| 1. |
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| 2. |
- Ahlman, B., et al.
(författare)
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Short-term starvation alters the free amino acid content of human intestinal mucosa
- 1994
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Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 86:6, s. 653-662
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Tidskriftsartikel (refereegranskat)abstract
- 1. The effects of short-term starvation and refeeding on the free amino acid concentrations of the intestinal mucosa were characterized in male subjects (n=6), using endoscopically obtained biopsy specimens from the duodenum and from all four segments of the colon.2. The alterations in the amino acid concentrations in response to short-term starvation were overall uniform in both duodenal and colonic mucosa as well as in plasma. Most amino acids decreased, whereas branched-chain amino acids increased.3. In the colon, glutamic acid and glutamine decreased during the starvation period, whereas they remained unaltered in the duodenum. This was the major difference in response to short-term starvation between the amino acid concentrations in the intestinal mucosa of the duodenum and colon.4. Refeeding for 3 days normalized the amino acid concentrations except for glutamic acid, asparagine and histidine, which remained low in the colon, and threonine, which showed an overshoot in both parts of the intestine. S. The changes in mucosal amino acid concentrations seen in response to starvation and refeeding were uniform in the four segments of the colon. This suggests that sampling from the rectum/sigmoid colon will give representative values for the free amino acid concentrations of the entire large intestine.
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| 3. |
- Andersson, C, et al.
(författare)
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Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes
- 2002
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Ingår i: Clinical science (London, England : 1979). - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 103:4, s. 417-424
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Tidskriftsartikel (refereegranskat)abstract
- Cystic fibrosis is a heterogenic disease, in which the phenotype can also vary for patients with the same genotype. In the present study the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in nasal epithelial cells from 19 adult patients with cystic fibrosis was investigated. All patients had severe mutations, whereby no or little functional CFTR is expected in the plasma membrane. Of the patients, 15 were homozygous for ΔF508-CFTR (i.e. CTFR lacking residue Phe-508). The others were ΔF508-heterozygous with 3659delC, 394delTT or 2183AA→G. Nasal epithelial cells, obtained by nasal brushings, were loaded with the fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide to measure Cl- efflux. In most of the cystic fibrosis patients, forskolin plus isobutylmethylxanthine was unable to elicit any response. Unexpectedly, cells from three cystic fibrosis patients (two ΔF508/ΔF508 patients and one ΔF508/3659delC patient) responded to stimulation in a wild-type manner. It was investigated whether this residual chloride transport function was associated with a milder phenotype. Clinical parameters studied were lung function, number of antibiotic courses, Shwachman score, Bhalla score, age at chronic colonization with Pseudomonas aeruginosa and the pattern of essential fatty acids in serum phospholipids. Unknown factors may affect the presence of functional CFTR in patients with severe CFTR mutations. However, we could not find a correlation between the response to cAMP and any of the phenotype parameters. It appears that functional cAMP transport in the nasal epithelium is no guarantee of a mild phenotype and, conversely, that a patient lacking cAMP-dependent chloride transport can develop a mild phenotype.
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| 4. |
- Andersson, Irene, 1978, et al.
(författare)
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Endothelial dysfunction in growth hormone transgenic mice
- 2006
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 110:2, s. 217-25
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Tidskriftsartikel (refereegranskat)abstract
- Acromegaly [overproduction of GH (growth hormone)] is associated with cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH) develop hypertension and hypercholesterolaemia and could be a model for cardiovascular disease in acromegaly. The aims of the present study were to investigate the effects of excess GH on vascular function and to test whether oxidative stress affects endothelial function in bGH transgenic mice. We studied the ACh (acetylcholine)-induced relaxation response in aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female bGH transgenic mice and littermate control mice, without and with the addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase). Intracellular superoxide anion production in the vascular wall was estimated using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with 69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas endothelial function in aorta was intact in young but impaired in aged bGH transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries from young mice and in aortas from aged mice; however, MnTBAP did not correct endothelial dysfunction in carotid arteries from aged bGH transgenic mice. There was no difference in intracellular superoxide anion production between bGH transgenic mice and control mice, whereas mRNA expression of EC-SOD and eNOS was increased in aortas from young bGH transgenic mice compared with control mice (P < 0.05). We interpret these data to suggest that bGH overexpression is associated with a time- and vessel-specific deterioration in endothelial function, initially caused by increased oxidative stress and later by other alterations in vascular function.
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| 5. |
- Andersson, S E, et al.
(författare)
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Cutaneous vascular reactivity is reduced in aging and in heart failure: association with inflammation
- 2003
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Ingår i: Clinical Science. - 1470-8736. ; 105:6, s. 699-707
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we have investigated whether changes in vascular reactivity in congestive heart failure (CHF) patients can be detected in the cutaneous microvessels and whether these changes are due to endothelial dysfunction, are affected by increasing age and related to an ongoing inflammation. The responses to local warming and iontophoretically administered endothelium-dependent and -independent vasodilators were investigated in healthy young adults, healthy elderly adults and elderly adults with CHE The results were correlated with plasma concentrations of vascular risk factors and markers for endothelial dysfunction and inflammation. The vasorelaxant responses were reduced in the elderly groups and were attenuated further in the CHF group. This group also had increases in levels of several markers associated with inflammation, higher blood glucose and homocysteine levels, a lower low-density lipoprotein-cholesterol and a rise in the concentration of von Willebrand factor, indicating a prothrombotic endothelial function. The severity of the heart failure, measured as the plasma level of brain natriuretic peptide, correlated with the intensity of inflammation and to the changes in vascular risk factors and endothelial function. It is concluded that the reactivity of the cutaneous microvessels is reduced with age, and the presence of CHF causes a further impairment. There is endothelial dysfunction in CHF, but it is uncertain to what extent this contributes to the reduced vasodilatory capacity. The inflammatory response appears central for many of the manifestations of the CHF syndrome.
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| 6. |
- Annerén, Cecilia, 1972-
(författare)
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Tyrosine kinase signalling in embryonic stem cells
- 2008
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 115:1-2, s. 43-55
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Forskningsöversikt (refereegranskat)abstract
- Pluripotent ES (embryonic stem) cells can be expanded in culture and induced to differentiate into a wide range of cell types. Self-renewal of ES cells involves proliferation with concomitant suppression of differentiation. Some critical and conserved pathways regulating self-renewal in both human and mouse ES cells have been identified, but there is also evidence suggesting significant species differences. Cytoplasmic and receptor tyrosine kinases play important roles in proliferation, survival, self-renewal and differentiation in stem, progenitor and adult cells. The present review focuses on the role of tyrosine kinase signalling for maintenance of the undifferentiated state, proliferation, survival and early differentiation of ES cells.
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| 7. |
- Barle, H, et al.
(författare)
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Albumin synthesis in humans increases immediately following the administration of endotoxin
- 2002
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Ingår i: Clinical science (London, England : 1979). - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 103:5, s. 525-531
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Tidskriftsartikel (refereegranskat)abstract
- In order to investigate the immediate (i.e. within 3h) response of albumin synthesis to the administration of endotoxin, as a model of a moderate and well controlled catabolic insult, two measurements employing L-[2H5]phenylalanine were performed in 16 volunteers. One group (n = 8) received an intravenous injection of endotoxin (4ng/kg; lot EC-6) immediately after the first measurement of albumin synthesis, whereas the other group received saline. A second measurement was initiated 1h later. In the endotoxin group, the fractional synthesis rate of albumin was 6.9±0.6%/day (mean±S.D.) in the first measurement. In the second measurement, a significant increase was observed (9.6±1.2%/day; P<0.001). The corresponding values in the control group were were 6.6±0.6%/day and 7.0±0.6%/day respectively (not significant compared with first measurement and P<0.001 compared with the second measurement in the endotoxin group). The absolute synthesis rates of albumin were 148±35 and 201±49mg·kg-1·day-1 before and after endotoxin (P<0.01). In the control group, the corresponding values were 131±21 and 132±20mg·kg-1·day-1 (not significant compared with the first measurement and P<0.01 compared with the second measurement in the endotoxin group). In conclusion, these results indicate that albumin synthesis increases in the very early phase after a catabolic insult, as represented by the administration of endotoxin.
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| 8. |
- Beazer, Jack D., et al.
(författare)
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High-density lipoproteins vascular protective functions in metabolic and cardiovascular disease - could extracellular vesicles be at play?
- 2020
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Ingår i: Clinical Science. - : Portland Press on behalf of the Medical Research Society and the Biochemical Society. - 0143-5221 .- 1470-8736. ; 134:22, s. 2977-2986
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Forskningsöversikt (refereegranskat)abstract
- High-density lipoprotein (HDL) is a circulating complex of lipids and proteins known primarily for its role in reverse cholesterol transport and consequent protection from atheroma. In spite of this, therapies aimed at increasing HDL concentration do not reduce the risk of cardiovascular disease (CVD), and as such focus has shifted towards other HDL functions protective of vascular health - including vasodilatory, anti-inflammatory, antioxidant and anti-thrombotic actions. It has been demonstrated that in disease states such as CVD and conditions of insulin resistance such as Type 2 diabetes mellitus (T2DM), HDL function is impaired owing to changes in the abundance and function of HDL-associated lipids and proteins, resulting in reduced vascular protection. However, the gold standard density ultracentrifugation technique used in the isolation of HDL also co-isolates extracellular vesicles (EVs). EVs are ubiquitous cell-derived particles with lipid bilayers that carry a number of lipids, proteins and DNA/RNA/miRNAs involved in cell-to-cell communication. EVs transfer their bioactive load through interaction with cell surface receptors, membrane fusion and endocytic pathways, and have been implicated in both cardiovascular and metabolic diseases - both as protective and pathogenic mediators. Given that studies using density ultracentrifugation to isolate HDL also co-isolate EVs, biological effects attributed to HDL may be confounded by EVs. We hypothesise that some of HDLs vascular protective functions in cardiovascular and metabolic disease may be mediated by EVs. Elucidating the contribution of EVs to HDL functions will provide better understanding of vascular protection and function in conditions of insulin resistance and potentially provide novel therapeutic targets for such diseases.
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| 9. |
- Bennion, Douglas M, et al.
(författare)
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Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke : a nose-to-brain delivery approach.
- 2018
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 132:5, s. 581-593
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Tidskriftsartikel (refereegranskat)abstract
- Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients
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| 10. |
- Bergqvist, Anders, et al.
(författare)
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Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control
- 2015
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Ingår i: Clinical Science. - 1470-8736. ; 128:1, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- Real-world evaluation studies have shown that many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICSs). As conventional ICSs have poor access to the peripheral airways, the aim of the present paper was to study the relationship between peripheral airway inflammation and clinical control in allergic asthma. Consequently, bronchial and transbronchial biopsies were obtained from patients with poorly controlled asthma [n=12, asthma control test (ACT) score < 20], patients with well-controlled asthma (n= 12, ACT score >= 20) and healthy controls (n= 8). Tissue sections were immunostained to assess multiple leucocyte populations. To determine the degree of T-helper type-2 (Th2) immunity, the logarithmic value of the ratio between Th2 cells/mm(2) and Th1 cells/mm(2) was used as a surrogate score for Th2-skewed immunity. In the bronchi, the leucocyte infiltration pattern and the Th2-score were similar between patients with well-controlled asthma and those with poorly controlled asthma. In contrast, in the alveolar parenchyma, the expression of T-helper cells was significantly higher in patients with poorly controlled asthma than in patients with well-controlled asthma (P < 0.01). Furthermore, the alveolar Th2-score was significantly higher in patients with poorly controlled asthma (median 0.4) than in the controlled patients (median -0.10, P < 0.05). In addition, in contrast with bronchial Th2-score, the alveolar Th2-score correlated significantly with ACT score (r(s)=-0.62, P < 0.01) in the pooled asthma group. Collectively, our data reveal an alveolar Th2-skewed inflammation, specifically in asthmatic patients who are poorly controlled with ICSs, and suggest that pharmacological targeting of the peripheral airways may be beneficial in this large patient category.
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| 11. |
- Berndtson, Dan, et al.
(författare)
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Hypovolaemia after glucose/insulin infusions in volunteers
- 2008
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Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 115:12, s. 371-378
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Tidskriftsartikel (refereegranskat)abstract
- High-dose intravenous infusion of 5% glucose promotes rebound hypoglycaemia and hypovolaemia in healthy volunteers. To study whether such effects occur in response to glucose/insulin, 12 healthy firemen (mean age, 39 years) received three infusions over 1-2 h that contained 20 ml of 2.5% glucose/kg of body weight, 5 ml of 10% glucose/kg of body weight with 0.05 unit of rapid-acting insulin/kg of body weight, and 4 ml of 50% glucose/kg of body weight with 1 unit of insulin/kg of body weight. The plasma glucose concentration and plasma dilution were compared at 5-10 min intervals over 4 h. Regardless of the amount of administered fluid and whether insulin was given, the plasma glucose concentration decreased to hypoglycaemic levels within 30 min of the infusion ending. The plasma dilution closely mirrored plasma glucose and became negative by approx. 5%, which indicates a reduction in the plasma volume. These alterations were only partially restored during the follow-up period. A linear relationship between plasma glucose and plasma dilution was most apparent when the infused glucose had been dissolved in only a small amount of fluid. For the strongest glucose/insulin solution, this linear relationship had a correlation coefficient of 0.77 (n=386, P<0.0001). The findings of the present study indicate that a redistribution of water due to the osmotic strength of the glucose is the chief mechanism accounting for the hypovolaemia. It is concluded that infusions of 2.5%, 10% and 50% glucose, with and without insulin, in well-trained men were consistently followed by long-standing hypoglycaemia and also by hypovolaemia, which averaged 5%. These results emphasize the relationship between metabolism and fluid balance.
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| 12. |
- Che, K. F., et al.
(författare)
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The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers
- 2018
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Ingår i: Clinical Science. - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 132:9, s. 959-983
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Tidskriftsartikel (refereegranskat)abstract
- Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor kappa B (NF-kappa B); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-kappa B and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.
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| 13. |
- Che, Karlhans Fru, et al.
(författare)
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The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers
- 2018
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Ingår i: Clinical Science. - 0143-5221. ; 132:9, s. 959-983
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Tidskriftsartikel (refereegranskat)abstract
- Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.
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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. |
- Darsalia, Vladimer, et al.
(författare)
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Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats
- 2012
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Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 122:9-10, s. 473-483
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes is a strong risk factor for premature and severe stroke. The GLP-IR (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto-Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 mu g/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2-4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-IR agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.
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| 20. |
- Degens, H, et al.
(författare)
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Post-operative effects on insulin resistance and specific tension of single human skeletal muscle fibres
- 1999
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Ingår i: Clinical science (London, England : 1979). - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 97:4, s. 449-455
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Tidskriftsartikel (refereegranskat)abstract
- Surgery and accidental trauma are associated with a transient period of insulin resistance, substrate catabolism and muscle weakness. In the present study, we evaluated the changes in the force-generating capacity of chemically skinned single muscle fibres following abdominal surgery. Biopsies of the m. vastus lateralis were obtained in three patients 1 day before and 3 or 6 days after surgery. Part of the biopsy was frozen for histochemical analysis of the fibre cross-sectional area (FCSA) and myofibrillar protein content, and another part was used for single-fibre contractile measurements. All patients developed insulin resistance following surgery. The maximum velocity of unloaded shortening of single muscle fibres did not change following surgery. The FCSA did not decrease after surgery, as determined either from histochemical sections or from single fibres measured at a fixed sarcomere length of 2.76±0.09 μm (mean±S.D.). Further, the force-generating capacity of the single fibres, measured as maximal Ca2+-activated force (P0) or as P0 normalized to FCSA (specific tension), remained unchanged, as did the myofibrillar protein content of the muscle. In conclusion, the muscle weakness associated with post-operative insulin resistance is not related to a decreased specific tension or a loss of myofibrillar proteins. Other potential cellular mechanisms underlying post-operative weakness are discussed.
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| 21. |
- Degens, Hans, et al.
(författare)
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Post-operative effects on insulin resistance and specific tension of single skeletal muscle fibres
- 1999
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Ingår i: Clinical Science. - : Lippincott Williams & Wilkins. - 0143-5221 .- 1470-8736. ; 97:4, s. 449-455
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Tidskriftsartikel (refereegranskat)abstract
- Surgery and accidental trauma are associated with a transient period of insulin resistance, substrate catabolism and muscle weakness. In the present study, we evaluated the changes in the force-generating capacity of chemically skinned single muscle fibresfollowing abdominal surgery. Biopsies of the m. vastus lateralis were obtained in three patients 1 day before and 3 or 6 days after surgery. Part of the biopsy was frozen for histochemical analysis of the fibre cross-sectional area (FCSA) and myofibrillar protein content, and another part was used for single-fibre contractile measurements. All patients developed insulin resistance following surgery. The maximum velocity of unloaded shortening of single muscle fibres did not change following surgery. The FCSA did not decrease after surgery, as determined either from histochemical sections or from singlefibres measured at a fixed sarcomere length of 2.76+/-0.09 microm (mean+/-S.D.). Further, the force-generating capacity of the single fibres, measured as maximal Ca(2+)-activated force (P(0)) or as P(0) normalized to FCSA (specific tension), remained unchanged, as did the myofibrillar protein content of the muscle. In conclusion, the muscle weakness associated with post-operative insulin resistance is not related to a decreased specifictension or a loss of myofibrillar proteins. Other potential cellular mechanisms underlying post-operative weakness are discussed.
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| 22. |
- Edvinsson, Lars, et al.
(författare)
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Triptan-induced contractile (5-HT1B receptor) responses in human cerebral and coronary arteries: relationship to clinical effect
- 2005
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Ingår i: Clinical Science. - 1470-8736. ; 109:3, s. 335-342
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Tidskriftsartikel (refereegranskat)abstract
- Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine whether there was any relationship with the maximal plasma concentrations (Cmax; nM) of the drugs achieved following oral administration of clinically relevant doses to man using values reported in the literature. We also examined the expression of 5-HT1B receptors in atherosclerotic and normal coronary arteries. The vasocontractile responses to sumatriptan, rizatriptan or eletriptan were characterized by in vitro pharmacology. The ratio of Cmax/EC50 was calculated. 5-HT1B and 5-HT1D receptors were visualized by immunohistochemical techniques in coronary arteries. Sumatriptan, rizatriptan and eletriptan were powerful vasoconstrictors in cerebral artery. The rank order of agonist potency was eletriptan = rizatriptan = sumatriptan. In the coronary artery, the triptans were weaker vasoconstrictors. The rank order of potency was similar. In cerebral artery the ratio of Cmax/EC50 was not significantly different from unity, indicating a relationship between these two parameters. In general for the coronary artery, the ratios were significantly less than unity, indicating no direct relationship. Immunohistochemistry showed expression of 5-HT1B receptors in the medial layer, but did not reveal any obvious difference in 5-HT1B receptor expression between normal and atherosclerotic coronary arteries. The results support the notion that triptans are selective vasoconstrictors of cerebral arteries over coronary arteries and that there is a relationship between vasoconstrictor potency in cerebral arteries and clinically relevant plasma levels.
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| 23. |
- Ekholm, M, et al.
(författare)
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Long-term angiotensin-converting enzyme inhibition with ramipril reduces thrombin generation in human hypertension
- 2002
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Ingår i: Clinical science (London, England : 1979). - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 103:2, s. 151-155
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Tidskriftsartikel (refereegranskat)abstract
- Antihypertensive treatment reduces the risk of thromboembolic events in hypertension. The aim of this study was to examine the influence of angiotensin-converting enzyme inhibition on blood coagulation in subjects with mild-to-moderate essential hypertension. Fibrinogen, thrombin–antithrombin complex (TAT) and Factor VII were determined in plasma at rest and after a mental stress test following placebo for 6 weeks, or ramipril for 6 weeks or 6 months. Ramipril reduced resting TAT, and tended to reduce fibrinogen; Factor VII remained unchanged. Mental stress increased fibrinogen, but did not alter TAT or Factor VII activity. The reduced thrombin generation in patients taking ramipril may explain in part why angiotensin-converting enzyme inhibitors reduce thromboembolic complications in patients with cardiovascular disease.
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| 24. |
- Elksnis, Andris, et al.
(författare)
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Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK
- 2021
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Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 135:19, s. 2243-2263
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Tidskriftsartikel (refereegranskat)abstract
- The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against islet amyloid polypeptide (IAPP)-aggregation, thioredoxin interacting protein (TXNIP) up-regulation and beta-cell death. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme enoyl coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1). In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and acyl-CoA carboxylase (ACC) phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP down-regulation, which in turn protects against beta-cell death.
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| 25. |
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| 26. |
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| 27. |
- Forte, Amalia, et al.
(författare)
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Injury to rat carotid arteries causes time-dependent changes in gene expression in contralateral uninjured arteries
- 2009
-
Ingår i: Clinical Science. - 1470-8736. ; 116:1-2, s. 125-136
-
Tidskriftsartikel (refereegranskat)abstract
- Vascular surgery aimed at stenosis removal induces local reactions often leading to restenosis. Although extensive analysis has been focused on pathways activated in injured arteries, little attention has been devoted to associated systemic vascular reactions. The aim of the present study was to analyse changes occurring in contralateral uninjured rat carotid arteries in the acute phase following unilateral injury. WKY (Wistar-Kyoto) rats were subjected to unilateral carotid arteriotomy. Contralateral uninjured carotid arteries were harvested from 4 h to 7 days after injury. Carotid arteries were also harvested from sham-operated rats and uninjured rats. Carotid morphology and morphometry were examined. Affymetrix microarrays were used for differential analysis of gene expression. A subset of data was validated by real-time RT-PCR (reverse transcription-PCR) and verified at the protein level by Western blotting. A total of 1011 genes were differentially regulated in contralateral uninjured carotid arteries from 4 h to 7 days after arteriotomy (P < 0.0001; fold change, >= 2) and were classified into 19 gene ontology functional categories. To a lesser extent, mRNA variations also occurred in carotid arteries of sham-operated rats. Among the changes, up-regulation of members of the RAS (renin-angiotensin system) was detected, with possible implications for vasocompensative mechanisms induced by arteriotomy. In particular, a selective increase in the 69 kDa isoform of the N-domain of ACE (angiotensin-converting enzyme), and not the classical somatic 195 kDa isoform, was observed in contralateral uninjured carotid arteries, suggesting that this 69 kDa isoenzyme could influence local Angll (angiotensin II) production. In conclusion, systemic reactions to injury occur in the vasculature, with potential clinical relevance, and suggest that caution is needed in the choice of controls during experimental design in vivo.
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Fred, Rikard G., et al.
(författare)
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Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells
- 2015
-
Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 128:1, s. 17-28
-
Tidskriftsartikel (refereegranskat)abstract
- Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic and multi-functional type I cell surface membrane protein, which is known to be phosphorylated by the activated platelet-derived growth factor receptor (PDGFR). The tyrosine kinase inhibitor imatinib, which inhibits PDGFR and c-Abl, and which has previously been reported to counteract beta-cell death and diabetes, has been suggested to reduce atherosclerosis by inhibiting PDGFR-induced LRP1 phosphorylation. The aim of the present study was to study LRP1 function in beta-cells and to what extent imatinib modulates LRP1 activity. LRP1 and c-Abl gene knockdown was performed by RNAi using rat INS-1 832/13 and human EndoC1-beta H1 cells. LRP1 was also antagonized by treatment with the antagonist low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1). We have used PDGF-BB, a PDGFR agonist, and apolipoprotein E (ApoE), an LRP1 agonist, to stimulate the activities of PDGFR and LRP1 respectively. Knockdown or inhibition of LRP1 resulted in increased hydrogen peroxide (H2O2)(-) or cytokine-induced cell death, and glucose-induced insulin release was lowered in LRP1-silenced cells. These results indicate that LRP1 function is necessary for beta-cell function and that LRP1 is adversely affected by challenges to beta-cell health. PDGF-BB, or the combination of PDGF-BB+ApoE, induced phosphorylation of extracellular-signal-regulated kinase (ERK), Akt and LRP1. LRP1 silencing blocked this event. Imatinib blocked phosphorylation of LRP1 by PDGFR activation but induced phosphorylation of ERK. LRP1 silencing blocked imatinib-induced phosphorylation of ERK. Sunitinib also blocked LRP1 phosphorylation in response to PDGF-BB and induced phosphorylation of ERK, but this latter event was not affected by LRP1 knockdown. siRNA-mediated knockdown of the imatinib target c-Abl resulted in an increased ERK phosphorylation at basal conditions, with no further increase in response to imatinib. Imatinib-induced cell survival of tunicamycin-treated cells was partially mediated by ERK activation. We have concluded that imatinib promotes LRP1-dependent ERK activation, possibly via inhibition of c-Abl, and that this could contribute to the pro-survival effects of imatinib on beta-cells.
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| 32. |
- Frostegard, J, et al.
(författare)
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Circulating oxidized low-density lipoprotein is increased in hypertension
- 2003
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Ingår i: Clinical Science. - 1470-8736. ; 105:5, s. 615-620
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Tidskriftsartikel (refereegranskat)abstract
- Oxidized low-density lipoprotein (OxLDL) and autoantibodies to OxLDL (aOxLDL) are implicated in the development of atherosclerosis. The objective of this study was to determine the importance of these factors in hypertension, a major risk factor for atherosclerosis. Samples were obtained from I I I men with established hypertension (diastolic pressure > 95 mmHg) from the Swedish component of an ongoing hypertension study (European Lacidipine study on Atherosclerosis, ELSA) and from 75 normotensive control men, who were from a Swedish population-screening programme (diastolic pressure < 80 mmHg). The presence of carotid atherosclerosis and the intima-media thicknesses were determined by ultrasonography. A monoclonal antibody to OxLDL, EO6, was used to determine oxidation epitopes in LDL. aOxLDL of IgG and IgM subclass were tested by ELISA against OxLDL. Hypertensive men had increased OxLDL levels compared with normotensives (P = 0.002), whereas autoantibodies tested were largely similar between groups. There was no association between the antibodies tested, or OxLDL and carotid atherosclerosis. Age was not associated with OxLDL or aOxLDL measurements. Taken together, our findings indicate that OxLDL is elevated in hypertensive men, which may predispose to atherosclerosis in hypertension. In contrast, aOxLDL levels were unchanged and the role of aOxLDL may depend on disease stage and/or type.
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| 33. |
- Fugmann, Andreas, et al.
(författare)
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Central and peripheral haemodynamic effects of hyperglycaemia, hyperinsulinaemia, hyperlipidaemia or a mixed meal
- 2003
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 105:6, s. 715-721
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the haemodynamic changes during hyperinsulinaemia, hyperglycaemia or hypertriglyceridaemia in relation to those following a mixed meal. Ten subjects were subjected to hypertriglyceridaemia (3.9 mmol/l) for 2 h by an infusion of Intralipid and heparin. Nine subjects received a hyperglycaemic clamp (12.5 mmol/l) with octreotide and low-dose insulin infusion to maintain normoinsulinaemia (10 m-units/l). Ten subjects received saline for 2 h as a control and, thereafter, 2 h of normoglycaemic hyperinsulinaemic clamp (80 m-units/l). Finally, ten subjects were evaluated for 2 h following an ordinary mixed meal. Calf blood flow was measured by venous occlusion plethysmography and cardiac index by thoracic bioimpedance. Both the mixed meal and normoglycaemic hyperinsulinaemia lowered total peripheral resistance, and increased calf blood flow and cardiac index, whereas blood pressure decreased (P <0.05-0.001). Both hyperglycaemia and hypertriglyceridaemia increased calf blood flow, but blood pressure was unchanged. Total peripheral resistance was unchanged in hypertriglyceridaemia, whereas hyperglycaemia induced a significant increase. Normoglycaemic hyperinsulinaemia induced a haemodynamic pattern similar, but to a lesser extent, to the pattern seen following a mixed meal. Hyperinsulinaemia seems to be a major mediator of the haemodynamic response, but other factors are obviously also of great importance. Hypertriglyceridaemia and hyperglycaemia induced haemodynamic responses that are not similar to those seen following a mixed meal.
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| 34. |
- Galant, Natalie J., et al.
(författare)
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Transthyretin amyloidosis : an under-recognized neuropathy and cardiomyopathy
- 2017
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Ingår i: Clinical Science. - : PORTLAND PRESS LTD. - 0143-5221 .- 1470-8736. ; 131:5, s. 395-409
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Forskningsöversikt (refereegranskat)abstract
- Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is an underdiagnosed and important type of cardiomyopathy and/or polyneuropathy that requires increased awareness within the medical community. Raising awareness among clinicians about this type of neuropathy and lethal form of heart disease is critical for improving earlier diagnosis and the identification of patients for treatment. The following review summarizes current criteria used to diagnose both hereditary and wild-type ATTR (ATTRwt) amyloidosis, tools available to clinicians to improve diagnostic accuracy, available and newly developing therapeutics, as well as a brief biochemical and biophysical background of TTR amyloidogenesis.
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| 35. |
- Gidlöf, Andreas C., et al.
(författare)
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Vitamin A : a drug for prevention of restenosis/reocclusion after percutaneous coronary intervention?
- 2008
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 114:1, s. 19-25
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Forskningsöversikt (refereegranskat)abstract
- The re-establishment of adequate blood flow in a vessel with a reduced lumen due to an atherosclerotic plaque by percutaneous vascular intervention is a well established procedure. However, the long-term outcome of such interventions is negatively influenced by the development of intimal hyperplasia/restenosis. Although extensively researched, this still represents a significant clinical problem. Retinoids, i.e. natural and synthetic derivates of vitamin A, represent a potential therapeutic compound, since they have been shown to influence the vast majority of processes that ultimately lead to reocclusion of the injured vessel. Retinoids exert their effects at the transcriptional level through their nuclear receptors. Targeting multiple processes, i.e. proliferation, migration, extracellular matrix composition and cell differentiation, as well as coagulation/fibrinolysis, should increase their future role in the prevention of restenosis. The purpose of this review is to summarize the diverse effects of retinoids on pathobiological and biological processes activated at sites of vascular injury with particular emphasis on intimal hyperplasia/restenosis after endovascular interventions.
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| 36. |
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| 37. |
- Guldstrand, MC, et al.
(författare)
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High-fat diets: healthy or unhealthy?
- 2007
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Ingår i: Clinical science (London, England : 1979). - 1470-8736. ; 113:9-1010, s. 397-399
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Tidskriftsartikel (refereegranskat)
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| 38. |
- Hedin, Annika, et al.
(författare)
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Volume expansion and plasma protein clearance during intravenous infusion of 5% albumin and autologous plasma
- 2005
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Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 108:3, s. 217-224
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Tidskriftsartikel (refereegranskat)abstract
- Autologous plasma may be used to replace plasma volume and plasma proteins during surgery, but its effectiveness is largely unknown. In the present study, the characteristics of predonated frozen and thawed autologous plasma were compared with those of 5% albumin in 15 male volunteers who received 10 ml/kg of body weight of these colloids as intravenous infusions over 30 min. Venous blood was sampled and urine was collected over 8 h to outline the volume expansion and blood-interstitial fluid space transport of three plasma proteins (albumin, fibrinogen and antithrombin) by means of mass balance analysis. The maximum plasma dilution of 5% albumin and autologous plasma averaged 17 and 21% respectively, and their half-lives were 2.5 and 2.9 h respectively (P<0.03). The between-subject variability in dilution was most pronounced for autologous plasma. Transport of protein from blood to the interstitial space occurred faster when the infused fluid contained the protein in question. The rate was highest at 60 min, and the process was still in progress at 8 h when approx. 60% of the infused albumin, 45% of the fibrinogen and 75% of the infused antithrombin had been translocated to the interstitial fluid space. In contrast with the proteins, excess plasma water was removed by urinary excretion. It is concluded that the volume expansion is equivalent for the two colloid fluids, although it is more predictable for 5% albumin. The transport of protein outlasted the volume expansion.
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| 39. |
- Huang, Zhen, et al.
(författare)
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Gender-specific regulation of pancreatic islet blood flow, insulin levels and glycaemia in spontaneously diabetic Goto-Kakizaki rats
- 2008
-
Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 115:1, s. 35-42
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Tidskriftsartikel (refereegranskat)abstract
- Patients with diabetes are often treated with a statin for hyperlipidaemia and an ACE (angiotensin-converting enzyme) inhibitor or angiotensin receptor antagonist for hypertension or albuminuria. These drugs may also exert beneficial metabolic effects, causing improved glucose tolerance in patients. Gender-related differences have also been observed in the clinical responsiveness to these drugs, but the mechanism behind this is unclear. In the present study, we have investigated whether these drugs and the fatty acid palmitate influence the pancreatic microcirculation, thereby having an impact on insulin secretion and glycaemia in vivo, in spontaneously diabetic male and female Goto-Kakizaki rats. In male rats, pancreatic IBF (islet blood flow) and total PBF (pancreatic blood flow) were increased significantly by pravastatin, captopril and irbesartan. Serum insulin levels were increased by pravastatin and captopril. Palmitate suppressed pancreatic IBF and increased blood glucose. In female animals, pancreatic IBF was stimulated by captopril, candesartan and irbesartan. Total PBF was increased by captopril, candesartan and irbesartan, and by pravastatin. Palmitate suppressed pancreatic IBF and serum insulin secretion. In conclusion, the present study lends support to the view that a local pancreatic RAS (renin-angiotensin system) and pravastatin may be selectively influencing the pancreatic microcirculation and therefore affecting insulin secretion and glycaemia. NEFAs (non-esterified fatty acids) impaired pancreatic IBF, suppressed insulin secretion and increased blood glucose. Substantial gender-related differences in the vascular and metabolic responses to these drugs prevail in this animal model of diabetes.
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| 40. |
- Huang, Zhen, et al.
(författare)
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Vasoactive drugs enhance pancreatic islet blood flow, augment insulin secretion and improve glucose tolerance in female rats
- 2007
-
Ingår i: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 112:1-2, s. 69-76
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Tidskriftsartikel (refereegranskat)abstract
- Pravastatin, irbesartan and captopril are frequently used in the treatment of patients with Type 2 diabetes. These drugs also exert beneficial metabolic effects, causing an improved glucose tolerance in patients, but the precise mechanisms by which this is achieved remain elusive. To this end, we have studied whether these drugs influence insulin secretion in vivo through effects on islet blood perfusion. Captopril (3 mg/kg of body weight), irbesartan (3 mg/kg of body weight) and pravastatin (0.5 mg/kg of body weight) were injected intravenously into anaesthetized female Wistar rats. Blood flow rates were determined by a microsphere technique. Blood glucose concentrations were measured with test reagent strips and serum insulin concentrations were measured by ELISA. Pancreatic blood flow was markedly increased by pravastatin (P<0.001), captopril (P < 0.05) and irbesartan (P<0.01). Pancreatic islet blood flow was significantly and preferentially enhanced after the administration of captopril (P<0.01), irbesartan (P<0.01) and pravastatin (P<0.001). Kidney blood flow was enhanced significantly by pravastatin (P < 0.01), irbesartan (P < 0.05) and captopril (P < 0.01). Captopril and pravastatin also enhanced late-phase insulin secretion and positively influenced glycaemia in intraperitoneal glucose tolerance tests. In conclusion, the present study suggests that a local pancreatic renin-angiotensin system and pravastatin treatment may be selectively controlling pancreatic islet blood flow, augmenting insulin secretion and thereby improving glucose tolerance. Our findings indicate significant gender-related differences in the vascular response to these agents. Since statins and renin-angiotensin system inhibitors are frequently used by diabetic patients, the antidiabetic actions of these drugs reported previously might occur, in part, through the beneficial direct islet effects shown in the present study.
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| 41. |
- Hägerkvist, Robert, et al.
(författare)
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Imatinib mesylate improves insulin sensitivity and glucose disposal rates in rats fed a high-fat diet
- 2008
-
Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 114:1, s. 65-71
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate whether imatinib affects insulin sensitivity and glucose disposal in HF (high-fat)-fed rats. Sprague-Dawley rats were fed either a standard pelleted rat food (low-fat diet) or an HF diet (60% fat) for 8 weeks. During the last 10 days of the HF diet regime, rats received saline alone or imatinib (50 or 100 mg/kg of body weight) daily by gavage. The higher dose of imatinib resulted in a decreased psoas fat pad weight in the HF-treated rats. Under euglycaemic hyperinsulinaemic clamp conditions, HF-fed rats exhibited increased insulin concentrations and decreased glucose disposal. The lower (50 mg/kg of body weight), but not the higher (100 mg/kg of body weight), dose of imatinib normalized insulin sensitivity and glucose disposal without affecting glucose metabolism in low-fat-fed rats. Hepatic glucose production at both fasting and hyperinsulinaemic conditions was only weakly affected by imatinib. We conclude that a moderate dose of imatinib efficiently counteracts HF-induced peripheral insulin resistance, and that further studies on the mechanisms by which imatinib increases insulin action in muscle and fat tissues might generate novel strategies for the treatment of Type 2 diabetes.
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| 42. |
- Iresjö, Britt-Marie, 1963, et al.
(författare)
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Initiation factors for translation of proteins in the rectus abdominis muscle from patients on overnight standard parenteral nutrition before surgery.
- 2008
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Ingår i: Clinical science (London, England : 1979). - 1470-8736. ; 114:9, s. 603-10
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have provided conflicting conclusions concerning the efficacy of improving protein balance in patients by standard intravenous nutrition [TPN (total parenteral nutrition)], which is either explained by suboptimal nutritional regimens or insensitive clinical methods. The aim of the present study was therefore to evaluate the effects on the initiation of translation of skeletal muscle proteins by standard overnight TPN. A total of 12 patients who underwent standard surgery were included. TPN was provided as an all-in-one treatment by constant infusion [0.16 gN.kg(-1) of body weight.day(-1) (30 kcal.kg(-1) of body weight.day(-1))]. Saline-infused patients served as controls. Rectus abdominis muscle biopsies were taken at the time of the operation. The phosphorylation state of the proteins for initiation of translation was quantified. Plasma glucose, and serum insulin, glycerol, triacylglycerols (triglycerides) and NEFAs (non-esterified fatty acids; 'free fatty acids') were not significantly altered during TPN infusion, whereas total plasma amino acids increased, as shown by increases in methionine, phenylalanine, threonine, alanine, arginine, aspartic acid, glycine and histidine (P<0.05). Overnight TPN increased the formation of active eIF4G-eIF4E (where eIF is eukaryotic-initiation factor) complexes (P<0.05), whereas the inhibitory complex 4E-BP1 (eIF4E-binding protein)-eIF4E was moderately decreased (P<0.06). TPN increased the amount of the most phosphorylated form of 4E-BP1 (P<0.05), and increased the amount (P<0.04) and phosphorylation (P<0.01) of p70(S6K) (70 kDa ribosomal protein S6 kinase). In conclusion, an overnight pre-operative constant infusion of standard TPN altered initiation factor complexes, indicating activation of the initiation of protein translation in rectus abdominis muscle in the presence of increased plasma amino acid levels, but without a concomitant increase in energy substrates and insulin. In contrast with our results from previous studies, the methodology used in the present study appears to be more sensitive in reflecting directional changes in human muscle protein synthesis compared with traditional methods, particularly based on measurements of amino acid flux.
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| 43. |
- Jensen, J., et al.
(författare)
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Deterioration in peak systolic velocity is closely related to ischaemia during angioplasty : a vectorcardiographic and tissue Doppler imaging study
- 2001
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Ingår i: Clinical Science. - : Portland Press Ltd.. - 0143-5221 .- 1470-8736. ; 100:2, s. 137-143
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Tidskriftsartikel (refereegranskat)abstract
- We tested the hypothesis that the extent of signs of ischaemia detected by vectorcardiography (VCG) during elective coronary angioplasty (percutaneous transluminal coronary angioplasty: PTCA) is related to systolic and diastolic myocardial velocities, as determined by tissue Doppler echocardiography. A total of 15 patients undergoing PTCA (12 men/three women; age 61 +/- 9 years), without prior myocardial infarction and with an election fraction of > 50%, were included. The balloon inflation was repeated three times, with minimum intervals of 2 min between inflations. Tissue Doppler echocardiography was performed. in an apical two- or four-chamber view, before and at the end of each inflation. Peak systolic velocity, time-to-peak systolic velocity (TTP), peak early (E-m) and late (A(m)) diastolic velocities, the E-m/A(m) ratio and jsovolumic relaxation time were measured in the basal segments of the left ventricle. VCG recordings were carried out during the whole procedure. ST vector magnitude (ST-VM) and ST change vector magnitude (STC-VM) were monitored. The total duration and area of each VCG change during inflation were calculated for each patient. Isovolumic relaxation time, peak E-m and A(m) values and the E-m/A(m) ratio did not change significantly during inflation. Peak systolic velocity decreased (6.7+/-2.0 to 5.3 +/- 1.9 cm/s; P < 0.001) and TTP increased (157 +/- 60 to 192 +/- 60 ms; P<0.01) during inflation. Both STC-VM rime (r = -0.68, P<0.01) and STC-VM area (r = -0.68, P < 0.01) were related to peak systolic velocity during inflation. STC-VM time was also related (r = 0.55, P < 0.05) to the difference in peak systolic velocity during compared with before inflation. ST-VM was less closely related to peak systolic velocity. Thus the duration and degree of ischaemia, as measured by VCG, are related to peak systolic velocity in the basal segments of the left ventricle.
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| 44. |
- Johansson, Maria E, 1977, et al.
(författare)
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Haemodynamically significant plaque formation and regional endothelial dysfunction in cholesterol-fed ApoE-/- mice
- 2005
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 108:6, s. 531-8
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Tidskriftsartikel (refereegranskat)abstract
- Flow-mediated vasodilation is suggested as one of the mechanisms involved in arterial expansive remodelling, which is thought to be a defence mechanism in atherogenesis. In the present study, we tested the hypothesis that lumen obstructive plaque formation is associated with failure of NO (nitric oxide)-dependent vasodilation in conduit vessels. Cardiac function and aortic root flow velocities were assessed using high-resolution echocardiography and two-dimensional-guided pulsed Doppler in ApoE(-/-) (apolipoprotein E-deficient) mice fed a standard or high-cholesterol diet. Endothelial function in the proximal and mid-descending aortic regions was studied using a myograph technique. Flow velocity at the aortic root of cholesterol-fed ApoE(-/-) mice was significantly increased as a result of lumen narrowing, detected via histological analysis. NO-dependent vasodilatory responses were selectively impaired in the atherosclerosis-prone vascular regions in cholesterol-fed ApoE(-/-) mice. In conclusion, consumption of a high-cholesterol diet results in lumen obstructive plaque formation in ApoE(-/-) mice, which significantly alters aortic root haemodynamics. This phenomenon is associated with impaired NO-dependent vasodilation in vessel segments known to be prone to atherosclerosis.
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| 45. |
- Jorfeldt, L., et al.
(författare)
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Influence of leg position and environmental temperature on segmental volume expansion during venous occlusion plethysmography
- 2003
-
Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 104:6, s. 599-605
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Tidskriftsartikel (refereegranskat)abstract
- Blood flow determinations by venous occlusion plethysmography applying the strain-gauge technique are frequently used. A problem with the strain-gauge technique is that the relationship between venous volume and transmural pressure is not linear and, furthermore, changes with the sympathetic tone. The present study tests the hypothesis that these factors lead to a redistribution of venous blood, which may impair the accuracy of the technique. The relative volume expansion rates of four leg segments were studied with the leg in different positions and at disparate temperatures, thereby inducing varying venous pressures and sympathetic tone (n = 6). With elevated leg and relaxed veins (at 50°C), the distal thigh showed a relatively low expansion rate (25.8 ± 4.5 ml·min-1, l-1), whereas values in the calf segments were higher (34.5-39.0ml·min-1·l-1). With lower initial transmural pressure, calf segments can increase their volume much more during occlusion compared with the distal thigh. In a higher transmural pressure region (lowered leg), the difference in compliance between limb segments is less. In this case, compliance and volume expansion rate was higher in the distal thigh (14.2, 13.5 and 22.2ml·min-1·l-1 at 10, 20 and 50°C respectively) than in the calf segments (for the distal calf: 6.4, 7.7 and 16.2 ml·min-1=1-1 respectively). There was a significant interaction (P < 0.001) between temperature and leg position, indicating a higher degree of sympathetic vasoactivity in the calf. It is concluded that blood flow determination by strain-gauge plethysmography is less accurate, due to a potential redistribution of the venous blood. Therefore possible influences of variations in sympathetic tone and venous pressure must be considered even in intra-individual comparisons, especially in interventional studies.
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| 46. |
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| 47. |
- Kappe, Camilla, et al.
(författare)
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Glucocorticoids suppress GLP-1 secretion : possible contribution to their diabetogenic effects
- 2015
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 129:5, s. 405-414
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Tidskriftsartikel (refereegranskat)abstract
- Evidence indicates that subtle abnormalities in GC (glucocorticoid) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin GLP-1 (glucagon-like peptide 1). However, although defective GLP-1 secretion has been correlated with insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the present study, we sought to determine whether GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate that the GR (glucocorticoid receptor) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces SGK1 (serum-and glucocorticoid-inducible kinase 1) expression, but did not influence preproglucagon expression or cell viability. In addition, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, whereas the secretory response to a phorbol ester was unaltered. Furthermore, in vivo administration of dexamethasone to rats reduced the circulating levels of GLP-1 concurrent with induction of insulin resistance and glucose intolerance. We can conclude that GR activation in GLP-1-producing cells will diminish the secretory responsiveness of these cells to subsequent carbohydrate stimulation. These effects may not only elucidate the pathogenesis of steroid diabetes, but could ultimately contribute to the identification of novel molecular targets for controlling incretin secretion.
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| 48. |
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| 49. |
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| 50. |
- Kuhre, Rune E., et al.
(författare)
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The regulation of function, growth and survival of GLP-1-producing L-cells
- 2016
-
Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 130:2, s. 79-91
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Forskningsöversikt (refereegranskat)abstract
- Glucagon-like peptide-1 (GLP-1) is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signalling exerts numerous pleiotropic effects on various tissues, regulating energy absorption and disposal, as well as cell proliferation and survival. In Type 2 Diabetes (T2D) reduced plasma levels of GLP-1 have been observed, and plasma levels of GLP-1, as well as reduced numbers of GLP-1 producing cells, have been correlated to obesity and insulin resistance. Increasing endogenous secretion of GLP-1 by selective targeting of the molecular mechanisms regulating secretion from the L-cell has been the focus of much recent research. An additional and promising strategy for enhancing endogenous secretion may be to increase the L-cell mass in the intestinal epithelium, but the mechanisms that regulate the growth, survival and function of these cells are largely unknown. We recently showed that prolonged exposure to high concentrations of the fatty acid palmitate induced lipotoxic effects, similar to those operative in insulin-producing cells, in an in vitro model of GLP-1-producing cells. The mechanisms inducing this lipototoxicity involved increased production of reactive oxygen species (ROS). In this review, regulation of GLP-1-secreting cells is discussed, with a focus on the mechanisms underlying GLP-1 secretion, long-term regulation of growth, differentiation and survival under normal as well as diabetic conditions of hypernutrition.
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