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- Spanbroek, R, et al.
(författare)
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Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis
- 2003
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 100:3, s. 1238-1243
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Tidskriftsartikel (refereegranskat)abstract
- Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocyte-type 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.
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- da Silva, G. M., et al.
(författare)
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The effect of diverticular disease on the colonic J pouch
- 2004
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Ingår i: Colorectal disease. - 1462-8910. ; 6:3, s. 171-5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to assess the impact of the diverticular disease (DD) on function and on postoperative complications of the colonic J-pouch (CJP) with pouch-anal anastomosis. METHODS: Patients who underwent a CJP between December 1990 and August 2001, were retrospectively reviewed. The presence of DD in the CJP was assessed on pouchogram prior to ileostomy closure. A questionnaire designed to evaluate the degree of continence (total incontinence score (IS): 0 = worst, 20 = best) and pouch evacuation (total evacuation score (ES): 0 = worst, 28 = best) was used for comparison between patients with DD and those without DD (NDD). RESULTS: Sixty-six patients (47 males; 19 females) with a median age of 68 years (range 28-87 years) were included. The median follow-up period was 22 months (range 2-106 months). Twenty-four patients comprised the DD group and 42 were in the NDD group. The two groups were comparable for age, gender and time from ileostomy closure; all patients with postoperative chemoradiation therapy were in the NDD group. The total ES and IS total did not significantly differ between the two groups with a P-value of 0.11 and 0.09 respectively. Furthermore, there was no significant difference in the total incidence of pouch complications between the two groups (3 strictures, 1 leak, 1 fistula in the NDD group vs. 1 pelvic sepsis in the DD group; P = 0.4). CONCLUSIONS: The presence of DD in a CJP does not seem to impact pouch function or the postoperative complication rate.
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- Nesher, R, et al.
(författare)
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Defective stimulus-secretion coupling in islets of Psammomys obesus, an animal model for type 2 diabetes
- 2001
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 50:2, s. 308-314
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Tidskriftsartikel (refereegranskat)abstract
- Psammomys obesus is a model of type 2 diabetes that displays resistance to insulin and deranged β-cell response to glucose. We examined the major signaling pathways for insulin release in P. obesus islets. Islets from hyperglycemic animals utilized twice as much glucose as islets from normoglycemic diabetes-prone or diabetes-resistant controls but exhibited similar rates of glucose oxidation. Fractional oxidation of glucose was constant in control islets over a range of concentrations, whereas islets from hyperglycemic P. obesus showed a decline at high glucose. The mitochondrial substrates α-ketoisocaproate and monomethyl succinate had no effect on insulin secretion in P. obesus islets. Basal insulin release in islets from diabetes-resistant P. obesus was unaffected by glucagon-like peptide 1 (GLP-1) or forskolin, whereas that of islets of the diabetic line was augmented by the drugs. GLP-1 and forskolin potentiated the insulin response to maximal (11.1 mmol/l) glucose in islets from all groups. The phorbol ester phorbol myristic acid (PMA) potentiated basal insulin release in islets from prediabetic animals, but not those from hyperglycemic or diabetes-resistant P. obesus. At the maximal stimulatory glucose concentration, PMA potentiated insulin response in islets from normoglycemic prediabetic and diabetes-resistant P. obesus but had no effect on islets from hyperglycemic P. obesus. Maintenance of islets from hyperglycemic P. obesus for 18 h in low (3.3 mmol/l) glucose in the presence of diazoxide (375 μmol/l) dramatically improved the insulin response to glucose and restored the responsiveness to PMA. Immunohistochemical analysis indicated that hyperglycemia was associated with reduced expression ofα-protein kinase C (PKC) and diminished translocation of λ-PKC. In summary, we found that 1) P. obesus islets have low oxidative capacity, probably resulting in limited ability to generate ATP to initiate and drive the insulin secretion; 2) insulin response potentiated by cyclic AMP—dependent protein kinase is intact in P. obesus islets, and increased sensitivity to GLP-1 or forskolin in the diabetic line may be secondary to increased sensitivity to glucose; and 3) islets of hyperglycemic P. obesus display reduced expression of α-PKC and diminished translocation of λ-PKC associated with impaired response to PMA. We conclude that low β-cell oxidative capacity coupled with impaired PKC-dependent signaling may contribute to the animals' poor adaptation to a high-energy diet.
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