The art of surgery.

, Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.10863 In times when art usually depicted perfection, Caravaggio (1571-1610) painted everyday reality. He used people walking the streets of Rome to represent holy figures. Caravaggio loved many women. He killed a man in a duel and had to flee from Rome to avoid being 'beheaded by anybody who saw him'. In this biblical scene he painted, Judith Beheading Holofernes, Judith is a portrait of Fillide Melandroni, the reason for the duel. Holofernes is a self-portrait. Judith looks cruel, in mourning clothes, seeking revenge for the assassination of her lover. The maidservant, almost an evil spirit, has a voluminous thyroid goitre, and she seems to encourage the revenge of Fillide. Read more about Caravaggio and this painting in an essay online.

Treatment of rectovaginal fistula after colorectal resection with endoscopic stenting: long-term results.

AIM: To treat patients with rectovaginal fistula after anterior resection for cancer using self-expanding metal stents. METHOD: Ten patients of mean age of 56.3 years with rectovaginal fistula after colorectal resection for cancer were treated with endoscopic placement of a self-expanding metal stent. In three patients a diverting proximal stoma had been performed elsewhere. The rectal opening of the fistula was located from 3 to 10 cm from the anal verge (mean 6 cm). All patients had preoperative radiotherapy. In seven patients the stent was placed as the initial treatment while three referred patients had had multiple failed operations. RESULTS: There were no complications after the procedure. At a mean follow-up of 24 months the rectovaginal fistula has healed without major faecal incontinence in eight patients. In the remaining two the fistula has reduced significantly in size to allow a successful flap transposition. CONCLUSION: Endoscopic placement of a self-expanding metal stent is a valid adjunct to treat patients with rectovaginal fistula after colorectal resection for cancer.

Statins reduce levels of metalloproteinases in patients with carotid occlusive disease.

AIM: Pharmaceutical stabilization of an unstable low-grade carotid artery stenosis delays surgery and improve outcome. Statins can be used to reduce intimal media thickness. Our aim was to determine the clinical and biological effects of rosuvastatin on plaque stabilization or regression. METHODS: Forty-two consecutive male patients presenting with an asymptomatic internal carotid artery plaque uniformly anechogenic (group 1) 40-50% lumen diameter reduction formed the basis of the study. A group of 35 patients affected with a uniformly echogenic carotid artery stenosis (40-50%) served as control (group 2). Patients were followed-up every 8-month for 2 years with B-mode ultrasonography and color imaging. A computed tomography angiography (CTA) was performed before the initiation of the study period and at the end to confirm plaque characteristics and the degree of stenosis. Ticlopidine (250 mg/day) and rosuvastatin (10 mg/day) were administered. One blood sample was drawn at every control to assess the release of matrix metallopoteinases (MMPs)-1, -2, -3, -9, tissue inhibitors of metalloproteinases (TIMPs)-1 and -2. RESULTS: After the administration of rosuvastatin plasma level of MMP-1, -2, -3 and -9 significantly decreased in both groups (P<0.001). Conversely, plasma level of TIMP-1 and -2 significantly increased in both groups (P<0.001). B-mode ultrasonography and color imaging and CTA failed to demonstrate a stabilization or regression of uniformly anehogenic carotid plaque during follow-up. CONCLUSION: Rosuvastatin decreases the plasma level of MMPs and increases those of TIMPs. However, neither progression nor stabilization of low-grade unstable carotid plaques was seen.

Self-expandable metal stents in the treatment of benign anastomotic stricture after rectal resection for cancer.

AIM: To evaluate the use of self-expandable metallic stents to treat patients with symptomatic benign anastomotic stricture after colorectal resection. METHOD: Ten patients with a benign symptomatic anastomotic stricture after colorectal resection were treated with endoscopic placement of a self-expandable metal stent. RESULTS: The stent was placed successfully in all 10 patients without any major morbidity. At a mean follow-up of 18 months the stenosis was resolved successfully in 7 out 10 patients (70%). The remaining three patients were subsequently treated successfully with balloon dilatation. CONCLUSION: Self-expandable metal stents represent a valid alternative to balloon dilatation to treat patients with benign symptomatic anastomotic stricture after colorectal resection for cancer.

Self-expanding metal stents for treatment of anastomotic complications after colorectal resection.

Self-expanding metal stents (SEMS) can be used to treat patients with symptomatic anastomotic complications after colorectal resection. In the present case series, 16 patients with symptomatic anastomotic stricture after colorectal resection were treated with endoscopic placement of SEMS. Seven patients had a "simple" anastomotic stricture and nine patients had a fistula associated with the stricture. The anastomotic fistula healed without evidence of residual stricture or major fecal incontinence in seven of the nine patients. Overall the anastomotic stricture was resolved in 10 of the 16 patients. SEMS placement represents a valid adjunctive to treatment in patients with symptomatic anastomotic complications after colorectal resection for cancer.

Basic fibroblast growth factor mediates carotid plaque instability through metalloproteinase-2 and -9 expression.

OBJECTIVE(S): We hypothesized that basic fibroblast growth factor (bFGF) may exert a role in carotid plaque instability by regulating the expression of matrix metalloproteinases (MMP). METHODS: Plaques obtained from 40 consecutive patients undergoing carotid endarterectomy were preoperatively classified as soft or hard. Serum bFGF was pre- and postoperatively measured. The release of MMP-2 and MMP-9 in the blood serum, and the activity, production and expression in the carotid specimens was analyzed. Specific anti-bFGF inhibition tests were performed in vitro on human umbilical artery smooth muscle cells (HUASMC) to evaluate the role of bFGF in the activity, production and expression of MMP-2 and -9. RESULTS: Twenty-one (53%) patients had a soft carotid plaque and 19 (48%) a hard plaque. Preoperative bFGF serum levels were higher in patients with soft plaques [soft=34 (28-39) pg/mL and hard=20 (17-22) pg/mL-p<0.001] and postoperatively returned to normal values (when compared to 10 healthy volunteers). The serum levels of MMP-2 in patients' with soft plaques were higher than those in patients' with hard plaques [soft=1222 (1190-1252) ng/mL and hard=748 (656-793)ng/mL-p<0.0001]. MMP-9 serum values were 26 (22-29) ng/mL for soft plaques and 18 (15-21) ng/mL for hard plaques (p<0.0001). We found increased activity, production and expression of MMP-2 and -9 in soft plaques compared to hard plaques (p<0.001). In vitro inhibition tests on HUASMC showed the direct influence of bFGF on the activity, production and expression of MMP-2 and -9 (p<0.001). CONCLUSIONS: bFGF seems to exert a key role in carotid plaque instability regulating the activity, production and expression of MMP thus altering the physiologic homeostasis of the carotid plaque.

Bimodal concentration-dependent effect of thrombin on endothelial cell proliferation and growth factor release in culture.

BACKGROUND: The role of thrombin in the stimulation of endothelial cell (EC) proliferation is controversial. The aim of this study was to investigate if thrombin regulates cell proliferation and production of platelet-derived growth factor (PDGF), bovine fibroblast growth factor (bFGF), and transforming growth factor beta(1) (TGF-beta(1)) by bovine aortic ECs. METHODS: ECs, obtained from thoracic aortas of calves, were stimulated with thrombin at various concentrations (from 0.05 to 1.0 IU/ml) in serum free culture. Mitogenic activity of thrombin on ECs was determined by tritiated thymidine uptake. The release of PDGF, bFGF, and TGF-beta(1) was assessed by ELISA. PDGF release was confirmed by Western blot and bFGF and TGF-beta(1) mRNA expression was determined by polymerase chain reaction (PCR). RESULTS: Thrombin at high concentrations did not cause any increase in EC proliferation after 72 h of culture and induced inhibition of EC proliferation after 96 h and 8 days of culture. It induced a decrease in PDGF release and an increase in TGF-beta(1) release. Thrombin at low concentrations induced a significant increase in EC proliferation at 72 h, 96 h, and 8 days of culture. It induced an increase in PDGF release and a decrease in TGF-beta(1) release. bFGF release was higher than control at all thrombin concentrations. These data were confirmed by Western blot and PCR studies. CONCLUSIONS: Thrombin regulates EC growth through the inhibition of EC proliferation at high concentrations and through the stimulation of EC proliferation at low physiological concentrations. EC proliferation is partially mediated by autocrine production of PDGF, bFGF, and TGF-beta(1).

Basic fibroblast growth factor and myointimal hyperplasia after experimental polytetrafluoroethylene arterial grafting.

OBJECTIVE: To assess the role of polyclonal antibodies to basic fibroblast growth factor (bFGF) in inhibiting myointimal hyperplasia after insertion of polytetrafluoroethylene (PTFE) grafts in rats. DESIGN: Experimental study. SETTING: University laboratory, Italy. ANIMALS: 24 inbred Lewis rats. INTERVENTIONS: A segment of PTFE I cm long was interposed in the abdominal aorta. The animals were randomised in two groups, n = 12 in each. The first were given polyclonal antibodies to bFGF at the time of operation, and for the first two postoperative days; and the second were given non-specific IgG at the same time periods. MAIN OUTCOME AND MEASURES: Two animals died during the immediate postoperative period of anaesthetic complications. 12 animals (6 in each group) were killed 7 days postoperatively (24 hours after injection of 5-bromo-deoxyuridine BrdU) to assess smooth muscle cell proliferation. The remaining 10 animals (5 in each group) were killed after 1 month to assess the degree of anastomotic myointimal hyperplasia. RESULTS: Antibodies to bFGF resulted in less smooth muscle cell proliferation at the anastomoses as well as anastomotic myointimal hyperplasia. Smooth muscle cell proliferation was reduced to about half in animals treated with anti-bFGF antibodies. Neointimal thickness was reduced in treated animals. CONCLUSIONS: We conclude that after PTFE arterial grafting there is increased production of bFGF at the anastomotic regions that leads to smooth muscle cell proliferation and formation of myointimal hyperplasia. Agents that reduce the production of bFGF may also reduce the development of myointimal hyperplasia after PTFE arterial grafting.

Increased production of cytokines and growth factors by aortic allografts: A possible explanation for myointimal hyperplasia formation.

Accelerated myointimal hyperplasia is a major complication of arterial allografts. The aim of our study was to analyze the role of growth factors in the genesis of myointimal hyperplasia in arterial allografts. Two groups of experiments were performed: Isografts and Allografts. The Isograft group consisted of 18 inbred Lewis rats in which a 1-cm long segment of aorta was inserted as abdominal aortic interposition graft. The aortic segments were obtained from syngeneic Lewis rats. The Allograft group consisted of 18 inbred Lewis rats, in which a 1-cm long segment of aorta was interposed at the level of the abdominal aorta. The aortic segments were obtained from allogeneic Brown-Norway rats. No immunosuppression was used. The animals were sacrificed 4 weeks after surgery and the aortic grafts were analyzed by light, electron microscopy (n = 3 for each group) and immunohistochemistry (n = 3 for each group). In addition, aortic segments (n = 12 for each group) were put in an organ culture to assess production of growth factors. All allografts showed evidence of severe myointimal hyperplasia, which was minimal in isografts. PDGF, bFGF and TGF-beta(1) production, generally considered to be the cause of myointimal hyperplasia, was not increased in allografts, whereas IL-1, TNF-alpha and GM-CSF production was increased in allografts and probably lymphocytes were the source of these cytokines (p < 0.001). We conclude that myointimal hyperplasia in aortic allografts is associated with an increase of IL-1, TNF-alpha and GM-CSF produced by lymphocytes.

Thrombin induces production of growth factors from aortic smooth muscle cells.

BACKGROUND: Myointimal hyperplasia is a common complication of arterial recontructive surgery. The serine protease thrombin has a major role in vessel wall healing and eventual myointimal hyperplasia formation. The aim of this study was to determine the effect of thrombin on the production of PDGF AA and bFGF by arterial smooth muscle cells. MATERIALS AND METHODS: Bovine smooth muscle cells were stimulated with thrombin in a serum-free culture. The release of PDGF AA and bFGF was assessed by ELISA. The effect of thrombin on the proliferation of confluent monolayers of bovine smooth muscle cells was determined by tritiated thymidine uptake. RESULTS: Smooth muscle cells stimulated with thrombin released more PDGF AA (P < 0.001) and bFGF (P < 0.001) than the control. Addition of anti-PDGF AA and anti-bFGF antibodies to the medium of smooth muscle cell cultures neutralized the mitogenic effect of thrombin (P < 0.001). CONCLUSIONS: The findings of our study suggest that thrombin may lead to myointimal hyperplasia formation through induction of PDGF and bFGF production by smooth muscle cells.

Suppression of smooth muscle cell proliferation after experimental PTFE arterial grafting: a role for polyclonal anti-basic fibroblast growth factor (bFGF) antibody.

OBJECTIVES: To determine the role of polyclonal anti-basic Fibroblast Growth Factor (bFGF) antibody in inhibiting the proliferation of smooth muscle cells after experimental polytetrafluorethilene (PTFE) arterial grafting. MATERIALS: In 14 male inbred Lewis rats (weight 250 mg) a 1 cm long segment of PTFE was interposed at the level of abdominal aorta. Animals were randomised to receive polyclonal anti-bFGF antibody (group A: n = seven animals) or aspecific immunoglobulin (group B: n = seven animals). Anti-bFGF antibody or aspecific immunoglublin were given intraperitoneally at the end of operation, and for the first 2 postoperative days. Animals were sacrificed 7 days after surgery, 24 h after intraperitoneal injection of BromodeoxyUridin (BrdU) to label proliferating smooth muscle cells. RESULTS: One animal in each group died in the immediate postoperative period due to anaesthetic problems. All grafts were patent at the time of sacrifice. BrdU labelling index was statistically higher in the control group B animals at the level of the anastomotic regions (proximal anastomosis: group B 7.9% vs. group A 4.1%. Distal anastomosis: group B 5.1% vs. group A 2.6% p = 0.009) and at the level of PTFE graft (group B 3.8% vs. group A 2.6% p = 0.002), while there was no statistical difference between the control thoracic aorta of the two groups. MAIN CONCLUSIONS: bFGF plays a major role in the proliferation of smooth muscle cells at the level of the anastomoses after arterial PTFE grafting. Agents able to block the action of bFGF may be useful in inhibiting the formation of myointimal hyperplasia.

Oxidised LDL (OxLDL) induces production of platelet derived growth factor AA (PDGF AA) from aortic smooth muscle cells.

OBJECTIVES: Elevated concentrations of oxidised low density lipoproteins (OxLDL) are associated with accelerated atherogenesis. The aim of our study was to determine the effect of OxLDL on the proliferation rate and platelet derived growth factor (PDGF) AA production on aortic smooth muscle cells. High density lipoproteins (HDL), which are known to have a protective effect against atherosclerosis, were used as control. MATERIALS AND METHODS: Bovine aortic smooth muscle cells were grown in presence of increased concentrations of OxLDL and HDL and in presence of control medium culture (DMEM). Proliferation rate was assessed by 3H-thymidine uptake. PDGF AA production was determined by ELISA and Western Blot Analysis. RESULTS: OxLDL increased the proliferation rate of aortic smooth muscle cells as compared to DMEM and HDL (p < 0.001). The mitogenic activity of OxLDL on smooth muscle cells was reduced adding anti-PDGF AA antibodies (p < 0.001). PDGF AA production by aortic smooth muscle cells was increased after exposure to OxLDL as compared to DMEM (p < 0.001). HDL significantly reduced the production of PDGF AA by aortic smooth muscle cells (p < 0.001). CONCLUSIONS: Part of the atherogenic effect of OxLDL is mediated through the autocrine production of PDGF AA from aortic smooth muscle cells.

Formation of myointimal hyperplasia and cytokine production in experimental vein grafts.

BACKGROUND: The purpose of this study was to determine the correlation between progression and regression of myointimal hyperplasia (MH) and cytokine production in experimental vein grafts. Although the autologous vein is the best suitable bypass conduit for reconstruction of peripheral arteries, at the end of the first year thrombosis in the coronary and lower extremity circulation ranges from 20% to 50%. Many of these failures are caused by MH. METHODS: In 76 inbred Lewis rats, a 1 cm long segment of inferior vena cava was inserted at the level of the abdominal aorta. The segments of inferior vena cava were obtained from syngeneic Lewis rats. In 56 animals the arterial vein graft was explanted 3 days (n = 10), 7 days (n = 10), 4 weeks (n = 26), and 12 weeks (n = 10) after operation. In 20 animals the vein graft was explanted 4 weeks after being in the arterial system and reimplanted as iliac venovenous bypass in syngeneic Lewis rats. These grafts were explanted 2 weeks (n = 10) and 8 weeks (n = 10) later. Grafts were analyzed by light and electron microscopy, morphometric study, and histochemical analysis and were put in an organ culture to assess cytokine production. RESULTS: We observed MH formation in arterial vein grafts and MH regression in reimplanted vein grafts (p < 0.001). MH formation was correlated with production of platelet-derived growth factor, basic fibroblast growth factor, interleukin-1, and tumor necrosis factor-alpha. MH regression was correlated with transforming growth factor-beta 1 production. CONCLUSIONS: On the basis of the results of our study, we conclude that MH formation in experimental vein grafts depends on production of platelet-derived growth factor, basic fibroblast growth factor, interleukin-1, and tumor necrosis factor-alpha, and MH regression depends on transforming growth factor-beta 1 production. Cytokine therapy may represent a valuable new treatment to prevent vein bypass failures caused by MH.

Shear stress induces transforming growth factor-beta 1 release by arterial endothelial cells.

BACKGROUND: Myointimal hyperplasia is a common complication after vascular reconstruction. Increasing shear stress has been shown to reduce formation of myointimal hyperplasia. The aims of our study were (1) to analyze the correlation between shear stress and release of transforming growth factor (TGF)-beta 1 by endothelial cells and (2) to determine the effect of TGF-beta 1 on smooth muscle cell proliferation. METHODS: Bovine arterial endothelial cells were subjected to increasing shear stress in an in vitro serum-free system. The release of TGF-beta 1 by endothelial cells was assessed by enzyme-linked immunosorbent assay and Western blot analysis. The effect of TGF-beta 1 on the proliferation of the subconfluent monolayer of bovine smooth muscle cells was determined by tritiated thymidine uptake. RESULTS: Shear stress induced a significant increase of the release of TGF-beta 1 by endothelial cells (p < 0.001). This phenomenon was proportional to the level of shear stress. The amount of TGF-beta 1 released by endothelial cells subjected to shear stress had a significant inhibitory effect on growth rate and tritiated thymidine uptake of smooth muscle cells. CONCLUSIONS: On the basis of the results of our study, we conclude that increasing shear stress induces release of TGF-beta 1 by arterial endothelial cells in a concentration that has a clear inhibitory effect on smooth muscle cell proliferation. This phenomenon could explain the inhibitory effect of increasing shear stress on the formation of myointimal hyperplasia.