摘要:

Basic fibroblast growth factor (bFGF), a constituent of bone and cartilage matrix, has been shown to be a potent mitogen for osteoblasts and chondrocytes and yet an inhibitor of chondrocyte terminal differentiation in cell culture. To characterize the effect of bFGF on bone formation, whole neonatal murine femora were cultured in the presence or absence of bFGF and a neutralizing antibody against bFGF. In vitro, femoral elongation was provided by cartilage growth only; the calcified diaphyseal zone stained by oxytetracycline did not increase. When bFGF was added to the culture medium, longitudinal growth of the proximal and distal cartilage was inhibited in a dose-dependent manner (p < 0.05), and the number of hypertrophic chondrocytes in the growth plate was reduced. This phenomenon was absent in the presence of a neutralizing antibody, which when given alone significantly promoted femoral elongation. In contrast, in vivo after transplantation into adult mice bearing dorsal skin fold chambers, femora rapidly calcified after revascularization. This observation supports the notion that bone formation largely depends on angiogenesis-mediated events. To verify this hypothesis, angiogenesis and bone formation were quantified using bFGF known to be a stimulator of angiogenesis. Calcification of grafted femora was accelerated by bFGF given intraperitoneally. The neutralizing antibody slightly suppressed angiogenesis and femoral elongation (not statistically significant), whereas intravenous injections of both substances did not reveal a significant modulatory effect. In vivo the effect of systemically administered bFGF was inhomogeneous, but there was a strong correlation between angiogenesis and endochondral calcification (p < 0.001). These results suggest that exogenous bFGF modulates bone formation in vitro by inhibition of terminal differentiation of chondrocytes in the growth plate, and angiogenesis and concomitant in vivo events are pivotal in the promotion of rapid bone formation.

ISSN:0167-6865    

DOI:10.1159/000179199

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The currently favoured hypothesis for the link between the raised venous pressure of chronic venous insufficiency and venous ulceration is based on the intermittent inappropriate activation of white blood cells. The damage initiated by the oxidative burst of the leucocyte leads to endothelial dysfunction, interstitial oedema, microthrombi and long-term microcirculatory damage including decreased capillary density. The net result is impairment of the potential for healing and hence ulceration.

ISSN:0167-6865    

DOI:10.1159/000179258

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

We have recently shown that the purified micronized flavonoid fraction (90% diosmin and 10% hesperidin) Daflon® 500 mg attenuates reperfusion injury in the striated skin muscle of the hamster. Herein, we report on the action of Daflon® 500 mg on postischemic macromolecular leakage of FITC-dextran 150 kD provoked by tourniquet ischemia. Intravital fluorescence microscopy was used for analysis of macromolecular leakage in the microcirculation model of the hamster. A tourniquet ischemia of 4 h duration was induced followed by reperfusion. Animals were treated by gavage of Daflon® 500 mg (n = 6) for 8 days at a daily dose of 30 mg kg-1 body weight. Control animals received equivalent volumes of the vehicle (5% Arabic gum solution, n = 6). Measurements of the microcirculatory parameters were made before induction of ischemia and at 0.5,2 and 24 h of reperfusion. After induction of ischemia, macromolecular leakage from postcapillary venules was significantly enhanced in vehicle-treated animals. Treatment with Daflon® 500 mg significantly attenuated macromolecular leakage of FITC-dextran 150 kD. Preliminary data from a histomorphometric analysis (n = 3/experimental group) indicated that the number of emigrated (extravascular) leukocytes after ischemia reperfusion was markedly reduced in Daflon® 500 mg-treated animals as compared to controls. These data indicate that Daflon® 500 mg prevents leakage of the macromolecular tracer FITC-dextran 150 kD from postcapillary venules after postischemic reperfusion, presumably through an inhibitory action on the emigration of activated leuko

ISSN:0167-6865    

DOI:10.1159/000179259

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The aim of our study was to investigate the vascular effects of recombinant human granulocyte colony-stimulating factor (rh G-CSF) in a rat model of irreversible vascular failure. Male anesthetized rats were subjected to the clamping of the splanchnic arteries for 45 min. This surgical procedure resulted in an irreversible state of shock (splanchnic artery occlusion shock) characterized by high mortality rate (0% survival, 120 min following the release of clamps), a profound hypotension and vascular dysfunction consisting of a marked hyporeactivity to phenylephrine (PE 1 nM-10 µM) of aortic rings. Administration of recombinant human granulocyte colony-stimulating factor (20 µg/kg i.v. 5 min after the release of occlusion) increased survival rate (90% 4 h after the release of occlusion), blunted the profound hypotension and reverted the marked vascular dysfunction. Finally, rh G-CSF inhibited the activity of inducible nitric oxide synthase in peritoneal macrophages activated with endotoxin. Our data suggest that rh G-CSF may influence vascular function when low-flow states occu

ISSN:0167-6865    

DOI:10.1159/000179200

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

A growing body of evidence indicates that neutrophils play a critical role in disrupting the microvascular barrier in skeletal muscle. Recent studies from our laboratory and by others indicate that administration of antibodies directed against P-selectin, ICAM-1, or the common subunit (CD 18) of CD 11/CD 18 was as effective as neutrophil depletion in attenuating ischemia/ reperfusion (I/R)-induced microvascular barrier disruption and edema formation in skeletal muscle. These studies have important implications with regard to the pathogenesis of leg ulceration in view of our more recent work indicating that the increase in tissue pressure induced by edema formation secondary to microvascular barrier disruption may lead to the development of capillary no-reflow. The resulting maldistribution of blood flow during reperfusion exacerbates muscle injury induced by ischemia. Daflon® 500 mg is a purified, micronized flavonoid fraction that exhibits a number of anti-inflammatory properties and is used clinically to treat venous insufficiency. In view of these actions and the demonstrated role of neutrophil adhesion in the pathogenesis of I/R, we sought to determine whether this agent would prevent leukocyte adhesion and microvascular barrier disruption in postischemic rat cremaster muscles and small bowel. Rats were treated with Dafion 500 mg (80 mg/kg/ day by gavage) or its vehicle for 2 (cremaster studies) or 10 (mesenteric studies) days prior to the experiments. Leukocyte/endothelial cell interactions and venular protein leakage were quantitated using intravital microscopic techniques in rat cremaster muscles and mesenteries subjected to ischemia (60 min for cremaster, 20 min for mesentery) and reperfusion (60 min). The results indicated that Dafion 500 mg was as effective as the anti-adhesive monoclonal antibodies in reducing postischemic leukocyte adhesion and emigration and venular protein leakage in these models

ISSN:0167-6865    

DOI:10.1159/000179261

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

A small-bowel manometry tube was supplied with two single-fiber micro-probes, which recorded blood flow in the proximal small intestine by the laser-Doppler flowmetry (LDF) technique. In all experiments, saline was infused intravenously as control during the first migrating motor complex (MMC) cycle, and a drug or another saline control given intravenously during the second MMC cycle. Recordings were performed during phase I of MMC, i.e. when motor pattern showed quiescence. Adrenaline increased blood perfusion values by 140% in proximal duodenum and 95% in distal duodenum. The α2-adrenoceptor agonist clonidine decreased the corresponding values by 34 and 25%, respectively, while oxymetazoline decreased perfusion by 33 and 44% at the same levels. The β-adrenoceptor agonist isoprenaline increased blood perfusion values by 172% in the proximal duodenum and 194% in the distal duodenum, whereas the antagonist propranolol decreased the corresponding values by 45 and 52%, respectively. In a separate group of subjects, propranolol was given after adrenaline. The increase in blood perfusion regularly seen after adrenaline was blocked after propranolol administration. In conclusion, our findings validate semi-invasive LDF technique for studies of hemodynamics in human small intestine under basal motor conditions and in drug-induced blood flow change

ISSN:0167-6865    

DOI:10.1159/000179201

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The aim was to study the effect of oral administration of three different doses of S-5682 and α-tocopherol on an oxidant-induced injury by tert-butylhydroperoxide (TBOOH) resulting in increased plasma leakage from postcapillary venules in the hamster cheek pouch microcirculation. Hamsters were on a standard laboratory animal diet with normal vitamin E and C content. Five groups of hamsters (n = 6) were treated orally with placebo (10% lactose solution), S-5682 (5, 20 or 80 mg/kg/day) suspended in 10% lactose solution, or α-tocopherol (1 mg/kg/day) for 10 days prior to oxidant challenge with TBOOH. Topical application of 10-4M TBOOH for 5 min to hamsters given FITC-dextran 30 min prior to TBOOH resulted in reversible increases in the number (mean ± SE) of leaks in postcapillary venules: placebo, 117 ± 7 leaks/ cm2; S-5682, 5 mg/kg/day, 68 ± 3 leaks/cm2 (p < 0.01); S-5682,20 mg/kg/day, 41 ± 3 leaks/cm2 (p < 0.01); S-5682, 80 mg/kg/day, 25 ± 2 leaks/cm2 (p < 0.001), and α-tocopherol, 1 mg/kg/day, 18 ± 1 leaks/cm2 (p < 0.001). The efficacy of inhibition of oxidant-induced leakage by S-5682 was similar to that seen with the same dose (20 mg/kg/day) of histamine, bradykinin, leukotriene B4 or ischemia/reperfusion-induced leakage, suggesting a common pathway for the induction of plasma leakage by these mediators. The maximal dose of S-5682 (80 mg/kg/day) was as effective as α-tocopherol (1 mg/kg/day) in inhibiting plasm

ISSN:0167-6865    

DOI:10.1159/000179262

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Objective: To assess the efficacy of a micronized purified flavonoid fraction (Daflon 500 mg = Dios) in venous leg ulcer healing, in addition to compression therapy and standardized local care. Design: Double-blind, multicentre, randomized, parallel groups, controlled versus placebo trial; stratification according to ulcer size. Subjects: 107 patients, with venous ulcer of the leg for at least 3 months, and accepting bandaging therapy. Results: 105 patients (Dios = 53, placebo = 52) were available for an intention to treat (ITT) analysis. Age (mean ± SD, 71 ± 11 years), gender (M = 33, F = 74) and ulcer size were evenly distributed among both groups. 99 patients completed the protocol (Dios = 51, placebo = 48). Among the 91 patients with ulcer size < 10 cm (Dios = 44, placebo = 47), a significantly higher number of patients had complete ulcer healing at 2 months in the Dios group (n = 14) in comparison to the placebo group (n = 6) after ITT analysis (32 vs. 13%, p = 0.028) and after per protocol analysis (32 vs. 14%, p = 0.048), and a shorter time duration of healing (p = 0.037). Among the 14 patients with ulcer size ≤10cm (Dios = 9, placebo = 5), no ulcer healed. Conclusion: This study showed that a 2-month course of purified micronized flavonoid fraction (2 tablets/day), in addition to conventional treatment, is of benefit in patients by accelerating complete healing of venous leg ulcers which are ≤ 10 cm in dia

ISSN:0167-6865    

DOI:10.1159/000179263

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

We have measured the plantar forefoot skin circulation by the uptake of sodium fluorescein (fluorescein flowmetry), 133Xe clearance and laser Doppler fluxmetry in 24 healthy subjects and correlated measurements under basal conditions and after provocation by alcohol intake and application of external heat. To assess the change in skin circulation between the initial measurement at rest and the second measurement after provocation, the coefficient of correlation (r) of the fluorescein flowmetry to the fast slope of the 133Xe elimination curve was 0.46 (p < 0.05), to the slow slope of the 133Xe elimination curve 0.66 (p < 0.001) and to laser Doppler fluxmetry 0.86 (p < 0.001). The coefficient of correlation (r) of the fluorescence appearance time to fluorescein flowmetry was 0.65 (p < 0.001), to the fast slope of the 133Xe elimination curve 0.14 (p = 0.42), to the slow slope of the 133Xe elimination curve 0.47 (p < 0.05) and to laser Doppler fluxmetry 0.63 (p < 0.00l). The uptake of sodium fluorescein as measured by fluorescein fluxmetry correlates well with both 133Xe clearance and laser Doppler fluxmetry in assessing a change in skin circulation in healthy humans. The fluorescence appearance time also correlates to the slow slope of the 133Xe elimination curve and to laser Doppler fluxmetry though to a lesser extent.

ISSN:0167-6865    

DOI:10.1159/000179202

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The use of Daflon 500 mg has been shown to improve venous tone, microvascular permeability, lymphatic activity, and microcirculatory nutritive flow. This study aimed to assess the effects of Daflon 500 mg at a daily dose of 2 tab/day on microcirculatory, haemorheologic parameters, white blood cell counts and neutrophil activation in patients suffering from chronic venous insufficiency (CVI). This was a single-centre double-blind placebo-controlled study comparing two parallel groups of CVI patients who were treated for 2 months with Daflon 500 mg (n = 39) or placebo (n = 38). Evaluations were performed before treatment (D0) and at the end of treatment (D60). Blood samples were drawn from a foot vein before and at the end of a 15-min period of venous hypertension provoked by a cuff inflated to 100 mm Hg. Red blood cell (RBC) deformability was determined by the initial flow rate filtration technique using a Hanss haemorheometer. RBC aggregation was evaluated by a Myrenne aggregometer based on analysis of transmitted light through a blood sample during flow. RBC disaggregation was evaluated by Sefam erythro-aggregometer based on analysis of the backscattered light through a blood sample in a Couette flow. Microcirculatory parameters were assessed by means of laser Doppler fiuxmetry and transcutaneous oxymetry measurements and consisted of continuous records of blood flux (BF) and TcPO2 before and during 15 min of venous hypertension. Results are expressed as absolute values at baseline (before stasis) and at the end of stasis, before and after 2 months of treatment. Univariate analysis showed a significant reduction of the stasis-induced RBC aggregation index (Daflon 500 mg: -0.07 ± 0.20; placebo: 0.04 ± 0.18; mean ± SD; p = 0.03). Multivariate analysis identified a subset of 5 variables (RBC aggregation, RBC count, microcirculatory BF, amplitude and frequency of vasomotion) that produced a good discrimination model between the two treatments. Linear combination of these 5 variables in 48 patients with complete data showed a significant difference (p < 0.001) between the groups. These changes suggest a protective effect of Daflon 500 mg on the deleterious influence of stasis on microcirculatory (BF) and hemorheologic (RBC aggregation) parameters in CVI patients in comparison to patients receiving place

ISSN:0167-6865    

DOI:10.1159/000179264

出版商:S. Karger AG    

年代:1997

数据来源: Karger