Creating leadership collectives for sustainability transformations.

Enduring sustainability challenges requires a new model of collective leadership that embraces critical reflection, inclusivity and care. Leadership collectives can support a move in academia from metrics to merits, from a focus on career to care, and enact a shift from disciplinary to inter- and trans-disciplinary research. Academic organisations need to reorient their training programs, work ethics and reward systems to encourage collective excellence and to allow space for future leaders to develop and enact a radically re-imagined vision of how to lead as a collective with care for people and the planet. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11625-021-00909-y.

Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall.

BACKGROUND: -Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor. Methods and Results-Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non-hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (P:=0.037) and 100 ng/mL (P:=0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testosterone group, 0.16). Associated with this inhibitory effect on plaque size was a 50% increase of the amount of androgen receptor mRNA in the arterial segments treated with testosterone. CONCLUSION: -The beneficial effects of testosterone on postinjury plaque development underlines, at least in males, the important role of androgens in the vascular system. As our data suggest, the vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor-dependent pathways in the vascular system.

Intracoronary beta-irradiation with a liquid (188)re-filled balloon: six-month results from a clinical safety and feasibility study.

BACKGROUND: Coronary irradiation is a new concept to reduce restenosis. We evaluated the feasibility and safety of intracoronary irradiation with a balloon catheter filled with (188)Re, a liquid, high-energy beta-emitter. METHODS AND RESULTS: Irradiation with 15 Gy at 0.5-mm tissue depth was performed in 28 lesions after balloon dilation (n=9) or stenting (n=19). Lesions included 19 de novo stenoses, 4 occlusions, and 5 restenoses. Irradiation time was 515+/-199 seconds in 1 to 4 fractions. There were no procedural complications. One patient died of noncardiac causes at day 23. One asymptomatic patient refused 6-month angiography. Quantitative angiography after intervention showed a reference diameter of 2. 77+/-0.35 mm and a minimal lumen diameter of 2.36+/-0.43 mm. At 6-month follow-up, minimal lumen diameter was 1.45+/-0.88 mm (late loss index 0.57). Target lesion restenosis rate (>50% in diameter) was low (12%; 3 of 26). In addition, we observed 9 stenoses at the proximal or distal end of the irradiation zone, potentially caused by the short irradiation segment and the decreasing irradiation dose at its borders ("edge" stenoses). The total restenosis rate was 46% and was significantly lower (29% vs 70%, P=0.042) when the length of the irradiated segment was more than twice the lesion length. CONCLUSIONS: Coronary irradiation with a (188)Re-filled balloon is technically feasible and safe, requiring only standard percutaneous transluminal coronary angioplasty techniques. The target lesion restenosis rate was low. The observed edge stenoses appear to be avoidable by increasing the length of the irradiated segment.

Smooth muscle cell proliferation and restenosis after stand alone coronary excimer laser angioplasty.

It has been shown that coronary excimer laser angioplasty can remove atherosclerotic intracoronary tissue. Stand alone coronary excimer laser angioplasty was successfully performed in a 53 year old white man with 90% stenosis of the left anterior descending coronary artery and exertional angina (Canadian Cardiovascular Society class III). The lesion was reduced to a 30% residual stenosis with use of a 1.2 mm and subsequently a 1.8 mm diameter laser catheter. Early follow-up angiography 24 h later revealed persistent patency and unchanged lesion diameter of the target vessel. The patient was free of symptoms during the 2 month follow-up period, but died suddenly while playing in a tennis tournament 63 days after the procedure. Postmortem histologic examination revealed 80% restenosis at the lesion site without plaque disruption or thrombosis. Specific staining of the histologic specimen for smooth muscle cells using alpha-actin revealed significant smooth muscle cell proliferation at the site of coronary excimer laser angioplasty. However, most of the vessel narrowing appeared to be due to underlying fibrotic plaque as a result of insufficient tissue ablation. This was probably related to the size of the currently available catheters, which are too small to create a large channel.

Incidence of intimal proliferation and apoptosis following balloon angioplasty in an atherosclerotic rabbit model.

OBJECTIVE: The aim of this study was to determine the occurrence of apoptosis in relation to the proliferative response in the intimal layer after experimental balloon angioplasty of a pre-existing plaque. METHODS: After induction of an intimal plaque in the right carotid artery by electrical stimulation, 26 rabbits underwent balloon angioplasty. Twelve animals served as a control group without performance of angioplasty after plaque induction. To study the time course of intimal apoptosis and cell proliferation the vessels were excised on day 7, 14 and 28 after balloon angioplasty. For in situ detection of apoptosis, the TUNEL-technique (TdT-mediated d-UTP fluorescein nick end labeling) was used. In addition, bromodeoxyuridine labeling in all animals allowed the determination of the percentage of cells undergoing DNA synthesis in the neointimal area. Additionally, smooth muscle cells were detected by immunostaining of alpha-actin and macrophages by a specific antibody (RAM 11). RESULTS: Within 28 days of balloon angioplasty, the number of cells undergoing apoptosis remained at a very low level and was not significantly different to the control group without interventional treatment (controls: 0.1 +/- 0.15%; 7 days: 0.44 +/- 0.68%; 14 days: 0.13 +/- 0.11%; 28 days: 0.1 +/- 0.1%). In contrast, the number of cells undergoing DNA synthesis was significantly increased at day 7 after angioplasty (3.72 +/- 2.0% vs. 0.51 +/- 0.29% in controls), resulting in an increase of the total intimal area from 0.088 +/- 0.037 mm2 in the control animals up to 0.256 +/- 0.172 mm2 at day 28 following balloon dilatation. CONCLUSIONS: Our data showed that significant changes in the occurrence of apoptosis are not involved in the regulation of cellular turnover during the examined time period after vessel wall injury. The lacking up-regulation of apoptosis in comparison to the increased cell proliferation in order to maintain the tissue balance is perhaps an important regulatory mechanism leading to intimal hyperplasia after vascular injury in this animal model. Overall, we suggest that there may be a delicate balance between cell proliferation and apoptosis in smooth muscle cells of the vessel wall, and only small shifts in this balance could account for both cellular accumulation in restenotic lesions as well as cell death in mature atheroma.

Endovascular irradiation with the liquid beta-emitter Rhenium-188 to reduce restenosis after experimental wall injury.

OBJECTIVE: Postinterventional irradiation is a new therapeutic concept in the prevention of restenosis. The liquid beta-emitter Rhenium-188 allows endovascular brachytherapy using a conventional balloon catheter without the problem of centering the radiation source. In an animal model of restenosis the feasibility and the dose dependent effect of intravascular brachytherapy with a Rhenium-188 filled balloon catheter was investigated. METHODS: In 68 male New Zealand White rabbits after endothelial denudation of the right common carotid artery with a Fogarty catheter, endovascular irradiation was performed with a Rhenium-188 filled 3.0-mm balloon catheter using different dosages (0, 7.5, 15, 30, 45 and 60 Gy at the surface of the vessel). Then 4 weeks after the intervention the vessels were excised and histologically analyzed. RESULTS: Whereas at 7.5 Gy the intimal area (median [first quartile; third quartile]) did not differ significantly from the control (0.46 mm(2) [0.33 mm(2), 0.75 mm(2)] vs. 0.49 mm(2) [0.34 mm(2), 0.66 mm(2)]), neointimal hyperplasia was decreased significantly at 15 Gy (0.15 mm(2) [0.04 mm(2), 0.17 mm(2)]) and 30 Gy (0.07 mm(2) [0.04 mm(2), 0. 10 mm(2)]), and completely inhibited at the highest dosages (45 Gy: 0 mm(2) [0 mm(2), 0.04 mm(2)]; 60 Gy: 0 mm(2) [0 mm(2), 0.01 mm(2)]). CONCLUSIONS: Catheter transmitted endovascular irradiation with the liquid beta-emitter Rhenium-188 after vascular injury is feasible and effectively reduced neointimal hyperplasia in hypercholesterolemic rabbits. A significant reduction of the neointimal formation could be found already at a radiation absorbed dose of 15 Gy at the vessel surface. Following a surface dosage of 45 Gy the proliferative response to the vessel injury is almost completely abolished.

Local and systemic delivery of low molecular weight heparin stimulates the reendothelialization after balloon angioplasty.

OBJECTIVE: Recent investigations revealed the importance of endothelial cell integrity and function in the pathogenesis of restenosis after angioplasty. Agents which stimulate reendothelialization may prevent restenosis after interventional procedures. The results of in vitro studies suggested that heparin and low molecular weight heparin administration may enhance the recovery of the endothelium. In this study the extent of endothelial denudation and the occurrence and time course of endothelial regeneration after experimental balloon angioplasty followed by subcutaneous or local delivery of low molecular weight heparin was investigated. METHODS: A total of 102 rabbits were included in the study. An atheromatous plaque was induced by electrical stimulation in the right carotid artery of the animals. All animals underwent balloon angioplasty. Thirty-two rabbits received no further medical treatment. Twenty-five rabbits received subcutaneous low molecular weight heparin reviparin (400 anti-Xa-units/day) during the following 7 days. In 25 animals the dilated arterial segments were treated locally with reviparin (1500 anti-Xa-units/4 ml, 2 atm) using a porous balloon (2.5 mm, 35 holes, diameter 75 microns). Twenty animals served as control group without intervention. The vessels were excised 3, 7, 14, 28 and 56 days following intervention. Sections were stained with an antibody against von Willebrand factor and PECAM 1 to confirm the endothelial origin of the lining cells. After bromodeoxyuridine labeling, the extent of proliferation was determined by using a monoclonal antibody. In addition, morphometric analysis of the intimal and medial area was performed. RESULTS: Three days after balloon angioplasty histomorphological analysis showed a reduction of about 60% of the preinterventional endothelial cell number in all three groups. Already one week after intervention there was a significantly higher number of endothelial cells in both groups of low molecular weight heparin treated animals compared to the untreated group (s.c. group 144 +/- 33, local group 142 +/- 32 versus untreated 79 +/- 17 endothelial cells, p < or = 0.05). This significant difference was maintained during the following four weeks and demonstrated a 2-fold increase in endothelial proliferation in the heparin treated animals compared with the untreated group. In addition, immunohistological examination showed a significant decrease in smooth muscle cell proliferation in the s.c. and local reviparin treated animals and a subsequent reduction of intimal thickening. CONCLUSION: Local delivery of low molecular weight heparin promotes reendothelialization and contributes to the inhibition of smooth muscle cell proliferation.

Kinetics and biotransformation of lormetazepam. II. Radioimmunologic determinations in plasma and urine of young and elderly subjects: first-pass effect.

A specific and sensitive radioimmunoassay has been developed for a new benzodiazepine, lormetazepam. After intravenous injection, lormetazepam levels in plasma fell in three (alpha, beta, gamma) dispositional phases, two of them (alpha, beta) mainly reflecting different distribution processes. The terminal (gamma) phase correlated well with the rate of renal elimination of glucuronides. Oral doses were completely absorbed with widely varying absorption half-lifes (t1/2s) amounting to an average of 0.67 +/- 0.53 hr. Dose-dependent maximum plasma levels were reached in about 2 hr. Lormetazepam undergoes first-pass metabolism of about 20% of an oral dose. Total clearance was in the range of 200 ml/min. There was a trend toward slower terminal disposition phase in elderly subjects. In younger subjects, the terminal phase t1/2 was about 10 hr. Lormetazepam glucuronide peak plasma levels were reached by about 6 hr. Thereafter, the level fell in one (elimination) phase, with a t1/2 of 12 hr in young subjects and with a significantly (p < 0.05) different t1/2 of about 20 hr in the elderly. Renal clearance was calculated as about 30 to 40 ml and did not show an age-dependent difference. Recovery of lormetazepam glucuronide with urine amounted to 70% to 80% of the dose during 72 hr after intravenous injection in both age groups.

Nikolaj Nikolajewitsch Anitschkow (1885-1964) established the cholesterol-fed rabbit as a model for atherosclerosis research.

The cholesterol-fed rabbit is a widely used model for experimental atherosclerosis research. In regard to this, one name is periodically mentioned: Nikolaj Nikolajewitsch Anitschkow. Those infrequent reminders of an important name in modern medical history do not pay an adequate tribute to basic findings concerning the pathology and pathogenesis of atherosclerosis. In contrast to research groups at that time conducting experiments with protein enriched diets, Anitschkow demonstrated, in 1913 in St. Petersburg, that it was cholesterol only that caused these atherosclerotic changes in the rabbit arterial intima, which was very similar to human atherosclerosis. By analysing the plaque's development and histology, Anitschkow was able to identify the cell types, on which modern atherosclerosis research is now focussing with a new set of immunohistochemical methods: smooth muscle cells, macrophages and lymphocytes. He noted early (fatty streaks) and advanced (atheromatous plaques) lesions and, by standardizing cholesterol feeding, he discovered that the amount of cholesterol uptake was directly proportional to the degree of atherosclerosis formation. His explanation for this observation was what modern terminology calls 'response-to-injury'. With modern immunohistochemical and molecular-biological methods, the cholesterol-fed rabbit can be used to investigate the pathophysiological aspects which also contribute to human atherosclerosis, such as lipoproteins, diabetes, mitogens, growth-factors, adhesion molecules, endothelial-function, receptor-pathways or platelets. This model can be combined with a number of other methods causing endothelial dysfunction and injury, such as balloon denudation, electric stimulation, cuff implantation, artificial hypertension, diabetes or infection. Bred strains of hereditary hypercholesterolemic rabbits or those resistant to a cholesterol-diet provide further possibilities to expand experimental designs.

17beta-estradiol, gender independently, reduces atheroma development but not neointimal proliferation after balloon injury in the rabbit aorta.

The aim of the present study was to investigate anti-proliferative and anti-atherogenic properties of 17beta-estradiol in balloon injured female and male rabbit aortae. Thirty-two female and 32 male New Zealand White rabbits where gonadectomised. Vascular injury was performed with a balloon catheter in the lower abdominal aorta. Male and female rabbits were randomised into four groups of eight animals each. Only two of four groups received a 0.5% cholesterol-enriched diet. One cholesterol-diet group and one normal-diet group received intramuscular injections of estradiol valerate (1 mg/kg body weight/week). After 28 days, the denuded part of the abdominal aorta was excised and analysed by morphometry and immunohistochemistry. Estrogen treatment did not show an inhibitory effect on neointimal proliferation in normo-cholesterolemic male or female rabbits. A gender independent inhibitory effect of 17beta-estradiol was seen on atheroma development in cholesterol-fed female and male rabbits, while plasma total cholesterol levels were significantly reduced in male rabbits only. The 17beta-estradiol treatment was associated with a significantly decreased number of luminal endothelial cells in normo and hyper-cholesterolemic female rabbits, as evaluated by immunohistochemical staining for 'von Willebrand factor'. Staining for Ki-67-positive proliferating cells after 28 days showed a statistically significant increased proliferative activity in the neointima of hyper-cholesterolemic female rabbits. The neointimal content of macrophages increased significantly in all hyper-cholesterolemic rabbits. Under 17beta-estradiol treatment, the number of macrophages was increased in female and decreased in male rabbits by tendency. Additionally, the 'classical' vascular estrogen receptor was present in both female and male rabbit aortae without statistically significant differences. In conclusion, 17beta-estradiol did not reduce post-injury neointima formation in normo-cholesterolemic rabbits. However, in hyper-cholesterolemic rabbits, 17beta-estradiol reduced atheroma development gender independently. This effect cannot be explained by lowering of plasma cholesterol levels or endothelium-mediated pathways, and requires further investigation on, for example, antioxidative, antiproliferative or estrogen receptor mediated effects.

Tc-99m-labeled endothelin derivative for imaging of experimentally induced atherosclerosis.

OBJECTIVE: to characterize the potential of an endothelin derivative labeled with technetium-99m (Tc-99m) for the imaging of experimentally induced atherosclerosis. METHODS: neointima of different cellularity and severity of stenosis was induced in 32 rabbits by balloon denudation followed by distinct dietary regimens and drug application. Angiograms and scintigrams after injection of the Tc-99m-labeled endothelin derivative were obtained. The aorta was dissected for autoradiography, sudan-III-staining, morphometry, and immunohistology. RESULTS: the lesions induced could be detected in vivo (whole body scintigram) in all the animals 15 min after the injection of the Tc-99m endothelin derivative. Autoradiography revealed a strong relationship between tracer accumulation and sudan-III-staining of lesions. Accumulation of the endothelin derivative correlated with the number of neointimal smooth muscle cells (SMC), but not with the number of medial SMC, neointimal macrophages, and neointimal area. CONCLUSIONS: the results indicate that in vivo imaging of atherosclerosis with an endothelin derivative is a feasible method of detecting and characterizing atherosclerotic arterial wall lesions at early stages.

Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis.

The aim of the present study was to determine the effect of progesterone on the action of estrogen in the development of atherosclerosis. A total of 48 female New Zealand white (NZW) rabbits were ovariectomized. The animals were separated into 6 groups of 8 animals each and received subsequently a 0.5% cholesterol diet for 12 weeks. During this cholesterol feeding period, either estradiol (1 mg/kg body weight (BW)/week), progesterone (25 mg/kg BW/week), or combined estradiol/progesterone (in above dosages) was administered intramuscularly in each group (n = 8 each) of ovariectomized rabbits. One additional group of 8 animals received a combined estrogen/ progesterone regimen, but with progesterone at one third of the above mentioned dosage. In another 8 rabbits, progesterone was reduced to one ninth of the maximum dosage above, whereas estrogen was kept the same, at 1 mg/kg BW/week. Eight ovariectomized animals served as the control group and received no hormone treatment. After 12 weeks, the animals were sacrificed and the proximal aortic arch was removed for further histological examination. An inhibitory effect of estrogen of intimal thickening was found, in comparison to the control group (intimal area: 0.7 +/- 0.5 mm2 vs. 3.7 +/- 2.5 mm2, P < 0.01), whereas progesterone alone did not show a significant effect on intimal plaque size (intimal area: 4.0 +/- 2.3 mm2). In combination with progesterone (high dose), estrogen was not able to reduce intimal atherosclerosis (intimal area: 3.4 +/- 2.4 mm2). However, the beneficial effect of estrogen was not affected by progesterone, when this was reduced respectively to one third (intimal area: 0.8 +/- 0.7 mm2), or to one ninth of the highest dosage (intimal area: 0.6 +/- 0.4 mm2). Interestingly, these differences in atherosclerotic plaque development were observed without significant changes in plasma cholesterol concentrations by the administered hormones. In conclusion, progesterone was dose-dependently able to completely inhibit the beneficial effect of estrogen in experimental atherosclerosis, suggesting that progesterone exerts a direct inhibitory effect on the athero-protective action of estrogen. In the context of recently published data, the present work confirms the importance of the 'non-lipid-mediated', anti-atherosclerotic effect of estrogen, probably due to an interaction with six hormone receptors in vascular smooth muscle cells (VSMC).

Effect of 17-beta estradiol on pre-existing atherosclerotic lesions: role of the endothelium.

The atheroprotective effects of estrogen during the process of atherogenesis is well documented, whereas limited information is available about the effect of estrogen on pre-existing atherosclerotic lesions. After bilateral ovariectomy, 24 New Zealand White rabbits were randomized into three groups of eight animals each and subsequently fed a 0.5% cholesterol diet. In group I, the vessels were excised at day 84, whereas in group II, the cholesterol diet was continued for a total of 168 days. In group III, the animals were first fed with a cholesterol diet for 84 days; in the second phase of the experiment, the cholesterol diet was continued for a further 84 days with a combined estrogen treatment (1 mg estradiol valerate per kg body weight per week intramuscularly). At the end of the experiment, the proximal aortic arch, right carotid artery, thoracical aorta and abdominal aorta of each animal were excised and prepared for histological and immunohistological examination. By day 168, morphometrical analysis displayed a significantly lower plaque development under estrogen therapy in the carotid artery (0.08+/-0.18 mm(2) vs. 0.60+/-0.39 mm(2)), the thoracic aorta (0.56+/-0.94 mm(2) vs. 3.63+/-2.06 mm(2)), and in the abdominal aorta (0.55+/-0.70 mm(2) vs. 1.71+/-1.05 mm(2)) in comparison with the corresponding 168 day control group. However, estrogen treatment has failed to reduce further atherosclerotic plaque development in the aortic arch (9.42+/-1.79 mm(2) vs. 11. 64+/-3.29 mm(2)). Immunohistological detection of the 'anti-human factor VIII related antigen', i.e. the 'von Willebrand factor' (vWF), showed a significantly lower number of luminal cells positive for vWF in the aortic arch in the 84-day cholesterol group, compared with the corresponding controls of normocholesterolemic rabbits (65. 9+/-12.4% vs. 83.1+/-6.2%; P<0.05). Estradiol was able to inhibit the further progression of atherosclerosis when moderate vessel wall alterations were present, whereas pre-existing severe atherosclerosis was associated with a failure of the anti-atherosclerotic estrogen action. As suggested by the in situ detection of vWF as a morphological marker for endothelial cells, an intact endothelial layer might play an important role in mediating the beneficial effect of estrogen in the process of atherosclerosis.

Molecular imaging of atherosclerosis using a technetium-99m-labeled endothelin derivative.

UNLABELLED: Endothelins have been implicated in the pathogenesis of atherosclerosis and restenosis. The aim of this study was to characterize the potential of an endothelin derivative labeled with 99mTc for imaging experimental atherosclerosis in vivo. METHODS: Atherosclerosis was induced by balloon denudation of the infrarenal aorta in eight New Zealand white rabbits followed by a 6-wk period of a standard or 0.5% cholesterol diet in four animals, respectively. Another four rabbits served as controls, without balloon denudation and cholesterol feeding. Digital subtraction angiograms and planar whole-body scintigrams were obtained after intravenous injection of 74 MBq of the 99mTc-labeled endothelin derivative. The aorta was dissected for autoradiography, sudan-III staining, morphometry and immunohistology (anti-alpha-actin, RAM 11) 5 hr after injection. RESULTS: The lesions induced in the infrarenal aorta could be detected in vivo (whole-body scintigrams) in all treated animals only 15 min after injection of 99mTc-endothelin derivative. Autoradiography of the excised aorta revealed good correlation of tracer accumulation and sudan-III-stained lesions. The ratio of accumulation between the induced lesions and untreated vessel wall was 6.8 +/- 1.4 in the cholesterol-fed animals and 6.3 +/- 1.8 in the animals without cholesterol feeding. Accumulation of the endothelin derivative correlated with the number of smooth muscle cells (r = 0.924) but not with the amount of macrophages, the area or the maximum thickness of the plaques. CONCLUSION: Scintigraphic visualization of experimentally induced atherosclerosis in vivo is feasible using an endothelin derivative labeled with 99mTc.

Local intra-arterial drug delivery for prevention of restenosis: comparison of the efficiency of delivery of different radiopharmaceuticals through a porous catheter.

RATIONALE AND OBJECTIVES: Several radiopharmaceuticals were administered through a porous balloon catheter to compare the absolute amount deposited and the retention in the vessel wall. The reported efficiency of local drug delivery ranges from 0.001% to 0.1%, with poor retention after 24 hours. METHODS: An endothelin derivative (n = 6), pertechnetate (n = 6), hexamethylpropylene amineoxime (HMPAO) (n = 5), ethyl cysteinate dimer (ECD) (n = 5), and tin colloid (n = 5) were labeled with 185 MBq/mL 99m-technetium. After balloon denudation of the infrarenal aorta in 27 New Zealand White rabbits, 100 microL of each agent was administered through a porous balloon at a pressure of 4 bar. Dynamic and static whole-body scintigrams were obtained for 24 hours. The infrarenal aorta was excised and the activity calculated in a gamma counter. RESULTS: Apart from their retention in the region of local administration, the radiopharmaceuticals showed different distribution patterns. The highest regional tracer retention was observed with HMPAO. After administration of HMPAO, a significant difference between regional (vessel wall plus surrounding tissue: 14.5% of injected dose [ID]/24 hours) and local (vessel wall: 1.8% ID/24 hours) delivery was found. In contrast, ECD was eliminated quickly (local retention after 24 hours = 0% ID). The retention efficiencies were HMPAO > endothelin derivative > tin colloid > pertechnetate > ECD. CONCLUSIONS: The different physicochemical and pharmacokinetic properties of radiopharmaceuticals resulted in different delivery efficiencies after local application.

Covered stents for prevention of restenosis. Experimental and clinical results with different stent designs.

RATIONALE AND OBJECTIVES: Metallic stents in small vessels go along with a significant risk of restenosis and reocclusion. Different models of stents and covering materials have been purported to prevent intraluminal neointimal proliferation by cover-based closure of the spaces in the wire mesh. METHODS: Tantalum stents covered with polyethylacrylate/polymethylmethacrylate (PEM) were implanted in the infrarenal aorta of six New Zealand white rabbits by aortotomy and compared with eight rabbits treated with uncovered tantalum stents. For deployment, covered and uncovered stents necessitated a 7-French (F) and 5-F sheath, respectively. In addition, nine human patients with arteriosclerotic lesions of the superficial femoral arteries (stenosis > 5 cm or total occlusion) were treated percutaneously with a Dacron-covered nitinol vascular stent via a 9-F sheath. Patients were followed for a mean of 13.5 months, and control angiography was performed after 6 months. RESULTS: Experimental placement of the tantalum Wiktor stent was feasible technically in all cases. Five of six stents covered with PEM were occluded 3 days after placement despite the intravenous use of heparin and aspirin. In the group with uncovered stents, no area of stenosis greater than 10% was observed. There was a neointimal layer of 89 +/- 68 microns around the stent wires. Stent placement was successful in all patients. In four patients, a hyperergic reaction occurred, resulting in noninfectious periarteriitis. This complication was treated successfully with nonsteroidal antiinflammatory drugs. The primary patency was 50%, and the secondary patency (after application of a second covered stent in two patients) was 63%. CONCLUSIONS: The uncovered stent induces little neointimal proliferation around the stent wires. The insertion of stents covered with PEM into the rabbit aorta was accompanied by a strong thrombotic reaction, despite sufficient anticoagulation. Dacron-covered nitinol stents showed a surprisingly high restenosis rate after 9 months of follow-up. Further research concerning the in vivo properties of new covering materials is mandatory before routine vascular clinical application.

The phytoestrogens Genistein and Daidzein, and 17 beta-estradiol inhibit development of neointima in aortas from male and female rabbits in vitro after injury.

BACKGROUND: 17 beta-Estradiol and phytoestrogens are known to have beneficial effects on the cardiovascular systems of women. The exact mechanisms for how estrogens and phytoestrogens influence the cardiovascular system are not yet understood in detail. OBJECTIVE: The objective of this study was to investigate whether 17 beta-estradiol and the phytoestrogens Genistein and Daidzein have an effect on post-injury processes in vessel walls. METHODS: In this in-vitro experiment, the sex-specific effects of 50 micrograms/ml 17 beta-estradiol (equivalent to 180 mumol/l), and of the isoflavones Genistein (5 and 50 micrograms/ml, equivalent to 18.5 and 185 mumol/l), and Daidzein (5 and 50 micrograms/ml, equivalent to 19.7 and 197 mumol/l) on endothelium-denuded aortas from female and male rabbits after vascular injury were studied. Morphometry and immunohistochemistry were performed for quantitative and qualitative analysis. RESULTS: Neointimal cells were in part positive for alpha-actin staining of smooth muscle cells. Staining with 5'-bromo-2'deoxyuridine plus 2'-deoxycytidine showed that proliferative activity in the neointima had significantly decreased after 28 days for groups that had been treated with 50 micrograms/ml Genistein. Immunofluorescence staining for the expression of nuclear estrogen receptor protein in the arterial wall for aortic rings from female and male rabbits was positive. 17 beta-Estradiol, Genistein, and its analog Daidzein (with no protein tyrosine kinase activity) inhibited formation of neointima sex-independently at equivalent concentrations of 50 micrograms/ml. However, a concentration of 5 micrograms/ml Genistein decreased formation of neointima significantly for aortic rings from male rabbits only, whereas 5 micrograms/ml Genistein increased formation of neointima in rings from female rabbits, which corresponded to the increase in proliferative activity detected after 28 days. CONCLUSION: Genistein and Daidzein both inhibited proliferation at certain concentrations, so this effect is supposed to be independent from Genistein's protein tyrosine kinase activity. The antiproliferative properties of all three estrogens were observed in the absence of endothelium and therefore are independent from endothelium-mediated effects.

Estradiol concentrations in premenopausal women with coronary heart disease.

BACKGROUND: Because of the beneficial effects of estrogen, premenopausal women are normally protected against coronary heart disease (CHD) and are at lower risk for myocardial infarction; consequently, CHD occurs very rarely in menstrually active women. Given this background, the aim of the present study was to test the hypothesis that decreased concentrations of estrogen are associated with CHD in premenopausal women. METHODS: Fourteen premenopausal women with CHD were investigated and compared with a healthy control group comparable for age and cardiovascular risk factors. Relevant characteristics of patients and controls were assessed: age, blood pressure, body mass index, total cholesterol and high-density lipoprotein cholesterol, triglycerides, former pregnancies, ovariectomy and related surgical interventions, smoking history and former use of oral contraceptives. To ensure the premenopausal status of the participants, the regularity of the menstrual cycle and the follicle-stimulating hormone concentrations were also assessed. Plasma estradiol and progesterone and urine estrone concentrations (24 h urine collection) were measured at day 6 after estimated ovulation to assess the relative increase in plasma estradiol and progesterone during the second half of the menstrual cycle. RESULTS: Compared with the control group, premenopausal women with CHD had significantly lower concentrations of plasma estradiol (408.9 +/- 141 pmol/l and 287.8 +/- 109 pmol/l respectively; P = 0.0228) and total estrogen (2061 +/- 693 pg/mumol creatinine and 1607 +/- 448 pg/mumol creatinine respectively; P = 0.025) in the urine. However, the progesterone concentrations were not significantly different between the groups. These findings might be explained by a partial ovarian dysfunction, as the patient group had a significantly higher number of tubal sterilizations (eight compared with one). CONCLUSION: Our data provide support for the hypothesis that decreased concentrations of estradiol might be an additional pathogenetic factor for the development of CHD in menstrually active premenopausal women.

Effect of the antioxidant Nicanartine on the proliferative and inflammatory response after experimental balloon angioplasty.

BACKGROUND: Antioxidant treatment seems to reduce the development of restenosis after percutaneous transluminal angioplasty. In this study, the effect of Nicanartine, a new antioxidant drug with both antiproliferative and lipid-lowering properties, on the proliferative and inflammatory response after balloon angioplasty was investigated in a rabbit model of restenosis. METHODS: To induce pre-interventional plaques in the common carotid artery of 48 New Zealand White rabbits, electrostimulation was carried out for 28 days. After a break of 7 days, balloon angioplasty was performed in 36 animals, of which 18 received Nicanartine at a dose of 120 mg/kg body weight; the other 18 served as a control group. The vessels were excised by day 7 and 28 after balloon angioplasty and examined for intimal plaque size, macrophage content and proliferative activity. Bromodeoxyuridine labeling was used to determine proliferating cells in the dilated segment; macrophages were detected using the RAM-11 antibody. RESULTS: In the Nicanartine-treated group, immunohistological quantification 7 days after intervention showed a statistically significant (P< 0.05) reduction of both cells undergoing DNA synthesis (1.6+/-1.4% versus 3.7+/-2.2%) and intimal macrophages (0.7+/-1.2% versus 1.3+/-0.6%). Twenty-eight days after balloon angioplasty, proliferative activity in both groups was decreased to a level comparable to the non-dilated control groups. A clear trend towards smaller plaques could be seen in the Nicanartine group (0.146+/-0.077 mm2 versus 0.255+/-0.174 mm2). Total cholesterol levels did not differ significantly between the groups. CONCLUSION: Under treatment with Nicanartine a clear reduction in the proliferative and inflammatory response after balloon angioplasty was observed. Antioxidant treatment, especially with compounds having antiproliferative and lipid-lowering properties, appears to be an effective secondary preventive strategy after interventional treatment in patients with coronary artery disease.

Synthesis and antimicrobial activity of ethyl N-aryl-S-(triphenylstannyl)isothiocarbamates.

Five ethyl N-aryl-S-(triphenylstannyl)isothiocarbamates were synthesized by the reaction of triphenyltin iodide with the appropriate ethyl N-arylthiocarbamate in the presence of triethylamine. The IR spectrum of each compound was obtained over the 4000--200-cm--1 range, and some bands were assigned. These new compounds were found to be generally better antifungal agents than the previously tested N-substituted N'-cyano-S-(triphenylstannyl)isothioureas. The new compounds were also investigated for antibacterial activity and were especially inhibitory toward Gram-positive species. Except for their lower activity toward Bacillus subtilis, their antibacterial activity was identical to the previously tested N-phenyl-N'-cyano-S-(triphenylstannyl)isothiourea.