Platelet-derived growth factors induced lymphangiogenesis: evidence,unanswered questions and upcoming challenges

Crosstalk between angiogenesis and lymphangiogenesis in embryonic development continues during postnatal life and has specific mechanisms involving factors that initiate activation of the intracellular cascade for their specific receptors. Platelet-derived growth factors (PDGFs) and their corresponding receptors (PDGFRs) are known as important regulators of blood vessel development in both normal and pathologic angiogenesis. Despite some recent papers which reported a potential role of the PDGF/PDGFR axis in lymphatic spread of tumor cells, a few papers have suggested the potential role of PDGFs in tumor lymphangiogenesis development. The present paper summarizes the potential lymphangiogenic role of the PDGF/PDGFR axis, underlying upcoming challenges in the field.     

Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant*

The British Committee for Standards in Haematology first produced guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant in 2000. This revision updates those guidelines and covers the areas of diagnosis, treatment and assessment of response to therapy.     

Expression of BCL-2 and p53 in oncocytic (Hürthle cell) tumors of the thyroid: An immunohistochemical study

Previous studies have established that thyroid follicular neoplasms of higher malignant potential show a high p53 and low bc1-2 expression. This however has not been well studied in Oncocytic (Hürthle cell) neoplasms, the management of which remains controversial. We therefore studied the expression of p53 and bc1-2 in 18 Hürthle cell adenomas (HCA) and 8 Hürthle cell carcinomas (HCC) and compared them with their benign and malignant counterparts, respectively, including 16 follicular adenomas (FA) and 68 papillary carcinomas (PC). All 16 FA were bc1-2 positive, 4 were 2+, and 12 were 3+. On the other hand, 14/18 (78%) HCA showed bc1-2 expression, 5 were 1+, 6 were 2+, and only 3 were 3_. Similarly, HCC showed a weaker bc1-2 staining pattern compared to PC. Only 1 FA showed grade 1, p53 staining, the remaining 15 were negative, and 15/18 HCA showed p53 expression of varying grades. This difference in p53 staining was statistically significant (p=0.005). A significant p53 overexpression was also seen in HCC compared to PC (p=0.005). In conclusion, there appears to be an inverse relationship between p53 and bc1-2 expression in thyroid follicular neoplasms. A higher expression of p53 and lower levels bc1-2 in Hürthle cell neoplasms may have biological and clinical implications. This may support a more aggressive surgical treatment for HCA compared to FA.     

A comparative study of plasma concentrations of liposomal amphotericin B (L-AMP-LRC-1) in adults, children and neonates

Amphotericin B (AmpB) incorporated into small unilamellar liposomes prepared from soya phosphatidylcholine and cholesterol (L-AMP-LRC-1) has been shown to be safe and effective in patients with systemic fungal infections. In this report, we compared the plasma levels of AmpB in adults, children and neonates following administration of L-AMP-LRC-1. A 1.0 mg/kg dose of L-AMP-LRC-1 in adult patients resulted in peak concentrations of 1.02+/-0.14 mg/l (mean+/-S.D.) on day 1, which increased to 1.66+/-0.19 mg/l on day 28 after continued therapy. The area under the plasma concentration-time curve also increased from 13.05+/-1.52 on day 1 to 19.85+/-5.41 mg h/l on day 28. In children, the peak plasma concentration following 1.0 mg/kg per day dose of L-AMP-LRC-1 increased from 0.63+/-0.20 on day 1 to 1.10+/-0.53 mg/l on day 28. While in neonates, the levels increased from 0.54+/-0.17 on day 1 to 0.73+/-0.29 mg/l on day 28. These levels of AmpB in children and neonates were found to be significantly lower than in adults. This may be due to higher volume of distribution, since 1.0 mg/kg per day dose of L-AMP-LRC-1 was found to be effective in neonates.     

Sustained increases of plasma homocysteine,copper, and serum ceruloplasmin after coronary artery bypass grafting

BACKGROUND: Homocysteine (Hcy) is an independent risk factor for coronary artery disease, but there are no reports on Hcy levels in patients undergoing coronary artery bypass graft (CABG) surgery. Interactions between Hcy and copper may mediate the vasculopathic impact of Hcy, and this may play a role in vein graft failure. The aim of this study was to assess the perioperative levels of Hcy, copper, ceruloplasmin (CP), folate, and vitamin B12 in patients undergoing myocardial revascularization surgery. METHODS: Blood samples were taken from 55 consecutive patients undergoing elective conventional CABG (43 male; mean age, 63.2 +/- 5.2 years) 1 day preoperatively and postoperatively at 1 day, 6 days, and 6 weeks. Hcy, copper, CP, red cell folate, vitamin B12, creatinine, and C-reactive protein (CRP) were then measured using standard clinical chemistry methods. The same protocol was applied to 10 patients (7 male; mean age, 63.3 +/- 5.2 years) undergoing off-pump coronary artery bypass (OPCAB) surgery. RESULTS: In the conventional CABG group, there were significant increases in the plasma concentrations at 6 days and 6 weeks postoperatively of Hcy (from 10.1 to 11.6 and 13.5 micromol/L, respectively), plasma copper (from 13.5 to 20.3 and 18.5 micromol/L), and serum ceruloplasmin (from 0.3 to 0.41 and 0.44 g/L). CRP and vitamin B12 were elevated at 6 days but not 6 weeks after the operation. In contrast, red cell folate and creatinine were not significantly changed. The subgroup analysis for the OPCAB patients showed the same trend as for the conventional group. CONCLUSIONS: Coronary surgery precipitates a significant and sustained increase in the blood concentrations of Hcy and copper, which is not due to a decrease in folate and vitamin B12, altered renal function, or inflammation. Further studies are required to establish whether the concomitant increase in Hcy and copper plays an etiological role in vein graft disease.     

Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia

OBJECTIVE: To investigate the effect of sustained hyperhomocysteinaemia (HHCy) on cavernosal smooth muscle function in a rabbit model of HHCy, developed using a methionine-enriched diet in which cavernosal responses were characterized, as elevated plasma levels of homocysteine may be a risk factor for vasculogenic erectile dysfunction. MATERIALS AND METHODS: Six New Zealand White rabbits were fed a diet supplemented with methionine (20 g/kg chow) for 4 weeks, while six control animals were fed a standard diet. Cavernosal strips were mounted in an organ bath and relaxation assessed when stimulated with carbachol, sodium nitroprusside (SNP), or noncholinergic, nonadrenergic (NANC)-mediated relaxation to electrical-field stimulation (EFS). Cavernosal tissue cGMP levels were assessed using an enzyme-linked immunosorbent assay, and superoxide (O(2) (.-)) production assessed using an assay of the superoxide dismutase (SOD)-inhibitable reduction of ferricytochrome c. RESULTS: The methionine-rich diet led to an early but sustained HHCy; cavernosal strips from animals after 4 weeks of HHCy had a significantly impaired relaxation response to carbachol, an index of endothelium-dependent nitric oxide (NO)-mediated relaxation. This impairment was reversed by incubating with either SOD or catalase. Relaxation with either SNP, an index of endothelium-independent NO-mediated relaxation, or NANC-mediated EFS-induced relaxation, was unaffected by HHCy. There was a corresponding significant reduction in cavernosal cGMP levels (index of NO activity) in the HHCy group, with a more than five-fold increase in cavernosal tissue O(2) (.-) production. CONCLUSION: Supplementing the diet of rabbits with methionine for 4 weeks caused an early and sustained HHCy and promoted a marked inhibitory effect on endothelium-dependent relaxation and NO formation in isolated corpus cavernosum, an effect mediated by reactive oxygen species.     

The endothelin 1A receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein-carotid artery interposition grafts

OBJECTIVE: Late saphenous vein graft failure after coronary artery bypass graft surgery is initiated by medial thickening and neointima formation, both of which are mediated by the proliferation of vascular smooth muscle cells. Because porcine vein grafts contain high levels of endothelin 1 receptor subtypes and endothelin 1 promotes the proliferation of vascular smooth muscle cells, the effect of administration of the endothelin 1(A) receptor antagonist BSF 302146 ([+]-[S]-2-[4,6-dimethyl-pyrimidin-2-yloxy]-3,3-diphenyl-butanoic acid) on porcine vein graft thickening was investigated. METHODS: Saphenous vein-carotid artery interposition grafting was performed in 4 groups of large white pigs (30-35 kg, n = 10 for each group). BSF 302146 was administered orally (3, 10, and 30 mg x kg(-1) x d(-1)) for 4 weeks to one group of pigs, and placebo was administered to the other group (control animals). Pigs were then anesthetized, and the grafts were removed and fixed at 100 mm Hg with 4% paraformaldehyde. Histologic sections were prepared, and graft morphometry was carried out by using computer-aided planimetry. RESULTS: In vein grafts from animals treated with BSF 302146 compared with grafts from control animals (untreated), there were significant dose-dependent reductions in the increase in medial thickness and neointimal thickness, an increase in luminal area, and a decrease in proliferating cell nuclear antigen-positive cells in the medial-intimal area. CONCLUSIONS: The administration of BSF 302146 reduces graft thickening and promotes positive remodeling through an endothelin 1(A)-mediated effect on vascular smooth muscle cell replication. The administration of this endothelin 1(A) receptor antagonist might therefore be therapeutically effective in preventing late vein graft failure in patients undergoing coronary artery bypass grafting.