| 1. |
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| 2. |
- Back, M, et al.
(författare)
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Leukotriene receptors in atherosclerosis
- 2006
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Ingår i: Annals of medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 38:7, s. 493-502
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Bykov, Igor, et al.
(författare)
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Complement C3 contributes to ethanol-induced liver steatosis in mice.
- 2006
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Ingår i: Annals of medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 38:4, s. 280-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It is becoming increasingly clear that liver steatosis, a typical early consequence of alcohol exposure, sensitizes the liver to more severe inflammatory and fibrotic changes. On the other hand, activation of the key complement component C3, a central player in causing inflammation and tissue damage, is also known to be involved in the regulation of lipid metabolism. This prompted us to study the development of alcoholic liver steatosis in mice lacking C3 (C3-/-). RESULTS: Both C3-/- and normal C3+/+ mice were fed a steatosis-promoting high-fat diet with or without ethanol for 6 weeks. The diet without ethanol caused moderate liver steatosis in C3-/- but not in C3+/+ mice. As expected, ethanol-containing diet caused marked macrovesicular steatosis and increased the liver triglyceride content in C3+/+ mice. In contrast, ethanol diet tended to reduce steatosis and had no further effect on liver triglycerides in C3-/- mice. Furthermore, while in normal mice ethanol significantly increased the liver/body weight ratio, liver malondialdehyde level and serum alanine aminotransferase (ALT) activity, these effects were absent or small in C3-/- mice. A separate experiment with mice on chow diet confirmed the aberrant steatotic effect of ethanol in C3-/-mice: 4 hours after acute dosing of ethanol the liver triglyceride level had increased by 138% in C3+/+ mice (P<0.001), but only by 64% in C3-/- mice (n.s.). CONCLUSION. In C3-/- mice alcohol-induced liver steatosis is absent or strongly reduced after chronic or acute alcohol exposure. This suggests that the complement system and its component C3 contribute to the development of alcohol-induced fatty liver and its consequences.
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| 4. |
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| 5. |
- Correia, Sofia, et al.
(författare)
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Stem cell-based therapy for Parkinson's disease.
- 2005
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 37:7, s. 487-498
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Forskningsöversikt (refereegranskat)abstract
- Motor dysfunctions in Parkinson's disease are considered to be primarily due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Pharmacological therapies based on the principle of dopamine replacement are extremely valuable, but suffer from two main drawbacks: troubling side effects (e.g. dyskinesia) and loss of efficacy with disease progression. Transplantation of embryonic dopaminergic neurons has emerged as a therapeutic alternative. Enthusiasm following the success of the initial open-label trials has been dampened by the negative outcome of double-blind placebo controlled trials. Additionally, the emergence of graft-related dyskinesia indicates that the experimental grafting procedure requires further refinement before it can be developed into a therapy. Shortage of embryonic donor tissue limits large-scale clinical transplantation trials. We review three of the most attractive tissue sources of dopaminergic neurons for cell replacement therapy: human embryonic ventral mesencephalic tissue, embryonic and adult multipotent region-specific stem cells and embryonic stem cells. Recent developments in embryonic stem cell research and on their implications for a future transplantation therapy in Parkinson's disease are described. Finally, we discuss how human embryonic stem cells can be differentiated into dopaminergic neurons, and issues such as the numbers of dopaminergic neurons required for success and the risk for teratoma formation after implantation.
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| 6. |
- Falk, A, et al.
(författare)
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New neurons in old brains
- 2005
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Ingår i: Annals of medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 37:7, s. 480-486
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Tidskriftsartikel (refereegranskat)
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| 7. |
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| 8. |
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| 9. |
- Holme, I., et al.
(författare)
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Lipoprotein predictors of cardiovascular events in statin-treated patients with coronary heart disease. Insights from the Incremental Decrease in End-points through Aggressive Lipid-lowering Trial (IDEAL)
- 2008
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 40:6, s. 456-464
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Tidskriftsartikel (refereegranskat)abstract
- Background. Few studies have looked into the ability of measurements of apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1) or apoB/apoA-1 to predict new coronary heart disease (CHD) events in patients with CHD on statin treatment. Aims. In the IDEAL trial, to compare lipoprotein components to predict CHD events and to what degree differences in those parameters could explain the observed outcome. Methods. We compared the ability of treatment with atorvastatin 80 mg/day to that of simvastatin 20-40 mg/day to prevent CHD events in patients with CHD and used Cox regression models to study the relationships between on-treatment levels of lipoprotein components to subsequent major coronary events (MCE). Findings. Variables related to low-density lipoprotein cholesterol (LDL-C) carried more predictive information than those related to high-density lipoprotein cholesterol (HDL-C), but LDL-C was less predictive than both non-HDL-C and apoB. The ratio of apoB to apoA-1 was most strongly related to MCE. However, for estimating differences in relative risk reduction between the treatment groups, apoB and non-HDL-C were the strongest predictors. Interpretation. The on-treatment level of apoB/apoA-1 was the strongest predictor of MCE in the pooled patient population, whereas apoB and non-HDL-C were best able to explain the difference in outcome between treatment groups. Measurements of apoB and apoA-1 should be more widely available for routine clinical assessments. © 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS).
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| 10. |
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| 11. |
- Huth, Cornelia, et al.
(författare)
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Joint analysis of individual participants' data from 17 studies on the association of the IL6 variant -174G>C with circulating glucose levels, interleukin-6 levels, and body mass index.
- 2009
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Ingår i: Annals of medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 41:2, s. 128-38
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several studies have investigated associations between the -174G>C single nucleotide polymorphism (rs1800795) of the IL6 gene and phenotypes related to type 2 diabetes mellitus (T2DM) but presented inconsistent results. AIMS: This joint analysis aimed to clarify whether IL6 -174G>C was associated with glucose and circulating interleukin-6 concentrations as well as body mass index (BMI). METHODS: Individual-level data from all studies of the IL6-T2DM consortium on Caucasian subjects with available BMI were collected. As study-specific estimates did not show heterogeneity (P>0.1), they were combined by using the inverse-variance fixed-effect model. RESULTS: The main analysis included 9440, 7398, 24,117, or 5659 non-diabetic and manifest T2DM subjects for fasting glucose, 2-hour glucose, BMI, or circulating interleukin-6 levels, respectively. IL6 -174 C-allele carriers had significantly lower fasting glucose (-0.091 mmol/L, P=0.014). There was no evidence for association between IL6 -174G>C and BMI or interleukin-6 levels, except in some subgroups. CONCLUSIONS: Our data suggest that C-allele carriers of the IL6 -174G>C polymorphism have lower fasting glucose levels on average, which substantiates previous findings of decreased T2DM risk of these subjects.
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| 12. |
- Liuba, Petru, et al.
(författare)
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Residual adverse changes in arterial endothelial function and LDL oxidation after a mild systemic inflammation induced by influenza vaccination
- 2007
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 39:5, s. 392-399
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Tidskriftsartikel (refereegranskat)abstract
- Background. Several clinical studies have suggested possible increase in cardiovascular risk during and in the first weeks after an acute inflammatory disease. Using influenza vaccine as inflammatory stimulus, we investigated whether arterial endothelial dysfunction could persist beyond the inflammatory state, and whether amplified oxidative modification of low-density lipoprotein (LDL) accompanies this vascular disturbance. Methods and subjects. The brachial artery responses to hyperemia (flow-mediated dilatation (FMD), and to sublingual glyceryl trinitrate (GTN), and the carotid intima-media thickness were assessed by external ultrasound in eight healthy male volunteers (age 17-30 y) before, and 2 and 14 days after intramuscular administration of influenza vaccine. Plasma levels of high-sensitivity C-reactive protein (CRP), fibrinogen, cyclic guanosine monophosphate (cGMP), and antibodies against oxidized LDL (oxLDL) were measured at each time point. Data are means +/- standard errors of the mean (SEM). Results. Influenza vaccination caused a slight elevation in CRP (from 0.5 +/- 0.1 at baseline, to 2 +/- 0.6 mg/L, P=0.01) and fibrinogen (from 2.3 +/- 0.1 to 2.7 +/- 0.1 g/L, P=0.01) at 2 days, which completely resolved at 14 days (CRP: 0.6 +/- 0.2 mg/L, P=0.9, and fibrinogen: 2.3 +/- 0.1 g/L, P=0.8 versus baseline). OxLDL antibody levels rose significantly at 2 days (from 1 +/- 0.1 at baseline to 2 +/- 0.4, P=0.04), and remained elevated at 14 days (1.7 +/- 0.3, P=0.1 versus baseline). FMD of the brachial artery decreased at 2 days (from 8.3 +/- 1.2% at baseline, to 5.4 +/- 1%, P=0.05) with a further decrease at 14 days (4.9 +/- 0.8%, P=0.03 versus baseline). The dilatory responses to GTN and the carotid IMT remained unchanged throughout the study period (P>0.5). Conclusion. Abnormalities in arterial function and LDL oxidation may persist for at least 2 weeks after a slight inflammatory reaction induced by influenza vaccination. These could explain in part the earlier reported increase in cardiovascular risk during the first weeks after an acute inflammatory disorder.
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| 13. |
- Möllsten, Anna, et al.
(författare)
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Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.
- 2006
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 38:7, s. 522-528
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- BACKGROUND AND AIMS: The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO-production can be affected by polymorphisms in the endothelial NO-synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients. PATIENTS AND METHODS: A total of 1510 Finnish and Swedish T1D patients were included in a cross-sectional case-control study. Incipient DN was defined as an albumin excretion rate (AER) of 20-200 microg/min (n = 336). Overt DN = AER>200 microg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration 20 years, AER<20 microg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27 bp repeat (NOS4ab) and Glu298Asp (rs1799983). RESULTS: Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu-allele of the Glu298Asp-polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12-1.91). The variables smoking (OR = 2.13; 95% CI = 1.63-2.78), male sex (OR = 1.61; 95% CI = 1.23-2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02-1.03), systolic (OR = 1.05; 95% CI = 1.04-1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02-1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a-allele was not associated with DN. CONCLUSIONS: The Glu/Glu-genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.
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| 14. |
- Nijm, Johnny, et al.
(författare)
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Inflammation and cortisol response in coronary artery disease
- 2009
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Ingår i: ANNALS OF MEDICINE. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 41:3, s. 224-233
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is characterized by chronic inflammation involving autoimmune components. The degree of inflammatory activity, as detectable both within the atherosclerotic plaque and in the circulation, is associated with plaque destabilization and atherothrombotic complications. Endogenous glucocorticoids are modulators of innate and acquired immune responses, and as such play a key role in the reciprocal interaction between neuroendocrine and immune systems. Abnormalities in hypothalamic-pituitary-adrenal axis (HPA) function have been described in several chronic inflammatory disorders, and evidence has emerged lately that HPA dysfunction may be implicated also in the pathogenesis of coronary artery disease. This review is an outline of knowledge gained so far by previous studies of glucocorticoids in coronary atherosclerosis and myocardial infarction. The results consistently point towards a dysregulated cortisol secretion that may involve a failure to contain inflammatory activity. A dysfunctional HPA axis and its possible implications for coronary artery disease progress, including the hypothetical link between stress and inflammation, are discussed.
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| 15. |
- Okroj, Marcin, et al.
(författare)
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Rheumatoid arthritis and the complement system
- 2007
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 39:7, s. 517-530
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Tidskriftsartikel (refereegranskat)abstract
- Complement activation contributes to a pathological process in a number of autoimmune and inflammatory diseases, including rheumatoid arthritis (RA). In this review we summarize current knowledge of complement contribution to RA, based on clinical observations in patients and in vivo animal models, as well as on experiments in vitro aiming at elucidation of underlying molecular mechanisms. There is strong evidence that both the classical and the alternative pathways of complement are pathologically activated during RA as well as in animal models for RA. The classical pathway can be initiated by several triggers present in the inflamed joint such as deposited autoantibodies, dying cells, and exposed cartilage proteins such as fibromodulin. B cells producing autoantibodies, which in turn form immune complexes, contribute to RA pathogenesis partly via activation of complement. It appears that anaphylatoxin C5a is the main product of complement activation responsible for tissue damage in RA although deposition of membrane attack complex as well as opsonization with fragments of C3b are also important. Success of complement inhibition in the experimental models described so far encourages novel therapeutic approaches to the treatment of human RA.
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| 16. |
- Olofsson, Sigvard, 1948, et al.
(författare)
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Glycoconjugate glycans as viral receptors.
- 2005
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Ingår i: Annals of medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 37:3, s. 154-72
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Tidskriftsartikel (refereegranskat)abstract
- The carbohydrate parts of cell surface glycoproteins, glycolipids, and proteoglycans constitute receptors for many enveloped as well as non-enveloped human viruses. The majority of viral receptors of carbohydrate nature are negatively charged, including sulfated glycosaminoglycans (GAGs) or glycans containing sialic acid. Not uncommonly, virus-carbohydrate interactions are responsible for specific tissue tropism, where the affinity of influenza virus for glycans in the respiratory tract containing (a2-6)-linked sialic acid is an important example. Similarly, the number and spacing of sulfates may guide viruses to optimal GAG molecules, although this remains unproven on tissue level. A further understanding of structure and tissue distribution of carbohydrate virus receptors and their viral ligands is essential for elucidating the pathogenesis of such viruses. Also neutral glycans such as histo-blood group substances may function as virus receptors. Here, natural resistance to a given viral disease may occur in a human subpopulation due to lack of such receptors caused by deletion-mutants in critical human genes. As regards antiviral applications, the receptor-destroying enzymes, in contrast to receptor binding proteins, at the surface of, for example, influenza virus have proven to be an excellent target for intervention, which is why sialic acid analogues are now in clinical use both for prophylaxis and treatment.
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| 17. |
- Olsson, Anders
(författare)
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Is high HDL cholesterol always good?
- 2009
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Ingår i: ANNALS OF MEDICINE. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 41:1, s. 11-18
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Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- Because of the obvious negative relation between high-density lipoprotein (HDL) cholesterol and cardiovascular disease and the substantial residual risk of this disease even during treatment with high-dose statin there has been an urgent need to investigate the possible therapeutic benefit of increasing HDL. Even if treatment with nicotinic acid with its marked HDL-increasing effect has been encouraging, there is no evidence so far that specific increase of HDL cholesterol results in less cardiovascular disease. Treatment with the cholesterol ester transfer protein (CETP) inhibitor and HDL-increasing drug torcetrapib resulted in increased risk of cardiovascular disease. These negative results were followed by a lively discussion regarding the possible benefit of HDL-increasing treatment in general and CETP inhibition in particular. Suggested possible causes for the negative outcome by torcetrapib treatment are off-target non-CETP-related effect of this particular inhibitor, inability of very high blood HDL cholesterol levels to protect, induction of dysfunctional HDL, and direct atherogenic effect of CETP inhibition. It is concluded that still today little is known about the effect of specific therapeutic elevation of HDL cholesterol, particularly so through CETP inhibition on cardiovascular risk. New interventional studies on this therapeutic principle are welcomed and under way.
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| 18. |
- Partonen, Timo, et al.
(författare)
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Three circadian clock genes Per2, Arnt1, and Npas2 contribute to winter depression
- 2007
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Ingår i: Annals of Medicine. - New York : Informa Healthcare. - 0785-3890 .- 1365-2060. ; 39:3, s. 229-238
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Tidskriftsartikel (refereegranskat)abstract
- Background. Multiple lines of evidence suggest that the circadian clock contributes to the pathogenesis of winter depression or seasonal affective disorder (SAD). We hypothesized that sequence variations in three genes, including Per2, Arntl, and Npas2, which form a functional unit at the core of the circadian clock, predispose to winter depression.Methods. In silico analysis of the biological effects of allelic differences suggested the target single-nucleotide polymorphisms (SNPs) to be analyzed in a sample of 189 patients and 189 matched controls. The most relevant SNP in each gene was identified for the interaction analysis and included in the multivariate assessment of the combined effects of all three SNPs on the disease risk.Results. SAD was associated with variations in each of the three genes in gene-wise logistic regression analysis. In combination analysis of variations of Per2, Arntl, and Npas2, we found additive effects and identified a genetic risk profile for the disorder. Carriers of the risk genotype combination had the odds ratio of 4.43 of developing SAD as compared with the remaining genotypes, and of 10.67 as compared with the most protective genotype combination.Conclusion. Variations in the three circadian clock genes Per2, Arntl, and Npas2 are associated with the disease, supporting the hypothesis that the circadian clock mechanisms contribute to winter depression.
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| 19. |
- Pesonen, Erkki, et al.
(författare)
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Mannose-binding lectin as a risk factor for acute coronary syndromes.
- 2009
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 41, s. 591-598
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Tidskriftsartikel (refereegranskat)abstract
- Background. Mannose-binding lectin (MBL) is a multifunctional protein involved in innate immunity. We tested whether MBL and elevated viral and bacterial antibodies were risk factors for acute coronary events. Design. Controlled cohort study. Methods. A total of 354 patients with unstable angina pectoris (UA) or acute myocardial infarction (AMI) were compared with 334 paired controls. Results. Enterovirus titres were associated with increased risk of UA (odds ratio 10.04, P<0.001) and AMI (odds ratio 3.18, P=0.003), but titres did not correlate with either MBL concentration or genotype. Chlamydia pneumoniae heat shock protein 60 IgG concentrations were also associated with increased risk of UA (odds ratio 1.63, P=0.049). Compared to asymptomatic controls, patients had lower complement C3 serum concentrations (P<0.001), higher MBL serum concentration, and more frequently had MBL genotypes that determined high MBL levels (P<0.001). High MBL genotypes had odds ratios of 1.16 (P=0.010) for UA and 1.12 (P=0.007) for AMI. The elevation of MBL concentrations in the acute phase correlated with MBL concentrations after recovery (r=0.85, P<0.001). Conclusions. Elevated microbial titres, indicating an on-going inflammation, were associated with cardiovascular events. MBL might have a dual role both decreasing susceptibility to infections and increasing the risk of acute coronary syndromes.
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| 20. |
- Pettersson, Jenny, et al.
(författare)
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Can misfolded proteins be beneficial? The HAMLET case.
- 2009
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 41, s. 162-176
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Forskningsöversikt (refereegranskat)abstract
- By changing the three-dimensional structure, a protein can attain new functions, distinct from those of the native protein. Amyloid-forming proteins are one example, in which conformational change may lead to fibril formation and, in many cases, neurodegenerative disease. We have proposed that partial unfolding provides a mechanism to generate new and useful functional variants from a given polypeptide chain. Here we present HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) as an example where partial unfolding and the incorporation of cofactor create a complex with new, beneficial properties. Native alpha-lactalbumin functions as a substrate specifier in lactose synthesis, but when partially unfolded the protein binds oleic acid and forms the tumoricidal HAMLET complex. When the properties of HAMLET were first described they were surprising, as protein folding intermediates and especially amyloid-forming protein intermediates had been regarded as toxic conformations, but since then structural studies have supported functional diversity arising from a change in fold. The properties of HAMLET suggest a mechanism of structure-function variation, which might help the limited number of human protein genes to generate sufficient structural diversity to meet the diverse functional demands of complex organisms.
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| 23. |
- Veijola, Lea, et al.
(författare)
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Detection of Helicobacter species in chronic liver disease and chronic inflammatory bowel disease
- 2007
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 39:7, s. 554-560
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Tidskriftsartikel (refereegranskat)abstract
- Aim. To study the association between helicobacters and chronic liver diseases and chronic inflammatory bowel diseases. Patients and methods. Thirty-two patients with various chronic liver diseases and 137 patients with inflammatory bowel disease were enrolled. Antibodies to H. pylori, H. hepaticus, H. bilis, and H. pullorum were measured by enzyme immunoassay (EIA), and sera positive in a non-pylori helicobacter EIA were further examined by immunoblot assay. Detection of Helicobacter DNA in liver biopsies was done by denaturating gradient gel electrophoresis of PCR products (PCR-DGGE) and DNA sequence analysis. Results. Six inflammatory bowel disease patients, four with ulcerative colitis and two with Crohn's disease, and one liver disease patient with autoimmune cholangitis had antibodies to non-pylori helicobacters by an immunoblot assay. Four immunoblot assay-negative patients, three with autoimmune and one with non-autoimmune liver disease, had Helicobacter DNA in liver biopsies; three of the polymerase chain reaction (PCR) products were closely related to non-pylori helicobacters. Conclusion. Evidence for non-pylori helicobacters was scant in Finnish patients with inflammatory bowel disease or chronic but not end stage liver disease. We cannot, however, rule out their role in these diseases.
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| 25. |
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