| 1. |
- Ahlin, Sofie, 1985, et al.
(author)
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No Evidence for a Role of Adipose Tissue-Derived Serum Amyloid A in the Development of Insulin Resistance or Obesity-Related Inflammation in hSAA1(+/)- Transgenic Mice
- 2013
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
-
Journal article (peer-reviewed)abstract
- Obesity is associated with a low-grade inflammation including moderately increased serum levels of the acute phase protein serum amyloid A (SAA). In obesity, SAA is mainly produced from adipose tissue and serum levels of SAA are associated with insulin resistance. SAA has been described as a chemoattractant for inflammatory cells and adipose tissue from obese individuals contains increased numbers of macrophages. However, whether adipose tissue-derived SAA can have a direct impact on macrophage infiltration in adipose tissue or the development of insulin resistance is unknown. The aim of this study was to investigate the effects of adipose tissue-derived SAA1 on the development of insulin resistance and obesity-related inflammation. We have previously established a transgenic mouse model expressing human SAA1 in the adipose tissue. For this report, hSAA1(+/-) transgenic mice and wild type mice were fed with a high fat diet or normal chow. Effects of hSAA1 on glucose metabolism were assessed using an oral glucose tolerance test. Real-time PCR was used to measure the mRNA levels of macrophage markers and genes related to insulin sensitivity in adipose tissue. Cytokines during inflammation were analyzed using a Proinflammatory 7-plex Assay. We found similar insulin and glucose levels in hSAA1 mice and wt controls during an oral glucose tolerance test and no decrease in mRNA levels of genes related to insulin sensitivity in adipose tissue in neither male nor female hSAA1 animals. Furthermore, serum levels of proinflammatory cytokines and mRNA levels of macrophage markers in adipose tissue were not increased in hSAA1 mice. Hence, in this model we find no evidence that adipose tissue-derived hSAA1 influences the development of insulin resistance or obesity-related inflammation.
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| 2. |
- Olsson, Maja, 1975, et al.
(author)
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Establishment of a transgenic mouse model specifically expressing human serum amyloid a in adipose tissue.
- 2011
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5
-
Journal article (peer-reviewed)abstract
- Obesity and obesity co-morbidities are associated with a low grade inflammation and elevated serum levels of acute phase proteins, including serum amyloid A (SAA). In the non-acute phase in humans, adipocytes are major producers of SAA but the function of adipocyte-derived SAA is unknown. To clarify the role of adipocyte-derived SAA, a transgenic mouse model expressing human SAA1 (hSAA) in adipocytes was established. hSAA expression was analysed using real-time PCR analysis. Male animals were challenged with a high fat (HF) diet. Plasma samples were subjected to fast protein liquid chromatography (FPLC) separation. hSAA, cholesterol and triglyceride content were measured in plasma and in FPLC fractions. Real-time PCR analysis confirmed an adipose tissue-specific hSAA gene expression. Moreover, the hSAA gene expression was not influenced by HF diet. However, hSAA plasma levels in HF fed animals (37.7±4.0 µg/mL, n=7) were increased compared to those in normal chow fed animals (4.8±0.5 µg/mL, n=10; p<0.001), and plasma levels in the two groups were in the same ranges as in obese and lean human subjects, respectively. In FPLC separated plasma samples, the concentration of hSAA peaked in high-density lipoprotein (HDL) containing fractions. In addition, cholesterol distribution over the different lipoprotein subfractions as assessed by FPLC analysis was similar within the two experimental groups. The established transgenic mouse model demonstrates that adipose tissue produced hSAA enters the circulation, resulting in elevated plasma levels of hSAA. This new model will enable further studies of metabolic effects of adipose tissue-derived SAA.
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| 3. |
- Saiki, Atsuhito, et al.
(author)
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Tenomodulin is highly expressed in adipose tissue, increased in obesity, and down-regulated during diet-induced weight loss.
- 2009
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:10, s. 3987-94
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Journal article (peer-reviewed)abstract
- CONTEXT: Tenomodulin (TNMD), a putative angiogenesis inhibitor, is expressed in hypovascular connective tissues. Global gene expression scans show that the TNMD gene also is expressed in human adipose tissue and that its expression is regulated in response to weight reduction; however, more detailed information is lacking. OBJECTIVE: The aim of this study was to investigate TNMD tissue distribution and TNMD gene expression in human adipose tissue in relation to obesity and metabolic disease. DESIGN, PATIENTS, AND INTERVENTIONS: TNMD gene expression, tissue distribution, and TNMD gene expression in adipose tissue from different depots, from lean and obese subjects, and during diet-induced weight reduction were analyzed by DNA microarray and real-time PCR. MAIN OUTCOME MEASURE: We primarily measured TNMD gene expression. RESULTS: The TNMD gene was predominantly expressed in sc adipose tissue. TNMD gene expression was higher in sc than omental adipose tissue both in lean (P = 0.002) and obese subjects (P = 0.014). In both women and men, TNMD gene expression was significantly higher in the obese subjects compared to the lean subjects (P = 1.1 x 10(-26) and P = 0.010, respectively). In a multiple linear regression analysis, BMI was a significant independent predictor of TNMD gene expression. TNMD gene expression was down-regulated during diet-induced weight loss, with a 65% decrease after 18 wk of diet (P < 0.0001). CONCLUSIONS: We conclude that human adipose tissue TNMD gene expression is highly affected by obesity, adipose tissue location, and weight loss, indicating that TNMD may play a role in adipose tissue function.
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| 4. |
- Ahlin, Sofie, 1985, et al.
(author)
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Macrophage Gene Expression in Adipose Tissue is Associated with Insulin Sensitivity and Serum Lipid Levels Independent of Obesity.
- 2013
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In: Obesity (Silver Spring, Md.). - : Wiley. - 1930-739X .- 1930-7381. ; 21:12
-
Journal article (peer-reviewed)abstract
- Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.
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| 5. |
- Franck, Niclas, et al.
(author)
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Identification of adipocyte genes regulated by caloric intake
- 2011
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In: Journal of Clinical Endocrinology and Metabolism. - : Endocrine society. - 0021-972X .- 1945-7197. ; 96:2, s. E413-E418
-
Journal article (peer-reviewed)abstract
- CONTEXT: Changes in energy intake have marked and rapid effects on metabolic functions and some of the effects may be due to changes in adipose tissue gene expression that precede alterations in body weight. OBJECTIVE: To identify genes in adipose tissue regulated by changes in caloric intake independent of changes in body weight. RESEARCH DESIGN AND METHODS: Obese subjects were given a very-low calorie diet (VLCD; 450 kcal/day) for 16 weeks. After the diet, ordinary food was gradually reintroduced during 2 weeks while there were minimal changes in body weight. Adipose tissue gene expression was measured by microarray analysis. First, genes regulated during caloric restriction and in the opposite direction during the weight stable re-feeding phase were identified. To verify opposite regulation to that observed during caloric restriction, identified genes were further analyzed using adipocyte expression profiles from healthy subjects before and after overfeeding. Results were confirmed using real time PCR or immunoassay. RESULTS: Using a significance level of p<0.05 for all comparisons, 52 genes were downregulated and 50 were up-regulated by caloric restriction and regulated in the opposite direction by re-feeding and overfeeding. Among these were genes that affect lipogenesis (ACLY, ACACA, FASN, SCD), protein synthesis (4EBP1, 4EBP2), beta-oxidation (CPT1B), liberation of fatty acids (CIDEA) and glyceroneogenesis (PCK2). Interestingly, several of these are under control of the master regulator mTOR. CONCLUSIONS: The observed transcriptional changes indicate that mTOR plays a central role in the control of diet-regulated adipocyte genes involved in lipogenesis and protein synthesis.
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| 6. |
- Hjalmarsson, Clara, 1969, et al.
(author)
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Neuronal and glia-related biomarkers in cerebrospinal fluid of patients with acute ischemic stroke
- 2014
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In: Journal of Central Nervous System Disease. - 1179-5735. ; 19:6, s. 51-8
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Cerebral ischemia promotes morphological reactions of the neurons, astrocytes, oligodendrocytes, and microglia in experimental studies. Our aim was to examine the profile of CSF (cerebrospinal fluid) biomarkers and their relation to stroke severity and degree of white matter lesions (WML). METHODS: A total of 20 patients (mean age 76 years) were included within 5-10 days after acute ischemic stroke (AIS) onset. Stroke severity was assessed using NIHSS (National Institute of Health stroke scale). The age-related white matter changes (ARWMC) scale was used to evaluate the extent of WML on CT-scans. The concentrations of specific CSF biomarkers were analyzed. RESULTS: Patients with AIS had significantly higher levels of NFL (neurofilament, light), T-tau, myelin basic protein (MBP), YKL-40, and glial fibrillary acidic protein (GFAP) compared with controls; T-Tau, MBP, GFAP, and YKL-40 correlated with clinical stroke severity, whereas NFL correlated with severity of WML (tested by Mann-Whitney test). CONCLUSIONS: Several CSF biomarkers increase in AIS, and they correlate to clinical stroke severity. However, only NFL was found to be a marker of degree of WML.
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| 7. |
- Hägg, Daniel, 1974, et al.
(author)
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Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
- 2008
-
In: International journal of molecular medicine. - 1107-3756. ; 21:6, s. 697-704
-
Journal article (peer-reviewed)abstract
- Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
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| 8. |
- Jernås, Margareta, 1961, et al.
(author)
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MS risk genes are transcriptionally regulated in CSF leukocytes at relapse
- 2013
-
In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:4, s. 403-410
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Infiltrating T-helper cells, cytotoxic T-cells, B-cells and monocytes are thought to mediate the damage to myelin, oligodendrocytes and axons in multiple sclerosis (MS), which results in progressive disability. OBJECTIVE: The objective of this paper is to explore gene expression profiles of leukocytes in the cerebrospinal fluid (CSF) compartment of MS patients during relapse. METHODS: Global gene expression was analyzed by DNA microarray analysis of cells in CSF from MS patients and controls, and verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Fifty percent of the recently described risk genes for MS and 28% of non-risk genes were differently expressed in MS patients compared to controls (χ(2)-test, p=7.7 × 10(-5)). Genes involved in T- and NK-cell processes were up-regulated, and genes involved in processes targeting innate immunity or B-cells were down-regulated in MS. Increased expression of EDN1 and CXCL11 and decreased expression of HMOX1 was verified with real-time PCR and increased expression of CXCL13 was verified with ELISA in CSF. CONCLUSION: DNA microarray analysis is useful in identifying differently expressed genes in CSF leukocytes, which may be important in MS in vivo. Our findings suggest that many of the risk genes for MS are differently expressed in the disease-mediating leukocytes that penetrate the blood-brain barrier.
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| 9. |
- Malmeström, Clas, 1965, et al.
(author)
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Serum levels of LIGHT in MS
- 2013
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:7, s. 871-876
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Recently, a polymorphism in the LIGHT gene was shown to increase the risk of multiple sclerosis (MS) in a genome-wide association study (GWAS). OBJECTIVE: Our aim was to investigate if serum levels of LIGHT were affected by this polymorphism and by the disease itself. METHODS: Serum levels of LIGHT were investigated in four cohorts; 1) MS (n = 159) and controls (n = 160) in relation to rs1077667 genotype; 2) MS at relapse (n = 30) vs. healthy controls (n = 26); 3) MS (n = 27) vs. other neurological disease (OND, n = 33); and 4) MS patients before and after one year of treatment with natalizumab (n = 30). RESULTS: Carriers of the GG genotype had the lowest serum levels of LIGHT (p=0.02). Serum levels of LIGHT were increased in MS at relapse in two separate cohorts: vs. healthy controls (p=0.00005) and vs. remission (p=0.00006), other neurological disease (OND) (p=0.002) and OND with signs of inflammation (iOND; p=0.00005). Furthermore, serum levels of LIGHT were decreased by natalizumab treatment (p=0.001). CONCLUSION: Soluble LIGHT is an inhibitor of T-cell activation and GG carriers of rs1077667, with the highest risk for MS, had the lowest serum levels. The increased levels of LIGHT at times of increased MS activity suggest that soluble LIGHT is protective and may act to limit inflammation.
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| 10. |
- Olofsson, Louise, 1977, et al.
(author)
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CCAAT/enhancer binding protein alpha (C/EBPalpha) in adipose tissue regulates genes in lipid and glucose metabolism and a genetic variation in C/EBPalpha is associated with serum levels of triglycerides.
- 2008
-
In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 93:12, s. 4880-6
-
Journal article (peer-reviewed)abstract
- CONTEXT: CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor involved in adipogenesis and hepatic glucose and lipid metabolism. OBJECTIVE: The aim of the study was to test the hypothesis that adipose tissue C/EBPalpha regulates genes in lipid and glucose metabolism and to test for an association between a polymorphism in C/EBPalpha and metabolic parameters. DESIGN AND METHODS: Adipose tissue C/EBPalpha mRNA expression was analyzed at four time points in obese subjects with (n = 12) and without (n = 12) the metabolic syndrome during caloric restriction (450 kcal/d for 16 wk) using DNA microarray and real-time PCR. Adenoviral overexpression of C/EBPalpha was used to identify genes regulated by C/EBPalpha in 3T3-L1 cells. Association between a genetic variation in C/EBPalpha (rs12691) and metabolic parameters was tested in the Swedish Obese Subjects (SOS) study (n = 528) and replicated in Finnish individuals from the Botnia type 2 diabetes study (n = 4,866). RESULTS: During caloric restriction, adipose tissue C/EBPalpha mRNA levels were reduced in subjects with the metabolic syndrome (P = 0.024) and correlated to metabolic parameters. In 3T3-L1 cells, C/EBPalpha regulated the expression of adiponectin; hexokinase 2; lipoprotein lipase; diacylglycerol O-acyltransferase 1 and 2; ATP-binding cassette, sub-family D, member 2; acyl-coenzyme A synthetase long-chain family member 1; CD36; and hydroxysteroid 11-beta dehydrogenase 1. Furthermore, the expression of the human homologs, except adiponectin, correlated to C/EBPalpha mRNA levels in human adipose tissue. The AA genotype of rs12691 was associated with higher serum triglyceride levels in the SOS study (P = 0.022), and this association was replicated in the Botnia study (P = 0.041). CONCLUSIONS: Adipose tissue C/EBPalpha regulates several genes in glucose and lipid metabolism, and a genetic variation in C/EBPalpha is associated with triglycerides in two independent populations.
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| 11. |
- Olsson, Bob, 1969, et al.
(author)
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CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.
- 2016
-
In: The Lancet. Neurology. - 1474-4465. ; 15:7, s. 673-684
-
Journal article (peer-reviewed)abstract
- Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aβ42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease.
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| 12. |
- Olsson, Maja, 1975, et al.
(author)
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Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue and SELS genotype are associated with metabolic risk factors.
- 2011
-
In: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 60:1, s. 114-20
-
Journal article (peer-reviewed)abstract
- The selenoprotein S (SELS) is a putative receptor for serum amyloid A, and recent studies have suggested that SELS may be a link between type 2 diabetes mellitus and inflammation. Genetic studies of SELS polymorphisms have revealed associations with circulating levels of inflammatory markers and hard end points of cardiovascular disease. In this study, we analyzed SELS expression in subcutaneous adipose tissue and SELS genotype in relation to metabolic risk factors. DNA microarray expression analysis was used to study the expression of SELS in lean and obese siblings from the Swedish Obese Subjects Sib Pair Study. TaqMan genotyping was used to analyze 3 polymorphisms, previously found to be associated with circulating levels of inflammatory markers, in the INTERGENE case-control study of myocardial infarction and unstable angina pectoris. Possible associations between SELS genotype and/or expression with anthropometry and measures of metabolic status were investigated. Real-time polymerase chain reaction was used to analyze the SELS expression in isolated human adipocytes incubated with insulin. In lean subjects, we found correlations between SELS gene expression in subcutaneous adipose tissue and measures of obesity (waist, P = .045; sagittal diameter, P = .031) and blood pressure (diastolic, P = .016; systolic P = .015); and in obese subjects, we found correlations with measures of obesity (body mass index, P = .03; sagittal diameter, P = .008) and glycemic control (homeostasis model assessment of insulin resistance, P = .011; insulin, P = .009) after adjusting for age and sex. The 5227GG genotype was associated with serum levels of insulin (P = .006) and homeostasis model assessment of insulin resistance (P = .007). The expression of SELS increased after insulin stimulation in isolated human adipocytes (P = .008). In this study, we found an association between both SELS gene expression in adipose tissue and SELS genotype with measures of glycemic control. In vitro studies demonstrated that the SELS gene is regulated by insulin in human subcutaneous adipocytes. This study further supports a role for SELS in the development of metabolic disease, especially in the context of insulin resistance.
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| 13. |
- Palsdottir, Vilborg, 1979, et al.
(author)
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Postnatal deficiency of essential fatty acids in mice results in resistance to diet-induced obesity and low plasma insulin during adulthood
- 2011
-
In: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 1532-2823 .- 0952-3278. ; 84:3-4, s. 85-92
-
Journal article (peer-reviewed)abstract
- Our objective was to investigate the long-term metabolic effects of postnatal essential fatty acid deficiency (EFAD). Mouse dams were fed an EFAD diet or an isoenergetic control diet 4 days before delivery and throughout lactation. The pups were weaned to standard diet (STD) and were later subdivided into two groups: receiving high fat diet (HFD) or STD. Body composition, energy expenditure, food intake and leptin levels were analyzed in adult offspring. Blood glucose and plasma insulin concentrations were measured before and during a glucose tolerance test. EFAD offspring fed STD were leaner with lower plasma leptin and insulin concentrations compared to controls. EFAD offspring fed HFD were resistant to diet-induced obesity, had higher energy expenditure and lower levels of plasma leptin and insulin compared to controls. These results indicate that the fatty acid composition during lactation is important for body composition and glucose tolerance in the adult offspring.
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| 14. |
- Palsdottir, Vilborg, 1979, et al.
(author)
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Prenatal essential fatty acid deficiency in mice results in long-term gender-specific effects on body weight and glucose metabolism
- 2011
-
In: Molecular Medicine Reports. - : Spandidos Publications. - 1791-2997 .- 1791-3004. ; 4:4, s. 731-737
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Journal article (peer-reviewed)abstract
- Essential fatty acids are important for normal growth and development in early life. However, the long-term effects of prenatal essential fatty acid deficiency (EFAD) on the adult metabolism remain to be determined. The aim of this study was to investigate the effects of an EFAD diet given to mice during late gestation on body weight and body composition, and metabolism in the adult offspring. Pregnant dams were given an EFAD or a control diet during the last 10 days of gestation. After delivery, all mice were fed normal chow and the body weight of the offspring was measured weekly. Furthermore, food intake, energy expenditure and intraperitoneal glucose tolera-nce were analysed in the adult offspring in addition to body composition (analysed by dual-energy X-ray absorptiometry), plasma levels of leptin, triglycerides and cholesterol. The body weight was lower in the EFAD offspring as compared to the controls during the first 4 weeks of age, and remained lower in the females throughout the study. Lean body mass and plasma leptin levels were also lower in the female EFAD offspring as compared to the controls. Male EFAD offspring were found to have higher fasting glucose and insulin levels as well as higher insulin levels during the glucose tolerance test compared to the controls. However, no differences were found in blood lipids, food intake or energy expenditure between EFAD and control mice of either gender. These results demonstrate that an EFAD diet given during the last 10 days of gestation results in long-term gender-specific effects on body weight and insulin sensitivity in the adult offspring.
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| 15. |
- Bjarnason, Ragnar, 1959, et al.
(author)
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Cartilage oligomeric matrix protein increases in serum after the start of growth hormone treatment in prepubertal children
- 2004
-
In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 89:10, s. 5156-60
-
Journal article (peer-reviewed)abstract
- Both GH and IGF-I stimulate bone growth, but the molecular mechanisms mediating their effects on the growth plate are not fully understood. We measured gene expression by microarray analysis in primary cultured human chondrocytes treated with either GH or IGF-I. One of the genes found to be up-regulated by both GH and IGF-I was that encoding cartilage oligomeric matrix protein (COMP). This protein is predominantly found in the extracellular matrix of cartilage. Mutations in the COMP gene have been associated with syndromes of short stature. To verify that COMP is regulated by GH in vivo, we measured COMP levels in serum in short children treated with GH. The study included 113 short prepubertal children (14 girls and 99 boys) with a mean (+/- sd) age of 8.84 +/- 2.76 yr, height sd score of -2.74 +/- 0.67, and IGF-I sd score of -1.21 +/- 1.07 at the start of GH administration. Serum levels of COMP were 1.58 +/- 0.28, 1.83 +/- 0.28 (P < 0.0001), 1.91 +/- 0.28 (P < 0.0001), 1.78 +/- 0.28 (P < 0.001), and 1.70 +/- 0.24 (P < 0.05) microg/ml at baseline and after 1 wk and 1, 3, and 12 months, respectively.In conclusion, we have demonstrated that COMP expression is up-regulated by both GH and IGF-I in primary cultured human chondrocytes. Furthermore, serum levels of COMP increase after the start of GH treatment in short children.
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| 16. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(author)
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Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms
- 2001
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In: Endocrinology. ; 142:10, s. 4560-4567
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Journal article (peer-reviewed)abstract
- Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH.
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| 17. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(author)
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Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
- 2005
-
In: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
-
Journal article (peer-reviewed)abstract
- It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
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| 18. |
- Bäckström, David C, et al.
(author)
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Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease
- 2015
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In: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 72:10, s. 1175-1182
-
Journal article (peer-reviewed)abstract
- IMPORTANCE: Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies. OBJECTIVE: To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders. DESIGN, SETTING, AND PARTICIPANTS: Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by amovement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison. MAIN OUTCOMES AND MEASURES: Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria. RESULTS: Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders. CONCLUSIONS AND RELEVANCE: The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.
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| 19. |
- Carlsson, Björn, 1958, et al.
(author)
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Differences in associations between HSD11B1 gene expression and metabolic parameters in subjects with and without impaired glucose homeostasis
- 2010
-
In: Diabetes Research and Clinical Practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 88:3, s. 252-258
-
Journal article (peer-reviewed)abstract
- Aims: Animal studies indicate a role for 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) in the development of obesity. The association to glucose homeostasis is less clear. We investigated the relationship between HSD11B1 mRNA levels in adipose tissue and in skeletal muscle and anthropometric and metabolic measurements in humans with and without impaired glucose homeostasis. Methods: Twelve obese subjects with impaired glucose homeostasis (MetS+) and 12 obese controls (MetS-) received a Very Low Calorie Diet for 16 weeks and adipose tissue biopsies, blood samples and measurements were obtained. In a second cohort, skeletal muscle biopsies, blood samples and measurements were obtained from 18 subjects with type 2 diabetes (T2DM) and 17 subjects with normal glucose tolerance (NGT). Gene expression was measured by DNA microarray in both studies. Results: HSD11B1 mRNA levels were reduced during diet, and anthropometric measurements and metabolic parameters were associated with HSD11B1 mRNA levels in the MetS-group. However, in the MetS+ group these associations were lost or in opposite direction. This difference was also observed in skeletal muscle between T2DM and NGT. Conclusions: HSD11B1 mRNA levels are associated with metabolic parameters and anthropometric measurements in subjects with normal glucose homeostasis but not in subjects with impaired glucose homeostasis. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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| 20. |
- Clark, Stephen J, et al.
(author)
-
Association of Sirtuin 1 (SIRT1) Gene SNPs and Transcript Expression Levels With Severe Obesity.
- 2012
-
In: Obesity. - : Wiley. - 1930-7381. ; 20:1, s. 178-85
-
Journal article (peer-reviewed)abstract
- Recent studies have reported associations of sirtuin 1 (SIRT1) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case-control analyses were performed using 1,533 obese subjects (896 adults, BMI >40kg/m(2) and 637 children, BMI >97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians. Two SNPs (in high linkage disequilibrium (LD), r(2) = 0.96) were significantly associated with adult obesity, rs33957861 (P value = 0.003, odds ratio (OR) = 0.75, confidence interval (CI) = 0.61-0.92) and rs11599176 (P value: 0.006, OR = 0.74, CI = 0.61-0.90). Expression of SIRT1 mRNA was measured in BMI-discordant siblings from 154 Swedish families. Transcript expression was significantly correlated to BMI in the lean siblings (r(2) = 0.13, P value = 3.36 × 10(-7)) and lower SIRT1 expression was associated with obesity (P value = 1.56 × 10(-35)). There was also an association between four SNPs (rs11599176, rs12413112, rs33957861, and rs35689145) and BMI (P values: 4 × 10(-4), 6 × 10(-4), 4 × 10(-4), and 2 × 10(-3)) with the rare allele associated with a lower BMI. However, no SNP was associated with SIRT1 transcript expression level. In summary, both SNPs and SIRT1 gene expression are associated with severe obesity.
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| 21. |
- Constantinescu, Radu, 1966, et al.
(author)
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Cerebrospinal fluid biomarkers in patients with neurological symptoms but without neurological diseases
- 2019
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In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404.
-
Journal article (peer-reviewed)abstract
- Background: Elevated levels of the cerebrospinal fluid (CSF) neuronal injury markers (neurofilament light chain [NF-L] and total tau protein [t-tau]) and of the astroglial marker glial fibrillary acidic protein (GFAP) are found in etiologically different neurological disorders affecting the peripheral and the central nervous system. Aims: To explore the role of CSF biomarkers in the clinical management of patients admitted for alarming neurological symptoms, but in whom neurological disorders could be excluded. Methods: Study participants were patients seeking medical attention for neurological symptoms primarily considered to be caused by a neurological diagnosis and investigated according to clinical routine. Demographic, clinical, and CSF data were extracted retrospectively from medical records. Patients with a final neurological diagnosis were excluded. Results: Out of 990 patients, 900 with a neurological diagnosis were excluded leaving 90 patients without a final neurological diagnosis. Sixty-eight (75.6%) were females. Median (range) age at lumbar puncture was 34.7 (16.9-65.1)years. Age-adjusted CSF-NF-L, CSF-t-tau, and CSF-GFAP concentrations were normal in 89 (98.9%), 86 (95.6%), and 87 (96.7%) patients, respectively. Conclusion: In patients with significant neurological symptoms but in whom a neurological diagnosis could not be made, the CSF markers NF-L, t-tau, and GFAP did not indicate signs of neuronal or astroglial cell damage close to symptom onset. Consequently, increased levels of CSF markers are not expected in this patient group and, if present, should raise suspicion of underlying neurological disorders and motivate further investigations. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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| 22. |
- Cullen, Nicholas C., et al.
(author)
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Comparing progression biomarkers in clinical trials of early Alzheimer's disease
- 2020
-
In: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 7:9, s. 1661-1673
-
Journal article (peer-reviewed)abstract
- Objective: To investigate the statistical power of plasma, imaging, and cognition biomarkers as Alzheimer's disease (AD) clinical trial outcome measures. Methods: Plasma neurofilament light, structural magnetic resonance imaging, and cognition were measured longitudinally in the Alzheimer's Disease Neuroimaging Initiative (ADNI) in control (amyloid PET or CSF A beta 42 negative [A beta-] with Clinical Dementia Rating scale [CDR] = 0; n = 330), preclinical AD (A beta + with CDR = 0; n = 218) and mild AD (A beta + with CDR = 0.5-1; n = 697) individuals. A statistical power analysis was performed across biomarkers and groups based on longitudinal mixed effects modeling and using several different clinical trial designs. Results: For a 30-month trial of preclinical AD, both the temporal composite and hippocampal volumes were superior to plasma neurofilament light and cognition. For an 18-month trial of mild AD, hippocampal volume was superior to all other biomarkers. Plasma neurofilament light became more effective with increased trial duration or sampling frequency. Imaging biomarkers were characterized by high slope and low within-subject variability, while plasma neurofilament light and cognition were characterized by higher within-subject variability. Interpretation: MRI measures had properties that made them preferable to cognition and pNFL as outcome measures in clinical trials of early AD, regardless of cognitive status. However, pNfL and cognition can still be effective depending on inclusion criteria, sampling frequency, and response to therapy. Future trials will help to understand how sensitive pNfL and MRI are to detect downstream effects on neurodegeneration of drugs targeting amyloid and tau pathology in AD.
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| 23. |
- Eldh, Maria, 1980, et al.
(author)
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Exosomes Communicate Protective Messages during Oxidative Stress; Possible Role of Exosomal Shuttle RNA.
- 2010
-
In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:12
-
Journal article (peer-reviewed)abstract
- Exosomes are small extracellular nanovesicles of endocytic origin that mediate different signals between cells, by surface interactions and by shuttling functional RNA from one cell to another. Exosomes are released by many cells including mast cells, dendritic cells, macrophages, epithelial cells and tumour cells. Exosomes differ compared to their donor cells, not only in size, but also in their RNA, protein and lipid composition.
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| 24. |
- Grund, Sofia, et al.
(author)
-
CD69 is a good surrogate marker for IgVH gene mutation status in Swedish chronic lymphocytic leukemia (CLL) patients.
- 2010
-
In: Acta Haematologica Polonica. - 0001-5814. ; 41:1, s. 53-61
-
Journal article (peer-reviewed)abstract
- Chronic lymphocytic leukemia (CLL) patients with unmutated IgVH genes have poorer survival than patients with mutated IgVH genes. However, mutation analysis is not always available in the routine laboratory and therefore surrogate markers are needed. CD69 has in two previous studies been shown to be a marker for mutation status. Our aim was therefore to investigate if CD69 expression was a better marker for mutation status than ZAP-70 and CD38 in a sample of patients from the west of Sweden. We analyzed the expression of CD69 in CD19+ B cells from CLL patients and controls using flow cytometry. CD69 was higher expressed in B cells from CLL patients compared with controls (35±31% and 2.6±1.8% CD19+/CD69+ cells respectively, P=0.0010). Patients with unmutated IgVH genes had a higher percentage of CD19+/CD69+ cells compared with patients with mutated IgVH genes (70±24% vs. 18±12%, P=0.00076). Furthermore, there was a strong concordance, even better than for CD38 and ZAP-70, between expression of CD69 and IgVH mutation status (96%, P<0.0001). Thus, our data in combination with those from others indicate that CD69 may be an excellent surrogate marker for IgVH mutation status and ultimately survival. Furthermore, this analysis is well suited for routine analysis.
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| 25. |
- Grund, Sofia, et al.
(author)
-
The autocrine motility factor receptor is overexpressed on the surface of B cells in Binet C chronic lymphocytic leukemia.
- 2011
-
In: Medical Oncology. - : Springer Science and Business Media LLC. - 1559-131X .- 1357-0560. ; 28:4, s. 1542-8
-
Journal article (peer-reviewed)abstract
- Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a clinical spectrum reaching from discrete lymphocytosis to extensive enlargement of lymph nodes, spleen and liver, and bone marrow failure. The aim of this study was to identify genes that differentiate between patients with disease stage A vs. C according to Binet in order to better understand the disease. To achieve this, we performed DNA microarray analysis on B cells from CLL patients with stage A and C according to Binet and matched controls. Between CLL patients and controls, there were 1,528 differentially expressed genes and 360 genes were differentially expressed between Binet A and C patients. Due to the sheer number of regulated genes, we focused on the autocrine motility factor receptor (AMFR). AMFR has not previously been investigated in hematological disorders, but high expression of AMFR correlates with a more advanced stage and invasive potential in several human tumors. AMFR mRNA expression was higher in Binet A compared with Binet C patients (P=0.0053) and healthy controls (P=0.0051). Total AMFR protein was higher in Binet A patients compared to Binet C as analyzed by intracellular flow cytometry. However, AMFR exist both in the ER involved in protein degradation and on the cell surface involved in metastasis and cell motility. Cell surface AMFR was increased in Binet C compared with Binet A+B (P=0.016). In conclusion, the mRNA levels reflect the total amount of AMFR, whereas cell surface expression is associated with progression in CLL.
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| 26. |
- Jakobsson, Joel, et al.
(author)
-
Monocyte and microglial activation in patients with mood-stabilized bipolar disorder.
- 2015
-
In: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 40:2
-
Journal article (peer-reviewed)abstract
- Bipolar disorder is associated with medical comorbidities that have been linked to systemic inflammatory mechanisms. There is, however, limited evidence supporting a role of neuroinflammation in bipolar disorder. Here we tested whether microglial activation and associated tissue remodelling processes are related to bipolar disorder by analyzing markers in cerebrospinal fluid (CSF) and serum from patients and healthy controls.
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| 27. |
- Jernås, Margareta, 1961, et al.
(author)
-
Altered cytokine levels in pediatric ITP.
- 2015
-
In: Platelets. - : Informa UK Limited. - 1369-1635 .- 0953-7104. ; 26:6, s. 589-592
-
Journal article (peer-reviewed)abstract
- Immune thrombocytopenia (ITP) is an autoimmune disease where platelets are destroyed prematurely. In the majority of children, the disease resolves, but in some, it becomes chronic. Cytokines are important mediators of the immune response and are known to be dysregulated in autoimmune diseases. Therefore, our aim was to investigate differences in plasma levels of cytokines between children with ITP and healthy controls. We had two cohorts of children: one Swedish with 18 children with ITP and seven healthy children and a second Chinese one with 58 children with ITP and 30 healthy children. Plasma levels of chemokine (C-X3-C motif) ligand 1 (CX3CL1), transforming growth factor β1 (TGF-β1), and interleukin 22 (IL-22) were analyzed in both cohorts using enzyme-linked immunosorbent assays (ELISAs). We found lower plasma levels of TGF-β1 and elevated levels of CX3CL1 and IL-22 in children with ITP compared with controls in both the Swedish and the Chinese cohort. In conclusion, all three cytokines differ between pediatric ITP and healthy controls and may, therefore, be potential biomarkers for the disease.
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| 28. |
- Jernås, Margareta, 1961, et al.
(author)
-
Changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins in patients with critical illness.
- 2009
-
In: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 58:1, s. 102-8
-
Journal article (peer-reviewed)abstract
- Insulin resistance develops rapidly during critical illness. The release of adipokines from adipose tissue is thought to play a key role in the development of insulin resistance, as are elevated levels of acute-phase proteins. The aim of this study was to identify changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins during critical illness. From 8 patients with subarachnoidal hemorrhage, consecutive blood samples and adipose tissue biopsies were obtained at 3 time points, twice during intensive care (1-2 days [IC1] and 7-9 days after subarachnoidal hemorrhage) and once after 8 months (recovery). The patients received a continuous insulin infusion to maintain normal glucose levels reflecting insulin resistance. The DNA microarray analysis showed increased zink-alpha2 glycoprotein (ZAG) and phospholipase A2, group IIA messenger RNA levels during intensive care compared with recovery (P < .05). Real-time polymerase chain reaction confirmed the increased expression of ZAG and phospholipase A2, group IIA. Plasma levels of ZAG, serum amyloid A, and C-reactive protein were higher at 7 to 9 days after subarachnoidal hemorrhage compared with either IC1 or recovery (P = .0001); and plasma levels of retinol-binding protein 4 and adiponectin were lower at IC1 compared with recovery (P = .05). The described changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins may influence the development of insulin resistance during critical illness.
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| 29. |
- Jernås, Margareta, 1961, et al.
(author)
-
Differences in gene expression and cytokine levels between newly diagnosed and chronic pediatric ITP.
- 2013
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 122:10, s. 1789-92
-
Journal article (peer-reviewed)abstract
- Immune thrombocytopenia (ITP) is an autoimmune disease where platelets are destroyed prematurely. In the majority of children the disease resolves, but in some it becomes chronic. To investigate whether these 2 phases of the disease are molecularly similar or separate entities we performed DNA microarray analysis (GEO accession number: GSE46922) of T-cells from newly diagnosed children and children with chronic ITP. We found complete separation of the gene expression profiles between the 2 phases of the disease. Furthermore, the gene expression levels of several cytokines differed between the 2 phases of the disease. This was also reflected in plasma with increased levels of interleukin (IL)-16 and TNF-related weak inducer of apoptosis and lower levels of IL-4 in newly diagnosed compared with chronic ITP. Thus, our data indicate that chronic ITP in childhood is a separate disease entity, dissimilar in many aspects to the newly diagnosed phase.
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| 30. |
- Jernås, Margareta, 1961, et al.
(author)
-
Differential expression of T-cell genes in blood and bone marrow between ITP patients and controls : Running head: Regulated T-cells from bone marrow in ITP
- 2013
-
In: Thrombosis and Haemostasis. - 0340-6245. ; 109:1, s. 112-117
-
Journal article (peer-reviewed)abstract
- Primary immune thrombocytopenia (ITP) is an autoimmune disease characterised by premature platelet destruction in spleen, liver and bone marrow and a diminished production of platelets. T-cells are important in all forms of autoimmunity including ITP; however, very little is known about T-cells in organs where platelets are destroyed. Our aim was to investigate differences in gene expression in peripheral blood-derived T-cells and bone marrow-derived T-cells between ITP patients and controls. T-cells and subsequent RNA were isolated from blood and bone marrow from chronic ITP patients and healthy controls followed by DNA microarray analysis. There were 1554 differentially expressed genes in peripheral blood-derived T-cells and 976 in bone marrow-derived T-cells between ITP patients and controls and three genes were verified with real-time PCR. Using Gene Ontology functional enrichment analysis we found that genes involved in growth, development, migration, chemotaxis, adhesion and apoptosis were enriched in bone marrow-derived T-cells in ITP. Immune-related genes involved in T-helper cell differentiation, T-cell chemotaxis, migration, immunoglobulin-mediated immune response and classical and alternative pathway complement activation were also enriched in bone marrow-derived T-cells in ITP. Only 213 T-cell genes were differentially expressed in both blood and bone marrow between ITP patients and controls. In conclusion, our findings show that genes involved in major pathophysiologic pathways in ITP such as T-helper cell differentiation, autoantibody response and complement activation are altered in bone marrow-derived T-cells in ITP patients compared with controls. This further supports the concept that bone marrow is an important compartment in ITP.
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| 31. |
- Jernås, Margareta, 1961, et al.
(author)
-
Differential expression of T-cell genes in blood and bone marrow between ITP patients and controls
- 2013
-
In: Thrombosis and Haemostasis. - 0340-6245. ; 109:1, s. 112-117
-
Journal article (peer-reviewed)abstract
- Primary immune thrombocytopenia (ITP) is an autoimmune disease characterised by premature platelet destruction in spleen, liver and bone marrow and a diminished production of platelets. T-cells are important in all forms of autoimmunity including ITP; however, very little is known about T-cells in organs where platelets are destroyed. Our aim was to investigate differences in gene expression in peripheral blood-derived T-cells and bone marrow-derived T-cells between ITP patients and controls. T-cells and subsequent RNA were isolated from blood and bone marrow from chronic ITP patients and healthy controls followed by DNA microarray analysis. There were 1554 differentially expressed genes in peripheral blood-derived T-cells and 976 in bone marrow-derived T-cells between ITP patients and controls and three genes were verified with real-time PCR. Using Gene Ontology functional enrichment analysis we found that genes involved in growth, development, migration, chemotaxis, adhesion and apoptosis were enriched in bone marrow-derived T-cells in ITP. Immune-related genes involved in T-helper cell differentiation, T-cell chemotaxis, migration, immunoglobulin-mediated immune response and classical and alternative pathway complement activation were also enriched in bone marrow-derived T-cells in ITP. Only 213 T-cell genes were differentially expressed in both blood and bone marrow between ITP patients and controls. In conclusion, our findings show that genes involved in major pathophysiologic pathways in ITP such as T-helper cell differentiation, autoantibody response and complement activation are altered in bone marrow-derived T-cells in ITP patients compared with controls. This further supports the concept that bone marrow is an important compartment in ITP.
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| 32. |
- Jernås, Margareta, 1961, et al.
(author)
-
MicroRNA regulate immune pathways in T-cells in multiple sclerosis (MS)
- 2013
-
In: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 14:32
-
Journal article (peer-reviewed)abstract
- Background: MicroRNA are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed genome-wide expression analyses of mRNA and microRNA in T-cells from MS patients and controls.Methods: Heparin-anticoagulated peripheral blood was collected from MS-patients and healthy controls followed by isolation of T-cells. MicroRNA and RNA from T-cells was prepared and hybridized to Affymetrix miR 2.0 array and Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA), respectively. Verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).Results: We identified 2,452 differentially expressed genes and 21 differentially expressed microRNA between MS patients and controls. By Kolmogorov-Smirnov test, 20 of 21 differentially expressed microRNA were shown to affect the expression of their target genes, many of which were involved in the immune system. Tumor necrosis factor ligand superfamily member 14 (TNFSF14) was a microRNA target gene significantly decreased in MS. The differential expression of mir-494, mir-197 and the predicted microRNA target gene TNFSF14 was verified by real-time PCR and ELISA.Conclusion: These findings indicate that microRNA may be important regulatory molecules in T-cells in MS.
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| 33. |
- Jernås, Margareta, 1961, et al.
(author)
-
MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP)
- 2013
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:11, s. 2095-2098
-
Journal article (peer-reviewed)abstract
- MicroRNA are small non-coding RNA molecules that regulate gene expression. To investigate the role of microRNA in ITP, we performed genome-wide expression analyses of mRNA and microRNA in T-cells from ITP patients and controls. We identified 1,915 regulated genes and 22 regulated microRNA that differed between ITP patients and controls. Seventeen of the 22 regulated microRNA were linked to changes in target gene expression; 57 of these target genes were associated with the immune system, e.g. T-cell activation and regulation of immunoglobulin production. CXCL13 and IL-21 were two microRNA target genes significantly increased in ITP. We could demonstrate increased plasma levels of CXCL13 and others have reported increased plasma levels of IL-21 in ITP. Thus, regulated microRNA were significantly associated with both gene and protein expression of molecules in immunological pathways. We suggest that microRNA may be important regulatory molecules involved in the loss of tolerance in ITP.
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| 34. |
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| 35. |
- Jernås, Margareta, 1961, et al.
(author)
-
Regulation of carboxylesterase 1 (CES1) in human adipose tissue.
- 2009
-
In: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 383:1, s. 63-7
-
Journal article (peer-reviewed)abstract
- Carboxylesterase 1 (CES1) has recently been suggested to play a role in lipolysis. Our aim was to study the regulation of CES1 expression in human adipose tissue. In the SOS Sib Pair Study, CES1 expression was higher in obese compared with lean sisters (n=78 pairs, P=8.7x10(-18)) and brothers (n=12 pairs, P=0.048). CES1 expression was higher in subcutaneous compared with omental adipose tissue in lean (P=0.027) and obese subjects (P=0.00036), and reduced during diet-induced weight loss (n=24, weeks 8, 16, and 18 compared to baseline, P<0.0001 for all time points). CES1 expression was higher in isolated adipocytes compared with intact adipose tissue (P=0.0018) and higher in large compared with small adipocytes (P=4.1x10(-6)). Basal and stimulated lipolysis was not different in individuals with high, intermediate, and low expression of CES1. Thus, CES1 expression was linked to body fat and adipocyte fat content but not to lipolytic activity.
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| 36. |
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| 37. |
- Jönsson, Sofia, et al.
(author)
-
BCR-ABL1 transcript levels increase in peripheral blood but not in granulocytes after physical exercise in patients with chronic myeloid leukemia.
- 2011
-
In: Scandinavian journal of clinical and laboratory investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71:1, s. 7-11
-
Journal article (peer-reviewed)abstract
- Abstract In chronic myeloid leukemia (CML) treatment response is determined by measurements of BCR-AB1L transcripts in peripheral blood by quantitative real-time PCR (qRT-PCR) and a 2-5 fold increase is considered a warning sign. The BCR-ABL1 gene is mainly expressed in myeloid cells whereas quantification of BCR-ABL1 is performed on the nucleated cell fraction of peripheral blood. Hence, leukocyte composition of the nucleated cell fraction may affect the result of BCR-ABL1 quantification. The aim of this study was to investigate if changes in leukocyte composition of peripheral blood had any effect on BCR-ABL1 transcript levels in CML patients. Six CML patients in complete cytogenetic remission (CCgR) performed a maximal physical exercise test. Blood samples were collected before exercise, at maximal exhaustion and after exercise. A biphasic increase in leukocyte count was observed and the relative proportion of granulocytes in peripheral blood changed significantly after exercise compared with baseline (p < 0.001). The BCR-ABL1 transcript level increased significantly following exercise, in nucleated cell fraction of peripheral blood (p < 0.05) but not in isolated granulocytes. In the nucleated cell fraction, the mean BCR-ABL1 transcript level was 3.3-fold (range 0.7-6.8) higher 180 min after exercise compared with baseline (p < 0.01). In conclusion, physical exercise induced significant increases in BCR-ABL1 transcript levels concomitant with changes in leukocyte content of peripheral blood. We therefore suggest that variations in leukocyte composition of peripheral blood, causing pre-analytic variations that affect BCR-ABL1 quantification, have to be accounted for. Consequently, small variations in BCR-ABL1 transcript levels should be interpreted cautiously in CML patients in CCgR.
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| 38. |
- Jönsson, Sofia, et al.
(author)
-
Imatinib inhibits proliferation of human mesenchymal stem cells and promotes early but not late osteoblast differentiation in vitro.
- 2012
-
In: Journal of bone and mineral metabolism. - 1435-5604. ; 30:1, s. 119-23
-
Journal article (peer-reviewed)abstract
- Altered bone metabolism has been reported in patients with chronic myeloid leukemia treated with the tyrosine kinase inhibitor imatinib. Several studies have shown that imatinib inhibits the differentiation and activity of osteoclasts in vitro, whereas the effects of imatinib on osteoblast differentiation are less clear. In this study osteoblast differentiation was induced in human mesenchymal stem cells (hMSCs) by treatment with bone morphogenetic protein 2 in vitro. Imatinib inhibited proliferation of hMSCs in a dose-dependent manner. Even though imatinib promoted early osteoblast differentiation assessed by alkaline phosphate activity, mineralization measured by Alizarin Red staining (ARS) was reduced by imatinib. Moreover, the inhibitory effect of imatinib on mineralization was most prominent at low concentrations of imatinib. When we measured the relative mRNA expression levels of Runx2, we found that Runx2 expression was higher in imatinib-treated (5μM) cultures at early time points during differentiation. On the other hand, the expression of Osterix late during differentiation was lower in imatinib-treated (5μM) cultures, corresponding to the ARS results. Thus, the effect of imatinib on osteoblast differentiation is not only dependent on the drug concentration, but indeed also on the maturation stage of the cells. This finding might partly explain why previous studies on the effects of imatinib osteoblast differentiation have shown different results.
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| 39. |
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| 40. |
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| 41. |
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| 42. |
- Jönsson, Sofia, et al.
(author)
-
Secondary hyperparathyroidism but stable bone-mineral density in patients with chronic myeloid leukemia treated with imatinib.
- 2012
-
In: American journal of hematology. - 1096-8652. ; 87:5, s. 550-2
-
Journal article (peer-reviewed)abstract
- Imatinib is currently the standard treatment for chronic myeloid leukemia(CML). Previous studies have shown that imatinib affects bone metabolism in CML patients. However, these effects are not well-studied prospectively. The authors studied bone-mineral density (BMD) and bone metabolism in 17 CML patients and matched controls in 2007 and now repeated the analyses prospectively in 2011. All CML patients were in complete cytogenetic remission during this 4-year period and treated with 400 mg imatinib q.d. (n 5 15) or 600 mg imatinib q.d. (n 5 2). Mean treatment duration was 102 months (range 69–129) in 2011. The authors found that serum levels of parathyroid hormone increased significantly in the patients between 2007 and 2011, and seven out of 17 patients had secondary hyperparathyroidism in 2011. However, the mean areal and volumetric BMDs were stable in the CML patients over the 4-year-observation period. Moreover, the CML patients had significantly higher volumetric BMD in the cortical compartment when compared with controls in 2011 and 2007. Thus, despite a high incidence of secondary hyperparathyroidism,there were no signs of osteoporosis or osteomalacia in imatinib-treated CML patients as suggested earlier.
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| 43. |
- Lautner, Ronald, et al.
(author)
-
Apolipoprotein e genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.
- 2014
-
In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 71:10, s. 1183-91
-
Journal article (peer-reviewed)abstract
- Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown.
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| 44. |
- Lautner, Ronald, et al.
(author)
-
Biomarkers for microglial activation in Alzheimer's disease.
- 2011
-
In: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2011
-
Journal article (peer-reviewed)abstract
- Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques.
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| 45. |
- Lautner, Ronald, et al.
(author)
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Preclinical effects of APOE epsilon 4 on cerebrospinal fluid A beta 42 concentrations
- 2017
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In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 9
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Journal article (peer-reviewed)abstract
- Background: From earlier studies it is known that the APOE epsilon 2/epsilon 3/epsilon 4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid(1-42) (A beta 42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF A beta 42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF A beta 42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of A beta 42 were lower in APOE epsilon 4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE epsilon 4 on CSF A beta 42 was age dependent. The age at which CSF A beta 42 concentrations started to decrease was estimated at 50 years in APOE epsilon 4-negative individuals and 43 years in heterozygous APOE epsilon 4 carriers. Homozygous APOE epsilon 4 carriers showed a steady decline in CSF A beta 42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE epsilon 4 allele start to show a decrease in CSF A beta 42 concentration almost a decade before APOE epsilon 4 noncarriers already in early middle age. Homozygous APOE epsilon 4 carriers might deposit A beta 42 throughout the examined age span. These results suggest that there is an APOE epsilon 4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
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| 46. |
- Malmeström, Clas, 1965, et al.
(author)
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CSF levels of YKL-40 are increased in MS and replaces with immunosuppressive treatment.
- 2014
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In: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 269:1-2, s. 87-9
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Journal article (peer-reviewed)abstract
- The role of glial cells during different phases of multiple sclerosis (MS) is unclear. To monitor glial activation we analyzed the biomarkers YKL-40 and sCD14 in cerebrospinal fluid (CSF) from MS patients during different disease phases and in response to immunosuppressive treatment. CSF levels of YKL-40 were increased in MS during relapse, remission and secondary progression compared with healthy controls. Furthermore, YKL-40 levels in CSF decreased by mitoxantrone and natalizumab treatment. No differences were observed in CSF levels of sCD14. Thus, we can infer that glial activation is present in all MS phases and decreases by immunosuppressive treatment.
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| 47. |
- Malmeström, Clas, 1965, et al.
(author)
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Relapses in multiple sclerosis are associated with increased CD8+ T-cell mediated cytotoxicity in CSF.
- 2008
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In: Journal of neuroimmunology. - : Elsevier BV. - 0165-5728. ; 196:1-2, s. 159-65
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Journal article (peer-reviewed)abstract
- MS is thought to be mediated by CD4(+) T-helper cells. To investigate the importance of CD8(+) cytotoxic T-cells in MS we analyzed peripheral blood T-cells by DNA microarray, and plasma and CSF levels of granzymes from MS patients and controls. Cytotoxic gene expression was decreased in peripheral T-cells from RRMS patients whereas plasma levels of granzymes were unchanged. However, granzyme levels were elevated in the CSF of RRMS patients at relapse compared with controls and remission. Thus, CD8+ T-cell-mediated cytotoxicity is confined to the CSF/CNS compartment in RRMS patients and may be involved in the immunopathogenesis of clinical relapses.
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| 48. |
- Mañé-Martínez, M. A., et al.
(author)
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Glial and neuronal markers in cerebrospinal fluid in different types of multiple sclerosis
- 2016
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In: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728. ; 299, s. 112-117
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Journal article (peer-reviewed)abstract
- In the present study, CSF concentrations of NFL, t-tau, p-tau, GFAP, S-100B, YKL-40, MCP-1, α-sAPP, β-sAPP, and Aβ38, Aβ40, Aβ42 were measured in 324 MS patients to test whether a correlation among the biomarkers exists and whether the profile of CSF biomarkers varies among the different types of MS. The CSF concentrations of NFL were significantly higher in RRMS while CSF concentrations of GFAP were higher in PPMS. CSF concentrations of NFL correlated with YKL-40 in CIS patients while CSF concentrations of GFAP correlated with YKL-40 in RRMS patients. © 2016 Elsevier B.V.
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| 49. |
- Martínez, M Alba Mañé, et al.
(author)
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Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis.
- 2015
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 21:5, s. 550-61
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Journal article (peer-reviewed)abstract
- To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS.
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| 50. |
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