte-macrophage colony-stimulating factor, and interferon gamma mRNA in ovarian tumor tissue as compared to normal ovaries and ovarian tumor cell lines. Such differences could not be explained by the extent of T-cell infiltration, since comparing samples with the same intensity of T-cell receptor (TCR) constant region alpha-chain product from the tumor and normal biopsies demonstrated different cytokine patterns. No IL-2 gene expression was detected in the tumor biopsies. IL-2 mRNA, however, became expressed after stimulation of the tumor-derived cells via the CD3 molecule but not after growth in recombinant IL-2 alone. Using the same methodology, we also analyzed the TCR variable region beta-chain gene repertoire. No restriction or biased expression of these genes was observed.
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- Svartbo, B, et al.
(författare)
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Inpatient care quality: analyzing Swedish hospitals with stroke as a tracer
- 2000
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Ingår i: International journal of health care quality assurance incorporating Leadership in health services. - : Emerald. - 1366-0756. ; 13:4-5, s. 218-22
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Tidskriftsartikel (refereegranskat)abstract
- Mortality statistics are an important source of information concerning variations in time and place, identification of risk factors and the evaluation of treatment programs. In this study, a new death certificate was completed “blind” on the basis of hospital records from the last episode of care, across a random sample of 1,376 cases. The results showed that the overlap between the official register’s underlying cause of death and that of a panel was 72 per cent at the three‐digit level. The official underlying cause of death from cerebrovascular diseases (CVD) was 72 cases in this sample, while 93 were deemed to have CVD by a panel. Additionally, of the 1,233 cases originally reported as non‐CVD, the panel deemed non‐CVD to be the true underlying cause in 1,176 cases. The paper concludes that CVD was most often correctly reported as the underlying cause of death in the investigated ages up to 75 years but plain differences were found between specialities and in different hospital size.
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