| 1. |
- Ragnarsdottir, Bryndis, et al.
(author)
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TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections.
- 2008
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38 Suppl 2, s. 12-20
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Research review (peer-reviewed)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.
(author)
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Alterations of lipid metabolism in healthy volunteers during long-term ethanol intake
- 1977
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 7:2, s. 127-131
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Journal article (peer-reviewed)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.
(author)
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Characterization of the human skeletal muscle glycogen synthase gene (GYS1) promoter.
- 2004
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 34:2, s. 113-121
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Journal article (peer-reviewed)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.
(author)
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Sex and muscle structural lipids in obese subjects - an impact on insulin action?
- 2008
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38:7, s. 494-501
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Journal article (peer-reviewed)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.
(author)
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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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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 13:3, s. 215-220
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Journal article (peer-reviewed)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.
(author)
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Postprandial interstitial insulin concentrations in type 2 diabetes relatives
- 2006
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In: Eur J Clin Invest. - : Wiley. - 0014-2972 .- 1365-2362. ; 36:6, s. 383-8
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Journal article (peer-reviewed)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.
(author)
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Effects of weight reduction on plasma lipoproteins and adipose tissue metabolism in obese subjects
- 1981
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 11:6, s. 491-500
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Journal article (peer-reviewed)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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| 11. |
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| 12. |
- Keramidas, Michail E., et al.
(author)
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Long-term intermittent hyperoxic exposures do not enhance erythropoiesis
- 2012
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In: European Journal of Clinical Investigation. - : Wiley-Blackwell. - 0014-2972 .- 1365-2362. ; 42:3, s. 260-265
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Journal article (peer-reviewed)abstract
- Eur J Clin Invest 2011 ABSTRACT: Background Based on a report of a marked increase in the erythropoietin concentration ([EPO]) a few hours after the cessation of a single 2-h session of O(2) breathing, short periods of O(2) administration have been advocated as a therapy for anaemia. Accordingly, the purpose of the present study was to evaluate this theory by investigating the effect of 10 daily short-term exposures to normobaric O(2) over a 2-week period on the plasma [EPO] in healthy individuals. Material and methods Twenty men were assigned to either an experimental (NBO(2) ) or to a control (AIR) group. The NBO(2) group breathed 100% normobaric O(2) for 2 h every weekday over a 2-week period. The AIR group breathed air within the same time protocol. Blood samples were collected at the pre-, mid- and post-intervention periods to determine [EPO]. Results [EPO] of the NBO(2) group was significantly lower than that of the AIR group during the mid- and post-periods (P < 0·001). [EPO] of the NBO(2) group showed a slight, albeit statistically nonsignificant, decrease during the mid (∼ 11%)- and post (∼ 16%)-periods. Conclusions Daily short-term exposures to normobaric hyperoxia do not increase the [EPO] in healthy individuals. The increased O(2) tension suppresses [EPO]. Hence, administration of pure O(2) to enhance erythropoiesis is not warranted.
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| 13. |
- Mischak, Harald, et al.
(author)
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Implementation of proteomic biomarkers : making it work
- 2012
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 42:9, s. 1027-1036
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Journal article (peer-reviewed)abstract
- While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Bovo, Roberto, et al.
(author)
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Hearing impairment in the Sturge-Weber syndrome
- 2009
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In: European Journal of Clinical Investigation. - Oxford, UK : Wiley-Blackwell Publishing Inc.. - 0014-2972 .- 1365-2362. ; 39:9, s. 837-838
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Journal article (peer-reviewed)
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| 21. |
- Carlstedt, F., et al.
(author)
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Serum levels of parathyroid hormone are related to the mortality and severity of illness in patients in the emergency department
- 1997
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 27:12, s. 977-981
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Journal article (peer-reviewed)abstract
- Hypocalcaemia is a common finding in intensive care patients. In addition, raised levels of parathyroid hormone (PTH) have been described. The explanation and clinical importance of these findings are yet to be revealed. To investigate the occurrence of hypocalcaemia and elevated PTH levels and their relationship to morality and the severity of disease, serum levels of PTH, ionized calcium (Ca2+) and the cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) were measured on arrival in the emergency department in a broad spectrum of 140 acutely ill patients patients suffering from common diseases such as stroke, acute abdominal disorders, obstructive lung diseases, heart failure, acute myocardial infarction, angina pectoris, trauma and infectious diseases. A score (APACHE II) was calculated to assess the severity of disease. Elevated PTH levels (> 55 pg ml-1) were seen in 16% of the patients, being most frequent in patients with myocardial infarction (28%) and congestive heart failure (42%). The levels were significantly correlated with the APACHE II score (r = 0.48, P < 0.0001) and with the length of stay in hospital (r = 0.26, P < 0.002). PTH was also significantly (P < 0.03) elevated in non-survivors compared with survivors and was found to be a stronger predictor of mortality (P < 0.01) than the APACHE II score (P < 0.02) in Cox's proportional hazard analysis. No close relationships were found between the cytokine levels and the indices of calcium metabolism. In conclusion, a rise in serum levels of PTH was common and related to the severity of disease and mortality in a mixed emergency department population.
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| 22. |
- Cunningham, Janet L., et al.
(author)
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The biological hallmarks of ileal carcinoids
- 2011
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 41:12, s. 1353-1360
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Research review (peer-reviewed)abstract
- Endocrine tumours derived from the small intestine, ileal carcinoids, produce and secrete the hormones tachykinins and serotonin, which induces the specific symptoms related to the tumour. Because of their low proliferation rate, they are often discovered at late stages when metastases have occurred. The biology that characterizes these tumours differs in many ways from what is generally recognized for other malignancies. In this overview, the current knowledge on the development and progression of ileal carcinoids is described.
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| 23. |
- Farrokhnia, Nasim, et al.
(author)
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Differential early mitogen-activated protein kinase activation in hyperglycemic ischemic brain injury in the rat
- 2005
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 35:7, s. 457-463
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Journal article (peer-reviewed)abstract
- BACKGROUND: Hyperglycemia aggravates brain injury induced by focal ischemia-reperfusion. The mitogen-activated protein kinase (MAPK) members extracellular-signal regulated kinase (Erk) and c-Jun N-terminal kinase (JNK) have been proposed as mediators of ischemic brain injury, and Erk is strongly activated by combined hyperglycemia and transient global ischemia. It is unclear whether similar MAPK activation appears in focal brain ischemia with concomitant hyperglycemia. DESIGN: Hyperglycemia was induced in rats by an intraperitoneal bolus of glucose (2 g kg(-1)). The rats were then subjected to 90 min of transient middle cerebral artery occlusion (MCAO). Erk and JNK activation were investigated with immunofluorescence and Western blot along with infarct size measurement based on tetrazolium staining and neurological score. RESULTS: The hyperglycemic rats showed increased tissue damage and impaired neurological performance after 1 day compared with controls. The hyperglycemia was generally moderate (< 15 mM). Erk activation was increased after 30 min of reperfusion in the ischemic cortex of the hyperglycemic rats, while JNK activation was present on the contralateral side. Phospho-Erk immunofluorescence revealed marked neuronal activation of Erk in the ischemic cortex of hyperglycemic rats compared with controls. CONCLUSION: Besides confirming the detrimental effects of hyperglycemia on focal ischemia-reperfusion, this study shows that hyperglycemia strongly activates the pathogenic mediator Erk in the ischemic brain in the early phase of reperfusion. JNK activation at this stage is present in the nonischemic hemisphere. The functional relevance of these findings needs further investigation.
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| 24. |
- Farrokhnia, Nasim, et al.
(author)
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MEK-inhibitor U0126 in hyperglycaemic focal ischaemic brain injury in the rat
- 2008
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38:9, s. 679-85
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Journal article (peer-reviewed)abstract
- BACKGROUND: Hyperglycaemia aggravates ischaemic brain injury, possibly due to activation of signalling pathways involving mitogen-activated protein kinases (MAPK). In this study, the activation of MAPK/ERK was inhibited using the upstream inhibitor of MAPK-ERK-kinase (MEK) U0126, and the effects on focal brain ischaemia were evaluated during normo- and hyperglycaemia. MATERIALS AND METHODS: Temporary (90 min) middle cerebral artery occlusion (MCAO) was induced in five groups of rats. U0126 (400 microg kg(-1)) or vehicle was given as 60-min intravenous infusions starting either 30 min prior to MCAO or 30 min prior to reperfusion. The infarct size was determined by perfusion with tetrazolium red after 24 h of survival, and the neurology was tested with the 4-level scale of Bederson and performance on an inclined plane. The inhibitory effect on the targeted MEK enzyme was investigated by analysing the phosphorylation of the downstream target ERK with western immunoblotting. Two subgroups were investigated with magnetic resonance imaging (MRI), including diffusion-weighted (DWI) and perfusion-weighted imaging (PWI). RESULTS: U0126 effectively reduced the infarct size and improved neurology in hyperglycaemic rats both when given before and after ischemic onset. This effect was not accompanied by any detectable changes in cerebral blood flow on MRI. Normoglycaemic rats had generally milder injuries compared with the hyperglycaemic and there was a nonsignificant trend for U0126 to reduce damage also in the nonhyperglycaemic groups. CONCLUSIONS: In conclusion, U0126 appears to be neuroprotective in this model of hyperglycaemic ischaemic brain injury. The findings support the pathogenic importance of the MEK-ERK pathway in hyperglycaemic-ischaemic brain injury.
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| 25. |
- García-Diz, Luis, et al.
(author)
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Assessing nutritional status of acute intermittent porphyria patients
- 2012
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In: European Journal of Clinical Investigation. - : Wiley-Blackwell. - 0014-2972 .- 1365-2362. ; 42:9, s. 943-952
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Journal article (peer-reviewed)abstract
- BACKGROUND: Acute intermittent porphyria (AIP) is a metabolic disease of haem synthesis, whose haem precursors may accumulate in the body. A well-balanced diet may prevent the symptoms, so that porphyric patients should be monitored closely during therapy for possible complications concerning any progression of acute porphyria. The aim was to evaluate the nutritional status of patients with AIP and to assess their compliance with nutritional recommendations, comparing the findings with a control group and assessing any possible nutritional deficiency.MATERIAL AND METHODS: Sixteen patients with AIP and a control group were evaluated by means of a lifestyle questionnaire, the Nutrition Screening Initiative checklist and a dietary questionnaire. The following diet quality indicators were calculated: animal and vegetal proteins, protein quality index, PUFA/SFA and MUFA + PUFA/SFA ratios, insoluble dietary fibre (DF)/total DF, soluble DF/total DF and insoluble DF/soluble DF ratios, thiamine, riboflavin and niacin density and the vitamin B6/protein ratio.STATISTICAL METHODS: Differences in continuous variables were compared using the unpaired Student's t-test and the chi-square test for nonparametric variables. The odds ratio (OR) of malnutrition was also used.RESULTS: Our patients showed a low intake of carbohydrates, a high lipid intake and very high protein intake, and accompanied by an inadequate intake of zinc, folic acid and tocopherol, increasing the risk of malnutrition for energy, Ca, Fe, Mg, K, folic acid and tocopherols.CONCLUSIONS: The patients with AIP studied individually show an increased risk of malnutrition and, given the potential increase of oxidative stress in patients with porphyria, it is recommended that they should increase their intake of carbohydrates, minerals and antioxidant nutrients.
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| 26. |
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| 27. |
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| 28. |
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| 29. |
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| 30. |
- He, T., et al.
(author)
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The role of colonic metabolism in lactose intolerance
- 2008
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38:8, s. 541-547
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Research review (peer-reviewed)abstract
- Lactose maldigestion and intolerance affect a large part of the world population. The underlying factors of lactose intolerance are not fully understood. In this review, the role of colonic metabolism is discussed, i.e. fermentation of lactose by the colonic microbiota, colonic processing of the fermentation metabolites and how these processes would play a role in the pathophysiology of lactose intolerance. We suggest that the balance between the removal and production rate of osmotic-active components (lactose, and intermediate metabolites, e.g. lactate, succinate, etc.) in the colon is a key factor in the development of symptoms. The involvement of the colon may provide the basis for designing new targeted strategies for dietary and clinical management of lactose intolerance.
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| 31. |
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Ingelsson, E, et al.
(author)
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Inflammatory markers in relation to insulin resistance and the metabolic syndrome
- 2008
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38:7, s. 502-509
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Journal article (peer-reviewed)abstract
- BACKGROUND: Inflammation has repeatedly been demonstrated to be associated with the metabolic syndrome (MetS) and insulin resistance, but the relative importance of different aspects of the inflammatory process is largely unexplored. DESIGN: We measured circulating interleukins (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10); other cytokines (tumour necrosis factor-alpha, interferon gamma and monocyte chemotactic protein-1), cell adhesion molecules [vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, E-selectin, P-selectin, l-selectin], and systemic inflammation markers [C-reactive protein (CRP) and leukocyte count] in 943 70 year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. We related these biomarkers to MetS and the homeostasis model assessment insulin resistance index (HOMA-IR). RESULTS: In a multivariable model including all inflammatory markers conjointly together with sex, log VCAM-1 [odds ratio (OR), 1.45; 95% confidence interval (CI), 1.22-1.72 per 1 SD increase; P < 0.0001], log E-selectin (OR, 1.33; 95% CI, 1.12-1.57 per 1SD increase; P = 0.001), and log CRP (OR, 1.41; 95% CI, 1.20-1.66 per 1-SD increase; P < 0.0001) were independently associated with MetS. These biomarkers were also independently associated with HOMA-IR. CONCLUSIONS: Among 17 inflammatory biomarkers, most of them previously not examined in relation to MetS and insulin resistance, VCAM-1, E-selectin and CRP demonstrated the strongest associations with MetS and insulin resistance in our community based sample of the elderly. The relative importance of these biomarkers in predicting the development of MetS, insulin resistance and cardiovascular disease needs to be further examined in a longitudinal setting.
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| 37. |
- Jansson, Per-Anders, 1961, et al.
(author)
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Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients--potential role of steroid hormones and leptin in the development of insulin resistance.
- 2002
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In: European journal of clinical investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 32:3, s. 172-8
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Journal article (peer-reviewed)abstract
- BACKGROUND: First-degree relatives of type 2 diabetes patients are at risk of developing diabetes and they display several metabolic and hormonal perturbations. The interplay between insulin resistance, steroid hormones and circulating leptin is, however, still not fully explored in this group. DESIGN: Thirty-three healthy first-degree relatives of type 2 diabetic patients (relatives; M/F 19/14) were compared to 33 healthy subjects without a family history of diabetes (controls) and the groups were matched for gender, age and body mass index (BMI). We performed euglycaemic hyperinsulinaemic clamps and blood was sampled for hormone analyses. RESULTS: Relatives exhibited decreased insulin sensitivity (index of metabolic clearance rate of glucose; MCRI) but when genders were analysed separately, this difference was significant only in males (11.3 +/- 1.3 vs. 15.0 +/- 1.5 units, means +/- SEM, P = 0.030). In male relatives morning cortisol and testosterone levels were lower, whereas leptin was higher than in male controls (P = 0.018, 0.008 and 0.063, respectively). In male relatives plasma testosterone levels were significantly associated with insulin sensitivity (r = 0.48, P = 0.040). Circulating leptin levels were inversely correlated with insulin sensitivity in all subject groups (r-values -0.49 to -0.66; P < 0.05, except in female control subjects P = 0.063). These associations were present also when age and BMI or waist:hip ratio were included in stepwise multiple regression analyses. CONCLUSION: Male subjects genetically predisposed for type 2 diabetes display several endocrine abnormalities including leptin, cortisol and testosterone levels. Dysregulation of these hormones may be important in the development of insulin resistance and type 2 diabetes.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
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| 42. |
- Lind, Lars, et al.
(author)
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Ageing impairs insulin-mediated vasodilatation but not forearm glucose uptake
- 2001
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 31:10, s. 860-864
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Journal article (peer-reviewed)abstract
- BACKGROUND: It is unclear if insulin-mediated vasodilatation is altered by ageing and if this affects insulin-mediated glucose uptake. MATERIAL AND METHODS: A 2-h euglycaemic hyperinsulinaemic clamp (56 mU m(-2) min(-1)) was performed in 10 healthy, nonobese elderly men (70-75 years) and 13 young men (23-28 years). Forearm blood flow (FBF) was measured by venous occlusion plethysmography and forearm glucose uptake was calculated by arterial and venous serum glucose determinations in the forearm. RESULTS: Insulin induced an increase in FBF in the younger men (from 3.9 +/- 1.1 SD to 5.9 +/- 2.2 mL min(-1) 100(-1)mL tissue, P < 0.001), but this insulin-mediated vasodilatation was completely blunted in the elderly subjects. Glucose extraction during the clamp was significantly higher in the elderly subjects (1.2 +/- 0.76 vs. 0.82 +/- 0.37 mmol L(-1) at 120 min, P < 0.01), resulting in a similar forearm glucose uptake in the two groups. On the other hand, whole-body glucose uptake was significantly decreased in the elderly subjects (5.3 +/- 1.8 vs. 8.0 +/- 1.1 mg kg(-1) min(-1), P < 0.001). CONCLUSION: The present study showed that the ability of insulin to induce vasodilatation is blunted in the forearm in healthy, nonobese elderly subjects. However, the elderly compensate for this impairment with an increased glucose extraction from arterial blood to maintain an unaltered forearm glucose uptake.
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| 43. |
- Lindell, Monica, et al.
(author)
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Variable Expression of CYP and Pgp Genes in the Human Small Intestine
- 2003
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 33:6, s. 493-499
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Journal article (peer-reviewed)abstract
- BACKGROUND: The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome p450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. METHODS: The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. RESULTS: Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. CONCLUSIONS: Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation.
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| 44. |
- Lindqvist, Ulla, et al.
(author)
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[11C]Hyaluronan uptake with positron emission tomography in liver disease
- 2000
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 30:7, s. 600-607
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Journal article (other academic/artistic)abstract
- BackgroundA hyaluronan-loading test has been developed for assessment of hyaluronan kinetics and applied in patients with liver and joint diseases. This test describes the metabolic process of hyaluronan but cannot define the specific contribution of different organs. A method for labelling of hyaluronan with the short-lived positron-emitting radionuclide 11C has been published and in this study applied in healthy subjects and liver diseases.Materials and methodsPositron emission tomography (PET) was used for the regional assessment and quantification of [11C]hyaluronan uptake in three healthy subjects, four patients with alcoholic liver cirrhosis, one with alcoholic hepatitis and one with liver steatosis. After intravenous administration of 60 MBq of 11C-labelled hyaluronan, a 55-min PET scan was performed over the liver and plasma radioactivity was analysed. Rate constants describing the transport of the [11C]hyaluronan tracer from plasma to the liver were calculated.ResultsHigh uptake was observed in the liver combined with a rapid elimination of tracer from plasma. The liver uptake rate (k1) was significantly lower in patients (0.018 min−1) than in healthy subjects (0.043 min−1, P = 0.002). The rate constants seem to be related to the severity of the disease as defined by the Child–Pugh score.ConclusionsThe study suggests that PET with [11C]hyaluronan could be an accurate method by which to assess liver dysfunction, in conditions where endothelial cell function is impaired. The possibility of quantification over extended portions of the body also opens up possibilities to explore regional differences in liver function and to assess other elimination routes of hyaluronan.
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| 45. |
- Lundberg, J. O. N., et al.
(author)
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Increased nitric oxide production in collagenous and lymphocytic colitis
- 1997
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 27:10, s. 869-871
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Journal article (peer-reviewed)abstract
- The production of nitric oxide (NO) is increased in active ulcerative colitis and in Crohn's disease. We have studied NO production in collagenous colitis (CC) and lymphocytic colitis (LC), both of which are inflammatory bowel disorders of unknown aetiology. NO levels were measured directly in gas sampled from the colon during colonoscopy. Plasma levels of NO metabolites (nitrate/nitrite) were also measured. Luminal NO levels were more than 100 times higher in patients with CC compared with controls. In addition, plasma levels of nitrate/nitrite were increased in the patients as compared with controls. Measurements of NO directly in the colon or its oxidation products in plasma may be a helpful tool in further understanding the role of NO in the pathophysiology of CC and LC. Moreover, it is tempting to speculate that these measurements could be clinically useful in the diagnosis and therapy monitoring of these two inflammatory bowel diseases.
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| 46. |
- Malinovschi, Andrei, et al.
(author)
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Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension
- 2011
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 41:8, s. 889-897
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Journal article (peer-reviewed)abstract
- Background Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysedexhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PHaetiology.Methods Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in22 patients with PH and 21 healthy controls. Alveolar NO (CalvNO) and bronchial flux (J’awNO) were calculatedusing the slope–intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH)and PH WHO Groups II–IV, according to the WHO clinical classification of PH.Results Exhaled NO was reduced at flow-rates in the range of 20)200 mL s)1 in patients with PAH (n = 13) vs.PH WHO Group II–IV (n = 9) (P < 0Æ05 all). Patients with PAH had higher CalvNO than healthy controls [2Æ61(2Æ23, 3Æ36) vs. 1.97 ppb (1Æ22, 2Æ49), P = 0Æ03] and similar to PH WHO Group II–IV (P = 0Æ51). Patients with PAHhad lower J’awNO than patients with PH WHO Group II–IV or healthy controls [430 (371, 702) vs. 807 (557, 993)or 731 pL s)1 (580, 818), P < 0Æ05 both]. Subjects with PAH were characterized by higher levels of salivary andplasma nitrite than healthy controls (P < 0Æ05 both).Conclusions Patients with PAH have lower bronchial NO flux compared to healthy controls and patients withPH WHO Group II–IV along with elevated salivary and plasma nitrite compared to controls. This implies reducedbronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects withPH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in thealveoli.
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| 47. |
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| 48. |
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| 49. |
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| 50. |
- Mattsson Hultén, Lillemor, 1951, et al.
(author)
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15-Lipoxygenase-2 is expressed in macrophages in human carotid plaques and regulated by hypoxia-inducible factor-1 alpha
- 2010
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In: European Journal of Clinical Investigation. - : Wiley. - 1365-2362 .- 0014-2972. ; 40:1, s. 11-17
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Journal article (peer-reviewed)abstract
- Background Macrophages are prominent in hypoxic areas of atherosclerotic lesions and their secreted cytokines, growth factors and activity of enzymes are involved in atherogenesis. Previously, we showed that 15-lipoxygenase (LOX)-2 is expressed in human monocyte-derived macrophages and that hypoxia increases 15-LOX-2 expression and secretion of pro-inflammatory molecules. Here we investigated whether human carotid plaque macrophages express 15-LOX-2 and whether its expression in macrophages is regulated by hypoxia through hypoxia-inducible factor 1α (HIF-1α). Materials and methods Carotid plaques from 47 patients with high-grade symptomatic carotid artery stenosis were analysed using immunohistochemistry, and stained areas were quantified by digital image analysis. Carotid plaque macrophages were isolated with anti-CD14 immunobeads using an immunomagnetic bead technique. Primary macrophages were transfected with HIF-1α siRNA or control siRNA before extraction of RNA and medium analysis. Results In paired tissue sections, the extent of staining for CD68 correlated with staining for 15-LOX-2 but not for 15-LOX-1. In carotid plaque macrophages isolated with anti-CD14 immunobeads, 15-LOX-2 mRNA was expressed at high levels. In primary macrophages, 15-LOX-2 expression was significantly increased by incubation with the HIF-1α stabilizer dimethyloxalylglycine. Knockdown of HIF-1α significantly decreased production of the 15-LOX-2 enzyme products 12- and 15-hydroxyeicosatetraenoic acid. In carotid plaques, HIF-1α staining correlated with staining for 15-LOX-2. Conclusions These results demonstrate that 15-LOX-2 is highly expressed in human plaques and is correlated with the presence of macrophages and HIF-1α. 15-LOX-2 enzyme activity can be modulated by HIF-1α. Thus, increased expression of 15-LOX-2 in macrophages in hypoxic atherosclerotic plaque may enhance inflammation and the recruitment of inflammatory cells.
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