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Biomedical subjects

Peter C Neligan

Publications and source records attributed to Peter C Neligan.

10 recordsLinked to original sources
PubMed2003

Vasodilator effect and mechanism of action of vascular endothelial growth factor in skin vasculature.

Various laboratories have reported that local subcutaneous or subdermal injection of VEGF(165) at the time of surgery effectively attenuated ischemic necrosis in rat skin flaps, but the mechanism was not studied and enhanced angiogenesis was implicated. In the present study, we used the clinically relevant isolated perfused 6 x 16-cm pig buttock skin flap model to 1) test our hypothesis that VEGF(165) is a potent vasodilator and acute VEGF(165) treatment increases skin perfusion; and 2) investigate the mechanism of VEGF(165)-induced skin vasorelaxation. We observed that VEGF(165) (5 x 10(-16)-5 x 10(-11) M) elicited a concentration-dependent decrease in perfusion pressure (i.e., vasorelaxation) in skin flaps preconstricted with a submaximal concentration of norepinephrine (NE), endothelin-1, or U-46619. The VEGF(165)-induced skin vasorelaxation was confirmed using a dermofluorometry technique for assessment of skin perfusion. The vasorelaxation potency of VEGF(165) in NE-preconstricted skin flaps (pD(2) = 13.57 +/- 0.31) was higher (P < 0.05) than that of acetylcholine (pD(2) = 7.08 +/- 0.24). Human placental factor, a specific VEGF receptor-1 agonist, did not elicit any vasorelaxation effect. However, a specific antibody to VEGF receptor-2 (1 microg/ml) or a specific VEGF receptor-2 inhibitor (5 x 10(-6) M SU-1498) blocked the vasorelaxation effect of VEGF(165) in NE-preconstricted skin flaps. These observations indicate that the potent vasorelaxation effect of VEGF(165) in the skin vasculature is initiated by the activation of VEGF receptor-2. Furthermore, using pharmacological probes, we observed that the postreceptor signaling pathways of VEGF(165)-induced skin vasorelaxation involved activation of phospholipase C and protein kinase C, an increase in inositol 1,4,5-trisphosphate activity, release of the intra-cellular Ca(2+) store, and synthesis/release of endothelial nitric oxide, which predominantly triggered the effector mechanism of VEGF(165)-induced vasorelaxation. This information provides, for the first time, an important insight into the mechanism of VEGF(165) protein or gene therapy in the prevention/treatment of ischemia in skin flap surgery and skin ischemic diseases.

Animals↗
PubMed2003

Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction.

The aim of this study was to investigate the efficacy and mechanism of action of a noninvasive remote ischemic preconditioning (IPC) technique for the protection of multiple distant skeletal muscles against ischemic necrosis (infarction). It was observed in the pig that three cycles of 10-min occlusion and reperfusion in a hindlimb by tourniquet application reduced the infarction of latissimus dorsi (LD), gracilis (GC), and rectus abdominis (RA) muscle flaps by 55%, 60%, and 55%, respectively, compared with their corresponding control (n = 6, P < 0.01) when they were subsequently subjected to 4 h of ischemia and 48 h of reperfusion. This infarct-protective effect of remote IPC in LD muscle flaps was abolished by an intravenous bolus injection of the nonselective opioid receptor antagonist naloxone (3 mg/kg) 10 min before remote IPC and a continuous intravenous infusion (3 mg/kg) during remote IPC and by an intravenous bolus injection of the selective delta 1-opioid receptor antagonist 7-benzylidenealtrexone maleate (3 mg/kg). However, this infarct-protective effect of remote IPC was not affected by an intravenous bolus injection of the ganglionic blocker hexamethonium chloride (20 mg/kg) or the nonspecific adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (10 mg/kg) or by a local intra-arterial injection of the adenosine1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (3 mg/muscle flap) given 10 min before remote IPC. It was also observed that this remote IPC of skeletal muscle against infarction was associated with a slower rate of muscle ATP depletion during the 4 h of sustained ischemia and a reduced muscle neutrophilic myeloperoxidase activity after 1.5 h of reperfusion. These observations led us to speculate that noninvasive remote IPC by brief cycles of occlusion and reperfusion in a pig hindlimb is effective in global protection of skeletal muscle against infarction. This infarct-protective effect is most likely triggered by the activation of opioid receptors in the skeletal muscle, and remote IPC is associated with an energy-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion.

Abdomen↗
PubMed2003

Microvascular free tissue transfer in elderly patients: the Toronto experience.

BACKGROUND: Microvascular free tissue transfer has become an accepted and versatile method of reconstruction in the head and neck region, offering a one-stage procedure and thus reducing the number and length of hospital stays. Many of the patients requiring head and neck free flaps are elderly, with concomitant medical problems, including respiratory and cardiovascular compromise, and are therefore potentially at higher risk of adverse outcomes. In addition, they frequently have a history of heavy alcohol and cigarette consumption, which can compound the risks. METHODS: We analyzed a series of 288 intraoral free flap reconstructions and arbitrarily divided them into four groups depending on age: <50, 51-60, 61-70, >70. These reconstructions were all performed for malignant lesions. Preoperative medical problems, including ischemic heart disease, hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, and diabetes, were assessed and compared among the different age groups. CONCLUSIONS: Our results suggest that free flap surgery is a safe technique in elderly patients with comparable surgical complications to a younger patient population. As a result of concomitant medical problems, however, postoperative medical complications are more frequent in the older age groups, with a resultant increase in length of hospital stay.

Age Distribution↗
PubMed2003

Development and validation of new model for microvascular transplantation of epiphyseal plate allografts with minimal adjoining epiphyseal and metaphyseal bone.

A model for the free allograft microvascular transplantation of rabbit proximal tibial epiphyseal plate allografts was developed, validated, and tested in an in vivo animal model. Transplants contained the minimum amount of adjacent epiphyseal and metaphyseal bone compatible with preservation of the epiphyseal-plate vascular supply, as determined by corrosion casting. Perfusion to this graft was evaluated quantitatively using radioactive microspheres, and qualitatively using India-ink injection. Female New Zealand White rabbits at 12 weeks of age were utilized. Vascularized transplantation of epiphyseal plate allografts was performed either into a defect of matched size in the iliac crest or into a soft-tissue pocket without bone contact. Cyclosporine A immunosuppression (CSA) was administered daily for 6 weeks. Two control groups underwent identical surgical procedures, but had no postoperative immunosuppression. Epiphyseal plates both with and without bone contact, in rabbits immunosuppressed postoperatively with CSA, demonstrated longitudinal growth and preserved viability as determined by positive bromodeoxyuridine uptake. Control epiphyseal plates transferred without postoperative immunosuppression were uniformly nonviable. This new model has value as a basis for further studies into the clinical applicability of isolated epiphyseal-plate transplants.

Animals↗
PubMed2003

Functional reconstruction of the oral cavity.

Reconstruction of the oral cavity is an intricate subject that reflects the complexity of the oral cavity itself. There is no perfect reconstruction. Presented here are the current optimal choices for the various regions within the oral cavity. We are constantly seeking to improve these reconstructions in an effort to restore optimal function to patients unfortunate enough to require surgical excision of this most elaborate of anatomic structures.

Adult↗
PubMed2003

Head and neck reconstruction with anterolateral thigh flap.

OBJECTIVE: Our goal was to present our experience with the free anterolateral thigh flap for reconstruction of various cutaneous and mucosal defects of the head and neck. STUDY DESIGN: We conducted a retrospective review of 37 patients who underwent reconstruction between 1994 and 2002. Outcome measures included ethnicity, flap harvest technique, vascular anatomy, flap success, general surgical complications, and donor site morbidity. RESULTS: The majority of our patients were white (n = 33). The size of the 39 free anterolateral thigh flaps varied from 24 to 252 cm(2). There was 1 arterial failure and flap loss (2.6%) and 2 venous occlusions that were both salvaged. The donor site was closed primarily in 37 cases and with a split-thickness skin graft in 2 cases. CONCLUSIONS: This is the first report on using the free anterolateral thigh flap in whites. This free transfer has proved to be a versatile and reliable flap for reconstruction of the head and neck.

Adult↗
PubMed2003

Perforator flaps: evolution, classification, and applications.

In this article, the authors review the literature regarding perforator flaps. Musculocutaneous perforator flaps have evolved from musculocutaneous flaps and offer several distinct advantages. By sparing muscle tissue, thus reducing donor site morbidity and functional loss, perforator flaps are indicated for a number of clinical problems. The versatility of the perforator flap makes it ideal for the reconstruction of three-dimensional defects such as breast reconstruction or as a thin flap for resurfacing shallow wounds when bulk is considered a disadvantage. The authors review the historical development of the perforator flap and discuss the advantages and disadvantages of perforator flaps compared with free and pedicled musculocutaneous flaps. The nomenclature traditionally used for perforator flaps is confusing and lacks a standardized anatomic basis. The authors present a method to describe all perforator flaps according to their artery of origin.

Humans↗
PubMed2003

Vasoconstrictor effect and mechanism of action of endothelin-1 in human radial artery and vein: implication of skin flap vasospasm.

Vasospasm in the vascular pedicle is a major cause of ischemic necrosis in autogenous skin transplantation (i.e., skin free flap surgery), and the pathophysiology is unclear. The clinical impression is that veins are more susceptible to vasospasm than arteries in the vascular pedicle of skin free flaps. The purpose of this study was to compare the vasoconstrictor response of the human radial artery (RA) and radial vein (RV) to endothelin (ET)-1 and to investigate the mechanism mediating ET-1-induced vasoconstriction. The isometric tension of RA and RV rings (4 mm) obtained from the vascular pedicle of human radial forearm skin free flaps were studied in organ chambers containing Krebs bicarbonate buffer. It was observed that ET-1 elicited concentration-dependent (5 x 10 (-11)to 2 x 10 (-8) ) contractions in RA and RV rings with similar contractile potency. However, the concentration-dependent contractile response to ET-1 was significantly (P < 0.05) higher in RV rings than in RA rings, with the maximum contractile response twice as high in RV rings than in RA rings. The contractile response to ET-1 in RA and RV rings was blocked by the ET receptor antagonist BQ 123 (10 (-5M)), but not by the ET receptor antagonist BQ 788 (5 x 10 (-6)). The ET(B) receptor agonist BQ 3020 (10 (-10) to 2 x 10(-8) ) had no significant contractile effect in RA and RV rings. Furthermore, the L-type Ca channel antagonist nifedipine (5 x 10 (-6)), the protein kinase C (PKC) inhibitor chelerythrine (10(-5M)), and the intracellular Ca chelator BAPTA-AM (10(-5M)) significantly reduced the contractile potency of ET-1 in RA rings and the maximum contractile response to ET-1 in RA and RV rings. It was concluded that the human RV is more responsive than RA to the contractile effect of ET-1. The contractile response to ET-1 in RA and RV is predominantly mediated by ET(A) receptors and the postreceptor mechanism involves L-type Ca (2+) channels, PKC, and intracellular Ca(2+).

Adult↗
PubMed2002

Efficacy of radioprotection in the prevention of radiation-induced craniofacial bone growth inhibition.

It has been reported that radiotherapy-induced craniofacial deformities can occur in 66 to 100 percent of survivors of childhood head and neck cancers. Recent interest in the effectiveness of radioprotectors in the protection of normal tissue against radiation injury led us to investigate a possible role of radioprotection in the prevention of radiation-induced craniofacial bone growth inhibition. Therefore, the objective of this study was to use the radioprotective agent amifostine (Ethyol, WR-2721) as a probe to determine the effectiveness of radioprotection in the prevention of radiation-induced craniofacial bone growth inhibition after single-dose orthovoltage radiation to the infant rabbit orbital-zygomatic complex. Seven-week-old male New Zealand white rabbits were randomized into three groups (n = 10 each): group 1, 0 Gy (sham radiation); group 2, 35-Gy single-dose orthovoltage radiation; and group 3, 35-Gy single-dose orthovoltage radiation and amifostine (300 mg/kg intravenously, given 20 minutes before radiation). Serial radiographs and computed tomographic scans were obtained for cephalometric analysis, bone volume, and bone density measurements until skeletal maturity at 21 weeks. Significant (p < 0.05) reductions in orbital-zygomatic complex linear bone growth, bone volume, and bone density were observed after 35-Gy radiation compared with nonirradiated controls. No significant differences were noted between groups in cephalometric analysis of the nontreated (nonirradiated) left orbital-zygomatic complex, indicating no crossover effect from the radiation beam. However, pretreatment with amifostine, 20 minutes before 35-Gy radiation, resulted in significant (p < 0.05) preservation of linear bone growth, bone volume, and bone mineral density in the rabbit orbital-zygomatic complex compared with controls. This study demonstrated for the first time the effectiveness of a radioprotector in the prevention of radiation-induced craniofacial bone growth inhibition, and it paves the way for investigation into the pathogenic mechanism and prevention of radiotherapy-induced craniofacial deformities.

Amifostine↗