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| 2. |
- Agardh, Carl-David, et al.
(författare)
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Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes.
- 2005
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Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1873-460X .- 1056-8727. ; 19:4, s. 238-246
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this Phase II study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 μg Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and humoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P=.0015) in the 20 μg but not in the other dose groups. In addition, both fasting (P=.0081) and stimulated (P=.0236) c-peptide levels increased from baseline to 24 weeks in the 20 μg dose group. GADA log levels clearly increased (P=.0002) in response to 500 μg Diamyd. The CD4+CD25+/CD4+CD25− cell ratio increased (P=.0128) at 24 weeks in the 20 μg group. No sudden increase in HbA1c or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes.
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| 3. |
- Agardh, Carl-David, et al.
(författare)
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Expression of antioxidant enzymes in rat retinal ischemia followed by reperfusion.
- 2006
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 55:7, s. 892-898
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the expression and protein levels of antioxidant enzymes in the rat retina exposed to oxidative stress induced by ischemia-reperfusion injury. Retinal ischemia was induced in female Wistar rats by ligation of the optic nerve and vessels behind the left eye bulb, and was followed by reperfusion for 0, 3, 6, or 24 hours. The right eye served as control. RNA and protein were extracted simultaneously from each retina. Expressions of the endogenous antioxidant enzymes glutathione peroxidase (GPx1), catalase (CAT), copper/zinc superoxide dismutase, manganese superoxide dismutase, and the catalytic subunit of glutamylcysteine ligase (GCLc) were analyzed with real-time reverse transcription polymerase chain reaction and related to the endogenous control cyclophilin B. Protein levels were measured with Western blot analysis. During the early phase (0 or 3 hours) of reperfusion, no changes were seen in enzyme expression. After 6 hours, GCLc expression increased by a factor of 1.14 (P =.034), followed by a decline of 0.80 after 24 hours (P =.00004), according to the comparative Ct method. After 24 hours of reperfusion, GPx1 expression increased by a factor of 1.14 (P =.028), and CAT had decreased by 0.82 (P =.022). Expressions of copper/zinc superoxide dismutase and manganese superoxide dismutase showed a tendency toward a decrease by factors of 0.86 (P =.055) and 0.88 (P =.053), respectively, after 24 hours. Protein levels did not differ for any of the antioxidants, regardless of reperfusion time. The slightly increased messenger RNA expression of GPx1 after 24 hours of reperfusion with a concomitant very modest decrease in CAT and GCLc expression and no change in protein levels indicate a very modest, if any, response to oxidative stress generated by ischemia followed by reperfusion in rat retina.
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| 4. |
- Agardh, Carl-David, et al.
(författare)
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The Aldose Reductase Inhibitor Fidarestat Suppresses Ischemia-Reperfusion-Induced Inflammatory Response in Rat Retina.
- 2009
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Ingår i: Pharmacology. - : S. Karger AG. - 1423-0313 .- 0031-7012. ; 84:5, s. 257-263
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies suggest that increased aldose reductase (AR) activity plays an important role in ischemia-reperfusion injury in the retina. The mechanisms are not completely understood, but may be linked to inflammation. In the present study, we investigated whether the AR inhibitor fidarestat suppressed the retinal inflammatory response induced by ischemia-reperfusion in a rat model. The inflammatory response was manifested by increased gene expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 (ICAM-1) as well as elevated protein levels of soluble ICAM-1. This response was partially suppressed by the AR inhibitor fidarestat. The findings may reveal beneficial effects of AR inhibition on retinal inflammation associated with ischemia-reperfusion and are in agreement with recent developments in pharmacological research suggesting that pathological conditions other than diabetes may benefit from AR inhibitors.
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| 5. |
- Agardh, Daniel, et al.
(författare)
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Coeliac disease-specific tissue transglutaminase autoantibodies are associated with osteoporosis and related fractures in middle-aged women
- 2009
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 44:5, s. 571-578
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate whether the serological marker for coeliac disease, tissue transglutaminase autoantibody (tTGAb), is associated with decreased bone mass density (BMD) and increased frequency of fractures in middle-aged women screened for osteoporosis. Material and methods. The study comprised 6480 women (mean age 56 years, range 50-64) who answered a number of questionnaires and who underwent dual X-ray absorptiometry of the wrist bone. Serum samples were analysed for tTGAb using radioligand binding assays. A tTGAb level of 4 U/ml was used to determine a positive value and a level of 17 U/ml was used as an alternative discrimination of high levels. Results. A tTGAb level 4 U/ml was found among 90/6480 (1.4%) women and correlated with lower BMD (multiple linear regression coefficient -382.1; 95% CI = - 673.6-90.7, p=0.011) and with fracture frequency (r=0.18, p=0.023). The 59 women with tTGAb levels 17 U/ml had a lower BMD (0.410.08 g/cm2 versus 0.440.08 g/cm2, p=0.001) and a lower T-score (-1.401.28 versus -0.901.40, p=0.003) as well as a higher prevalence of osteoporosis (13.4% versus 6.5%, p=0.008) compared with the remaining 6421 women with tTGAb levels 17 U/ml. Furthermore, fracture frequency was more pronounced in women with tTGAb levels 17 U/ml, among whom 19/59 (32.2%) had fractures during the study period compared with 1204/6421 (18.8%) among women with tTGAb levels 17 U/ml (p=0.009). Conclusions. High levels of tTGAb indicating coeliac disease are associated with lower BMD and higher fracture frequency in women between 50 and 64 years of age. Osteometry is therefore warranted in middle-aged women detected with tTGAb.
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| 6. |
- Agardh, Elisabet, et al.
(författare)
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Modifying a standard method allows simultaneous extraction of RNA and protein, enabling detection of enzymes in the rat retina with low expressions and protein levels
- 2006
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 55:2, s. 168-174
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to evaluate messenger RNA and protein expression in limited amounts of tissue with low protein content. The Chomczynski method was used for simultaneous extraction of RNA, and protein was modified in the protein isolation step. Template mass and cycling time for the complementary DNA synthesis step of real-time reverse transcription-polymerase chain reaction (RT-PCR) for analysis of catalase, copper/zinc superoxide dismutase, manganese superoxide dismutase, the catalytic subunit of glutamylcysteine ligase, glutathione peroxidase 1, and the endogenous control cyclophilin B (CypB) were optimized before PCR. Polymerase chain reaction accuracy and efficacy were demonstrated by calculating the regression (R2) values of the separate amplification curves. Appropriate antibodies, blocking buffers, and running conditions were established for Western blot, and protein detection and multiplex assays with CypB were performed for each target. During the extraction procedure, the protein phase was dissolved in a modified washing buffer containing 0.1% sodium dodecyl sulfate, followed by ultrafiltration. Enzyme expression on real-time RT-PCR was accomplished with high reliability and reproducibility (R2, 0.990-0.999), and all enzymes except for glutathione peroxidase 1 were detectable in individual retinas on Western blot. Western blot multiplexing with CypB was possible for all targets. In conclusion, connecting gene expression directly to protein levels in the individual rat retina was possible by simultaneous extraction of RNA and protein. Real-time RT-PCR and Western blot allowed accurate detection of retinal protein expressions and levels.
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| 7. |
- Fosmark, DS, et al.
(författare)
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Increased serum levels of the specific advanced glycation end product methylglyoxal-derived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus
- 2006
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 55:2, s. 232-236
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Tidskriftsartikel (refereegranskat)abstract
- Advanced glyeation end products (AGEs) are thought to play a major pathogenic role in diabetic retinopathy. The most important AGE is unknown, but as increased serum methylglyoxal-derived hydroimidazolone has been demonstrated in patients with type 2 diabetes mellitus, the aim of the present study was to elucidate possible associations between serum levels of hydroimidazolone and retinopathy in patients with type 2 diabetes mellitus. We recruited 227 patients with type 2 diabetes mellitus and retinopathy ranging from none to proliferative. Level of retinopathy was determined from 7 standard field stereo photographs per eye according to the Early Treatment Diabetic Retinopathy Study. The patients were 66 +/- 11 years old, with a known diabetes duration of 14 9 years. Serum levels of hydroimidazolone were determined with a competitive immunoassay. Serum levels of hydroimidazolone were increased in nonproliferative (median, 4.50 U/mL; interquartile range, 3.69-5.77 U/mL) and proliferative retinopathy (median, 4.88 U/mL; interquartile range, 3.70-6.52 U/mL) compared with patients without retinopathy (median, 4.02 U/mL; interquartile range, 3.47-4.88 U/mL) (P =.008 and .002, respectively). There was no association between hydroimidazolone and hemoglobin A(1c) (r = 0.04, P =.57). In addition, patients with proliferative retinopathy and a relatively short known duration of diabetes, that is, less than the median of 14 years, had increased serum levels of hydroimidazolone (median, 6.91 U/mL; interquartile range, 4.70-8.91 U/mL) compared with those with nonproliferative retinopathy (median, 4.34; interquartile range, 3.86-5.53U/mL, P =.015). Serum levels of hydroimidazolone are increased in type 2 diabetic patients with retinopathy. This association is independent of hitherto known associated factors, such as hemoglobin A(1c).
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| 8. |
- Fosmark, Dag S., et al.
(författare)
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Increased retinopathy occurrence in type 1 diabetes patients with increased serum levels of the advanced glycation endproduct hydroimidazolone
- 2009
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 87:5, s. 498-500
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We aimed to investigate associations between serum levels of the advanced glycation endproduct methylglyoxal-derived hydroimidazolone (MG-H1) and retinopathy in a sample of patients with type 1 diabetes. Methods: We conducted a cross-sectional study in a Scandinavian ophthalmology outpatient clinic on 61 randomly selected patients with type 1 diabetes. Blood samples and retinal photographs were taken at the same visit. Serum levels of hydroimidazolone immunoreactivity were determined using an immunoassay, and levels of retinopathy were determined from seven standard field stereo photographs of each eye according to the ETDRS method. Results were compared between patients with and without retinopathy. Results: Hydroimidazolone quartiles were significantly associated with retinopathy (p = 0.013). The most profound increase in occurrence of retinopathy was observed from the lowest to the second-lowest hydroimidazolone quartile. Adjusted for duration of diabetes using logistic regression, a significant difference in the presence of retinopathy was found when comparing the lowest quartile with the rest (p = 0.022). Conclusions: In our patients with type 1 diabetes, serum levels of hydroimidazolone were found to be associated with retinopathy. This is in keeping with findings in a larger sample of patients with type 2 diabetes.
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| 9. |
- Gustavsson, Carl Gunnar, et al.
(författare)
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Inflammatory activity increases with haemoglobin A(1)c in patients with acute coronary syndrome.
- 2009
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Ingår i: Scandinavian cardiovascular journal : SCJ. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 43:6, s. 380-385
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To study the relationship between inflammation, diabetes and HbA(1)c levels in patients with acute coronary syndrome (ACS). Design. Single-centre cross-sectional study comprising 688 consecutive patients with ACS (108 with diabetes) and 341 with stable coronary artery disease (SCAD) (51 with diabetes). High-sensitive C-reactive protein (hsCRP), albumin and fibrinogen concentrations, erythrocyte sedimentation rates (ESR) and leukocyte counts were measured. Results. hsCRP, fibrinogen and ESR levels were higher and albumin lower in ACS patients. ESR was higher, albumin lower and hsCRP borderline significantly higher (p=0.053) in ACS patient with diabetes compared to those without. All inflammatory markers were associated with HbA(1)c in all 688 ACS patients as well as in 540 non-diabetic ACS patients with normal HbA(1)c. In multivariate analyses, all inflammatory markers were independently associated with HbA(1)c in the entire ACS group, regardless of diabetes being present or not. When non-diabetic ACS patients were analyzed separately, only ESR and leukocyte counts were independently correlated with HbA(1)c. Conclusions. Patients with ACS had increased inflammatory activity, which increased with HbA(1)c levels in patients who neither had a history of diabetes nor HbA(1)c above normal, and was further exaggerated in the presence of diabetes.
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| 10. |
- Gustavsson, Carin, et al.
(författare)
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Inflammatory markers in nondiabetic and diabetic rat retinas exposed to ischemia followed by reperfusion.
- 2008
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Ingår i: Retina. - 0275-004X. ; 28:4, s. 645-652
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:: To examine the retinal inflammatory response to ischemia-reperfusion in nondiabetic and diabetic rats injected with either an omega-3-polyunsaturated fatty acid (docosahexaenoic acid [DHA]) or a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (pravastatin). METHODS:: Diabetes was induced by an intraperitoneal injection of streptozocin, and retinal ischemia was induced by ligation of the optic nerve and vessels, followed by reperfusion for 1 hour or 24 hours. Five minutes before surgery, an intravenous injection of DHA, pravastatin, or vehicle (ethanol) was administered. The mRNA expressions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, caspase-1, IL-1beta, P-selectin, vascular cellular adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1 were compared between ischemic and nonischemic retinas as well as diabetic and nondiabetic nonischemic retinas. RESULTS:: Ischemia induced increased expressions of TNF-alpha (P
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