Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion. (1/1180)

BACKGROUND: Mycophenolate mofetil (MMF) is used for immunosuppression after renal transplantation because it reduces lymphocyte proliferation by inhibiting inosine monophosphate dehydrogenase (IMPDH) in lymphocytes and GTP biosynthesis. In the present study we asked if therapeutic concentrations of MMF might interfere with mesangial cell (MC) proliferation which is involved in inflammatory proliferative glomerular diseases. METHODS: Rat and human MCs were growth-arrested by withdrawal of fetal calf serum (FCS) and stimulated by addition of FCS, platelet-derived growth factor (PDGF) or lysophosphatidic acid (LPA). Different concentrations of MMF (0.019-10 microM) were added concomitantly in the presence or absence of guanosine. MC proliferation was determined by [3H]thymidine incorporation. Cell viability was assessed by trypan blue exclusion. Apoptotic nuclei were stained using the Hoechst dye H33258. Cytosolic free Ca2+ concentrations were determined with the fluorescent calcium chelator fura-2-AM. RESULTS: MMF inhibited mitogen-induced rat MC proliferation with an IC50 of 0.45 +/- 0.13 microM. Human MCs proved to be even more sensitive (IC50 0.19 +/- 0.06 microM). Inhibition of MC proliferation was reversible and not accompanied by cellular necrosis or apoptosis. Addition of guanosine prevented the antiproliferative effect of MMF, indicating that inhibition of IMPDH is responsible for decreased MC proliferation. Early signalling events of GTP-binding-protein-coupled receptors, such as changes in intracellular Ca2+ levels were not affected by MMF. CONCLUSIONS: The results show that MMF has a concentration-dependent antiproliferative effect on cultured MCs in the therapeutic range, which might be a rationale for the use of this drug in the treatment of mesangial proliferative glomerulonephritis.  (+info)

Prevalence of angiographic atherosclerotic renal artery disease and its relationship to the anatomical extent of peripheral vascular atherosclerosis. (2/1180)

BACKGROUND: Recognition of the possible presence of atherosclerotic renal artery disease (ARAD) is important because of its progressive nature, and because of the potential for precipitating an acute deterioration in renal function by administration of angiotensin-converting enzyme inhibitors. The aim of this study was to identify the prevalence of ARAD in patients undergoing peripheral angiography and its relationship to the extent of their peripheral vascular disease (PVD). METHODS: The reports of the 218 patients who underwent peripheral angiography to investigate PVD in one centre in a calendar year, and in whom it was possible to image the renal arteries, were analysed retrospectively. The presence of atherosclerotic disease in the renal, aortic, iliac, femoral and distal areas was recorded for each patient. RESULTS: The prevalence of ARAD was 79/218 (36.2%). The greater the number of atherosclerotic areas of the arterial tree, the higher the prevalence of ARAD. Patients with aortic disease and bilateral iliac, femoral and distal vessel disease had the highest incidence of ARAD 19/38 (50%). The incidence of ARAD in those with femoral artery atherosclerosis was significantly higher than in those without femoral artery atherosclerosis (42.1% compared with 9.7%, P=0.001 chi2). There was no significant difference in those groups with or without iliac and distal disease. None of the 11 patients with normal femoral and iliac arteries had ARAD. CONCLUSIONS: Renal artery atherosclerosis is a common occurrence in patients with PVD. If extensive PVD is recognized during aortography, a high flush should be considered to examine the renal arteries, if they are not included in the main study.  (+info)

Arterial damage induced by cryopreservation is irreversible following organ culture. (3/1180)

OBJECTIVES: The aim of the present study was to investigate the changes which occur to the arterial wall following cryopreservation and thawing and to determine whether these changes are reversible after a week of culture in an organ bath. MATERIALS AND METHODS: Rat iliac arterial segments were cryopreserved. Once thawed, the arterial segments were cultured for a period of 0, 1, 2, 4 or 7 days. Freshly isolated rat iliac vessels cultured for 7 days served as the control group. Evaluation was made of ultrastructural changes, the expression of metalloproteinase activity (MMP-1, MMP-3 and MMP-9) and the apoptotic state of cells. RESULTS: The freezing-thawing process induced damage to the arterial segments compared to fresh control vessels. After 1 week of culture, arteries showed a high degree of tissue degeneration. Only a few individual endothelial cells remained on the luminal surface. There was a gradual increase in the proportion of apoptotic cells. The sequential expression of MMP-1 during the first 2 days and subsequent expression of MMP-3 and MMP-9 were of most significance. CONCLUSIONS: Cryopreservation induced damage to the vessels which could not be reversed by organ culture. The changes observed in the expression of metalloproteinases may be indicative of the degenerative process which occurs in the extracellular matrix.  (+info)

Surgical transluminal iliac angioplasty with selective stenting: long-term results assessed by means of duplex scanning. (4/1180)

PURPOSE: The safety of iliac angioplasty and selective stenting performed in the operating room by vascular surgeons was evaluated, and the short- and long-term results were assessed by means of serial duplex scanning. METHODS: Between 1989 and 1996, 281 iliac stenotic or occlusive lesions in 235 consecutive patients with chronic limb ischemia were treated by means of percutaneous transluminal angioplasty (PTA) alone (n = 214) or PTA with stent (n = 67, 23.8%). There were 260 primary lesions and 21 restenosis after a first PTA, which were analyzed separately. Stents were implanted in selected cases, either primarily in totally occluded arteries or after suboptimum results of PTA (ie, residual stenosis or a dissection). Data were collected prospectively and analyzed retrospectively. Results were reported in an intention-to-treat basis. Clinical results and patency were evaluated by means of symptom assessment, ankle brachial pressure index, and duplex scanning at discharge and 1, 3, 6, and every 12 months after angioplasty. To identify factors that may affect outcome, 12 clinical and radiological variables, including the four categories of lesions defined by the Standards of Practice Committee of the Society of Cardiovascular and Interventional Radiology, were analyzed separately. The statistical significances of life-table analysis of patency were determined by means of the log-rank test. RESULTS: There were no postoperative deaths or amputations. Local, general, and vascular complications occurred in 2.1%, 1.3% and 4.7% of cases, respectively (total, 8.1%). The mean follow-up period was 29.6 months. The cumulative patency rates +/- SE of the 260 PTAs (including 55 PTAs plus stents) were 92.9% +/- 1.5% at 1 month, 86. 5% +/- 1.7% at 1 year, 81.2% +/- 2.3% at 2 years, 78.8% +/- 2.9% at 3 years, and 75.4% +/- 3.5% at 5 and 6 years. The two-year patency rate of 21 redo PTAs (including 11 PTAs plus stents) was 79.1% +/- 18.2%. Of 12 predictable variables studied in the first PTA group, only the category of the lesion was predictive of long-term patency. The two-year patency rate was 84% +/- 3% for 199 category 1 lesions and 69.7% +/- 6.5% for 61 category 2, 3, and 4 lesions together (P =. 02). There was no difference of patency in the stented and nonstented group. CONCLUSION: Iliac PTA alone or with the use of a stent (in cases of occlusion and/or suboptimal results of PTA) offers an excellent long-term patency rate. Categorization of lesions remains useful in predicting long-term outcome. PTA can be performed safely by vascular surgeons in the operating room and should be considered to be the primary treatment for localized iliac occlusive disease.  (+info)

Disruption of skin perfusion following longitudinal groin incision for infrainguinal bypass surgery. (5/1180)

OBJECTIVE: The objective of our study was to investigate whether such an incision results in a reduction in blood flow, and therefore haemoglobin oxygen saturation, across the wound. DESIGN: Microvascular oxygenation was measured with lightguide spectrophotometry in 21 patients undergoing femoropopliteal or femorodistal bypass procedures. A series of measurements were made in the groin, medial and lateral to the surface marking of the femoral artery. The mean oxygen saturation on each side was calculated, and the contra-lateral groin was used as a control. The measurements were repeated at 2 and 7 days postop. RESULTS: Oxygen saturation in the skin of the operated groins was increased significantly from baseline at 2 days postop (f = 25.80, p < 0.001) and had begun to return to normal by day 7. The rise was more marked on the lateral side of the wound than on the medial (f = 12.32, p < 0.001). There was no such difference in the control groins. All wounds healed at 10 days. CONCLUSIONS: These results show a significant difference in skin oxygenation between the lateral and medial sides of the groin following longitudinal incision. This may contribute to the relatively high incidence of postoperative infection in these wounds.  (+info)

Effect and outcome of balloon angioplasty and stenting of the iliac arteries evaluated by intravascular ultrasound. (6/1180)

OBJECTIVES: To document the mechanism of percutaneous transluminal angioplasty (PTA) and stenting of the iliac arteries, and to relate the effect to patency. MATERIALS AND METHODS: Thirty-seven stenotic iliac arteries were examined by intravascular ultrasound (IVUS) and arteriography before and after PTA, and after stent deployment (n = 16). The patients were followed prospectively by duplex scanning at 3, 6, 12, 18 and 24 months after the intervention. RESULTS: The effect of PTA was established by both compression and stretching with the major contribution arising from stretching. There were differences in the effect of PTA dependent on plaque morphology: in homogeneous eccentric lesions, stretching contributed significantly more than compression to the luminal gain, while stretching and compression contributed equally in concentric or heterogeneous plaques. Stenting of the arteries had no effect on the free luminal area as measured by IVUS. The primary 1-year patency rate was 72%. The patency was related to the free luminal area and diameter and the heterogenicity of the plaque as evaluated by IVUS. The arteriographic measurements did not have any predictive value. CONCLUSION: IVUS was able to document the effect of PTA and stenting in the iliac arteries, and predict the outcome. The luminal gain and reduction in degree of stenosis seemed to be accomplished primarily by stretching of the arteries and to a lesser extent by plaque compression. Stenting did not change the IVUS measurements. Patency was related to the size of the free lumen and the heterogenicity of the plaque.  (+info)

Specific interaction of oxidized low-density lipoprotein with macrophage-derived foam cells isolated from rabbit atherosclerotic lesions. (7/1180)

Interaction of oxidized LDL (OxLDL) with macrophage-derived foam cells is one of the key events in the development and progression of atherosclerosis. To study this interaction, macrophage-derived foam cells were isolated from rabbit atherosclerotic lesions and the expression of scavenger receptors for OxLDL was examined. Atherosclerosis was induced in rabbits by denudation of the large arteries, followed by a hypercholesteremic diet. Macrophage-derived foam cells, characterized by immunostaining with an RAM-11 antibody (a macrophage marker), contained a high content of intracellular lipid. Maximal binding of radiolabeled OxLDL to isolated macrophage-derived foam cells (1652+/-235 ng 125I-OxLDL/mg of cell protein) was 20-fold higher compared with Bmax values of monocytes. Levels of association of OxLDL to macrophage-derived foam cells isolated from atherosclerotic lesions 12 weeks after denudation were >3-fold higher compared with the levels expressed by macrophage-derived foam cells isolated after 6 weeks. Association of 125I-OxLDL could be completely blocked by OxLDL, and partially by acetylated LDL and polyinosinic acid, indicating the presence of a specific binding site for OxLDL on macrophage-derived foam cells. The induction of scavenger receptors for OxLDL on macrophage-derived foam cells during the development of atherosclerosis, as described in this study, may facilitate the lipid accumulation in macrophage-derived foam cells, as observed in advanced atherosclerotic lesions.  (+info)

Strong induction of members of the chitinase family of proteins in atherosclerosis: chitotriosidase and human cartilage gp-39 expressed in lesion macrophages. (8/1180)

Atherosclerosis is initiated by the infiltration of monocytes into the subendothelial space of the vessel wall and subsequent lipid accumulation of the activated macrophages. The molecular mechanisms involved in the anomalous behavior of macrophages in atherogenesis have only partially been disclosed. Chitotriosidase and human cartilage gp-39 (HC gp-39) are members of the chitinase family of proteins and are expressed in lipid-laden macrophages accumulated in various organs during Gaucher disease. In addition, as shown in this study, chitotriosidase and HC gp-39 can be induced with distinct kinetics in cultured macrophages. We investigated the expression of these chitinase-like genes in the human atherosclerotic vessel wall by in situ hybridizations on atherosclerotic specimens derived from femoral artery (4 specimens), aorta (4 specimens), iliac artery (3 specimens), carotid artery (4 specimens), and coronary artery (1 specimen), as well as 5 specimens derived from apparently normal vascular tissue. We show for the first time that chitotriosidase and HC gp-39 expression was strongly upregulated in distinct subsets of macrophages in the atherosclerotic plaque. The expression patterns of chitotriosidase and HC gp-39 were compared and shown to be different from the patterns observed for the extracellular matrix protein osteopontin and the macrophage marker tartrate-resistant acid phosphatase. Our data emphasize the remarkable phenotypic variation among macrophages present in the atherosclerotic lesion. Furthermore, chitotriosidase enzyme activity was shown to be elevated up to 55-fold in extracts of atherosclerotic tissue. Although a function for chitotriosidase and HC gp-39 has not been identified, we hypothesize a role in cell migration and tissue remodeling during atherogenesis.  (+info)