| 1. |
- Ragnarsdottir, Bryndis, et al.
(författare)
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TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections.
- 2008
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38 Suppl 2, s. 12-20
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Forskningsöversikt (refereegranskat)abstract
- The susceptibility to urinary tract infection (UTI) is controlled by the innate immune response and Toll like receptors (TLRs) are the sentinels of this response. If productive, TLR4 signalling may initiate the symptomatic disease process. In the absence of TLR4 signalling the infected host instead develops an asymptomatic carrier state. The activation of mucosal TLR4 is also influenced by the properties of the infecting strain, and pathogens use their virulence factors to trigger 'pathogen-specific' TLR4 responses in the urinary tract but do not respond to the asymptomatic carrier strains in patients with asymptomatic bacteriuria (ABU). The TLR4 dependence has been demonstrated in mice and the relevance of low TLR4 function for protection for human disease was recently confirmed in children with asymptomatic bacteriuria, who expressed less TLR4 than age matched controls. Functional chemokines and functional chemokine receptors are crucial for neutrophil recruitment, and for the neutrophil dependent bacterial clearance. Interleukin (IL)-8 receptor deficient mice develop acute septic infections and chronic tissue damage, due to aberrant neutrophil function. This mechanism is relevant for human UTI as pyelonephritis prone children express low levels of the human CXCL8 (Il-8) receptor, CXC chemokine receptor 1 (CXCR1) and often have heterozygous CXCR1 polymorphisms. This review illustrates how intimately the innate response and the susceptibility to UTI are linked and sophisticated recognition mechanisms that rely on microbial virulence and on host TLR4 and CXCR1 signalling.
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| 2. |
- Belfrage, Per, et al.
(författare)
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Alterations of lipid metabolism in healthy volunteers during long-term ethanol intake
- 1977
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 7:2, s. 127-131
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Tidskriftsartikel (refereegranskat)abstract
- Nine young, healthy male volunteers were given ethanol (75 g/day) for 5 weeks. The ethanol was divided into five daily doses and taken so that blood ethanol levels never exceeded 0.04% (w/v). During the latter part of the ethanol intake period, there was a significant, transient increase of plasma triglyceride (TG) concentrations followed by reduction to normal levels. A three-fold increase of lipoprotein lipase activity (LLA) occurred in biopsy specimens of adipose tissue. An increase of alpha-lipoprotein concentrations, which correlated significantly with the decrease in plasma TG levels and the increase in adipose LLA, was also observed during the ethanol intake period. No changes were observed in plasma cholesterol and beta-lipoprotein levels. A transient, three-fold increase of TG concentrations occurred in liver biopsy specimens. Ultrastructural and cytochemical examinations of the biopsy specimens showed hyperplasia of the smooth endoplasmic reticulum, and increased canallicular activity of gamma-glutamyl transferase (gamma-GT) activity in most subjects towards the end of and after the ethanol intake period. Serum gamma-GT levels also increased significantly.
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| 3. |
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| 4. |
- Fredriksson, Jenny, et al.
(författare)
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Characterization of the human skeletal muscle glycogen synthase gene (GYS1) promoter.
- 2004
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 34:2, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- Background Impaired activation of the human skeletal muscle glycogen synthase by insulin is typical for type 2 diabetic patients. Regulation of glycogen synthase occurs mainly by phosphorylation/dephoshorylation but little is known whether there also is transcriptional regulation. Therefore we studied transcriptional regulation of the human skeletal muscle glycogen synthase gene (GYS1) and evaluated the effects of insulin and forskolin on the promoter activity. Methods Seven promoter fragments were expressed in C2C12 myoblasts and myotubes and in HEK293 cells, and the luciferase assay was used to determine transcriptional activity. Results The highest luciferase activity, 350-fold of the promoterless vector, was obtained with nucleotides -692 to +59 in myotubes (P < 0·001), while the nucleotides -250 to +59 provided the highest, 45-fold, activity in the HEK293 cells (P < 0·001). Longer promoter constructs (nucleotides -971, -1707 and -2158 to +59, respectively) had low promoter activity in both cell types. Forskolin treatment for 24 h resulted in approximately 30% decreased promoter activity in myotubes (P < 0·05). Insulin treatment for 0·5-3 h did not increase GYS1 promoter activity; instead the activity was slightly but significantly decreased after 24 h in myotubes (P < 0·005). Conclusions From our results we conclude that basal GYS1 promoter activity is obtained from the first 250 nucleotides of the promoter, while the nucleotides -692 to -544 seem to be responsible for muscle-specific expression, and nucleotides -971 to -692 for negative regulation. In myotubes, the GYS1 promoter was sensitive to negative regulation by forskolin, whereas insulin did not increase GYS1 transcription.
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| 5. |
- Haugaard, S B, et al.
(författare)
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Sex and muscle structural lipids in obese subjects - an impact on insulin action?
- 2008
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38:7, s. 494-501
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Tidskriftsartikel (refereegranskat)abstract
- Background Long-chain polyunsaturated fatty acid (LCPUFA) especially the n-3-FA of skeletal muscle phospholipids may facilitate insulin action, whereas saturated and trans-FA act oppositely. Community studies show that non-diabetic weight matched obese men and women display similar insulin resistance, despite the fact that an android fat distribution is detrimental to insulin action. The increased extramyocellular fat mass of obese women may act in a paracrine manner such that its release of free FA and cytokines may hamper in situ desaturation and elongation of FA in skeletal muscle phospholipids. Material and methods To test the hypothesis that obese women may display an inferior FA composition compared to obese men, the FA composition of skeletal muscle phospholipids was determined in vastus lateralis biopsies obtained from 12 non-diabetic obese women with a typical gynoid fat distribution, nine non-diabetic obese men with a typical android fat distribution and 12 (seven females) lean age matched healthy controls (body mass index 34.6 +/- 1.0 kg m(-2), 36.5 +/- 1.2 and 22.5 +/- 0.5; age 47 +/- 2 years, 51 +/- 3 and 49 +/- 2). Results Obese women displayed decreased LCPUFA n-3 and ratio of n-3/n-6 PUFA, whereas trans-FA and palmitic-FA (C16 : 0) were increased compared to obese men and controls (all Ps < 0.05). Plasma high-density lipoprotein cholesterol (HDL-C), triglycerides and a marker of insulin sensitivity were similar between obese women and men but impaired compared to controls (Ps < 0.05). Conclusions The data support the hypothesis that insulin resistant non-diabetic obese men display a more optimal skeletal muscle phospholipid FA composition than their female counterparts, which may be a mechanism to compensate the detrimental effect on insulin action of an android fat distribution.
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| 6. |
- Holmin, T, et al.
(författare)
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The influence of total hepatectomy on cerebral energy state, ammonia-related amino acids of the brain and plasma amino acids in the rat
- 1983
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 13:3, s. 215-220
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Tidskriftsartikel (refereegranskat)abstract
- The influence of total hepatectomy on cerebral energy state, ammonia-related amino acids of the brain tissue and plasma amino acids was studied in anaesthetized rats after total hepatectomy. The hepatectomy was performed with the aid of a microsurgical three-stage procedure. In the first stage, division of the inferior vena cava was performed. In the second stage 4 weeks later a porta-caval anastomosis was constructed, followed after 1 week by a total hepatectomy. The brain energy state, defined as the concentrations of phosphocreatine, ATP, ADP and AMP, was unchanged 4 h after the hepatectomy. Plasma amino acids did not differ significantly between hepatectomized and shunted control rats. On the other hand, clear-cut increases in the concentrations of glutamine, and decreases in the concentrations of glutamate and aspartate, were observed in the fronto-parietal part of the cerebral cortex and the brain stem. These changes might explain the minor manifestations of cerebral dysfunction in the early phase of the hepatectomized state.
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| 7. |
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| 8. |
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| 9. |
- Sandqvist, Madelene, 1974, et al.
(författare)
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Postprandial interstitial insulin concentrations in type 2 diabetes relatives
- 2006
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Ingår i: Eur J Clin Invest. - : Wiley. - 0014-2972 .- 1365-2362. ; 36:6, s. 383-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An endothelial barrier for the insulin transport from the circulation to the target tissues of insulin has previously been suggested to contribute to insulin resistance. The interstitial insulin concentration (I-insulin) and insulin kinetics following a mixed meal have, however, previously not been characterized in human adipose tissue. SUBJECTS AND METHODS: Eight nondiabetic first-degree relatives (FDR) of type 2 diabetes patients were recruited. Their I-insulin was measured by microdialysis after a test meal with or without oral administration of the insulin secretagogue nateglinide (120 mg). In parallel, adipose tissue blood flow and lipolysis were measured by xenon-clearance and microdialysis, respectively. RESULTS: The I-insulin increased after the test meal, and this response was more prominent on the day the subjects received the nateglinide tablet when compared with the day the subjects received the placebo tablet [I-insulin incremental area under the curve (IAUC) nateglinide 7612 +/- 3032 vs. Plac 4682 +/- 2613 pmol L(-1) min; P < 0.05, mean +/- SE]. However, the postprandial I-insulin(max)/P-insulin(max) ratio was similar on the two test days (nateglinide: 213 +/- 62 vs. 501 +/- 92 pmol L(-1), I/P-ratio: 0.38 +/- 0.06 and placebo: 159 +/- 39 vs. 410 +/- 74 pmol L(-1), I/P-ratio: 0.36 +/- 0.05). There was no difference in time of onset of insulin action in situ, or responsiveness, when comparing placebo and nateglinide. CONCLUSIONS: Microdialysis can now be used to measure the I-insulin in human adipose tissue following a mixed meal. The data also showed that the transendothelial delivery of insulin occurs rapidly, supporting the concept that transcapillary insulin transfer is a nonsaturable process in nondiabetic first-degree relatives of type 2 diabetes patients.
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| 10. |
- Sorbris, Ralph, et al.
(författare)
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Effects of weight reduction on plasma lipoproteins and adipose tissue metabolism in obese subjects
- 1981
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 11:6, s. 491-500
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Tidskriftsartikel (refereegranskat)abstract
- The relationship between obesity and alterations in adipose tissue metabolism and lipid transport was studied in fourteen obese subjects before and after a weight reduction of 4-22 kg. Blood glucose and plasma insulin patterns after peroral glucose intake improved significantly, and plasma glucagon levels decreased markedly after treatment. Plasma triglyceride and total cholesterol levels were not altered, but there was a 20% (P less than 0.05) increase in HDL concentrations. Plasma free fatty acid and glycerol concentrations decreased, in parallel to a decrease in lipolysis rate in vitro. Lipoprotein lipase and hepatic lipase activities in postheparin plasma, as well as the intravenous fat tolerance test, were normal and did not change significantly after weight loss. Lipoprotein lipase activity in adipose tissue, expressed per cell, was elevated and did not change after weight reduction. Also, the enzyme activity did not increase after glucose intake before or after treatment. The lack of effect on lipoprotein lipase activity and regulation in combination with significant improvements of other aspects of lipid and glucose transport is consistent with the view that alterations in LPL activity and regulation may represent an early and possibly primary defect in the development of obesity.
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