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The article discusses the importance of collaboration in plastic surgery and the barriers that prevent it from being more widespread. The author emphasizes that collaboration goes beyond mere interaction and involves actively participating in the management of each case. The reasons for the lack of collaboration include financial considerations, availability of specialists, and ego. The article also highlights the role of innovation in surgery and how it is often linked to collaboration. The author concludes by emphasizing the importance of teamwork and the benefits it brings to patient care and surgical outcomes. [Extracted from the article]

We tested our hypothesis that postischemic conditioning (PostC) is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mitochondrial permeability transition pore (mPTP). In bilateral 8 x 13 cm pig latissimus dorsi muscle flaps subjected to 4 h ischemia, muscle infarction increased from 22 [+ or -] 4 to 41 [+ or -] 1% between 2 and 24 h reperfusion and remained unchanged at 48 (38 [+ or -] 6%) and 72 (40 [+ or -] 1%) h reperfusion (P < 0.05; n = 4 pigs). PostC induced by four cycles of 30-s reperfusion/reocclusion at the onset of reperfusion after 4 h ischemia reduced muscle infarction from 44 [+ or -] 2 to 22 [+ or -] 2% at 48 h reperfusion. This infarct protective effect of PostC was mimicked by intravenous injection of the mPTP opening inhibitor cyclosporin A or NIM-811 (10 mg/kg) at 5 min before the end of 4 h ischemia and was abolished by intravenous injection of the mPTP opener atractyloside (10 mg/kg) at 5 min before PostC (P < 0.05; n = 4-5 pigs). PostC or intravenous cyclosporin A injection at 5 min before reperfusion caused a decrease in muscle myeloperoxidase activity and mitochondrial free [Ca.sup.2+] concentration and an increase in muscle ATP content after 4 h ischemia and 2 h reperfusion compared with the time-matched controls. These effects of PostC were abolished by intravenous injection of atractyloside at 5 min before PostC (P < 0.05; n = 6 pigs). These observations support our hypothesis that PostC is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mPTP. skeletal muscle postconditioning; mitochondrial permeability transition pore; neutrophil accumulation; mitochondrial calcium content; 5'-adenosine triphosphate synthesis

Skin ischemic necrosis due to vasospasm and/or insufficient vascularity is the most common complication in the distal portion of the skin flap in reconstructive surgery. This project was designed to test our hypothesis that preoperative subdermal injection of adenoviral vectors encoding genes for vascular endothelial growth factor-165 (Ad.VEGF-165) or endothelial nitric oxide (NO) synthase (Ad.eNOS) effectively augments skin viability in skin flap surgery and that the mechanism of Ad.VEGF-165 gene therapy involves an increase in synthesis/release of the angiogenic and vasodilator factor NO. PBS (0.5 ml) or PBS containing Ad.VEGF-165, Ad.eNOS, or adenovirus (Ad.Null) was injected subdermally into the distal half of a mapped rat dorsal skin flap (4 x 10 cm) 7 days preoperatively, and skin flap viability was assessed 7 days postoperatively. Local subdermal gene therapy with 2 x [10.sup.7]-2 x [10.sup.10] plaque-forming units of VEGF-165 increased skin flap viability compared with PBS-or Ad.Null-injected control (P < 0.05). Subderreal Ad.VEGF-165 and Ad.eNOS gene therapies were equally effective in increasing skin flap viability at 5 x [10.sup.8] plaque-forming units. Subdermal Ad.VEGF-165 therapy was associated with upregulation of eNOS protein expression, [Ca.sup.2 +]-dependent NOS activity, synthesis/release of NO, and increase in capillary density and blood flow in the distal portion of the skin flap. Injection of the NOS inhibitor [N.sup.omega]-nitro-L-arginine (15 mg/kg ira), but not the cyclooxygenase inhibitor indomethacin (5 mg/kg im), 45 rain preoperatively completely abolished the increase in skin flap blood flow and viability induced by Ad.VEGF-165 injected subdermally into the mapped skin flap 7 days preoperatively. We have demonstrated for the first time that 1) Ad.VEGF-165 and Ad.eNOS mapped skin flap injected subdermally into the mapped skin flap 7 days preoperatively are equally effective in augmenting viability in the rat dorsal skin flap compared with control, 2) the mechanism of subdermal Ad.VEGF-165 gene therapy in augmenting skin flap viability involves an increase in NO synthesis/release downstream of upregulation of eNOS protein expression and [Ca.sup.2+]-dependent NOS activity, and 3) the vasodilating effect of NO may predominantly mediate subdermal Ad.VEGF gene therapy in augmenting skin flap blood flow and viability. subdermal gene transfer; nitric oxide; capillary density; vasodilation; skin blood flow

We have previously demonstrated that remote ischemic preconditioning (IPC) by instigation of three cycles of 10-min occlusion/reperfusion in a hindlimb of the pig elicits an early phase of infarct protection in local and distant skeletal muscles subjected to 4 h of ischemia immediately after remote IPC. The aim of this project was to test our hypothesis that hindlimb remote IPC also induces a late phase of infarct protection in skeletal muscle and that [K.sub.ATP] channels play a pivotal role in the trigger and mediator mechanisms. We observed that pig bilateral latissimus dorsi (LD) muscle flaps sustained 46 [+ or -] 2% infarction when subjected to 4 h of ischemia/48 h of reperfusion. The late phase of infarct protection appeared at 24 h and lasted up to 72 h after hindlimb remote IPC. The LD muscle infarction was reduced to 28 [+ or -] 3, 26 [+ or -] 1, 23 [+ or -] 2, 24 [+ or -] 2 and 24 [+ or -] 4% at 24, 28, 36, 48 and 72 h after remote IPC, respectively (P < 0.05; n = 8). In subsequent studies, hindlimb remote IPC or intravenous injection of the sarcolemmal [K.sub.ATP] (S[K.sub.ATP]) channel opener P-1075 (2 [micro]g/kg) at 24 h before 4 h of sustained ischemia (i.e., late preconditioning) reduced muscle infarction from 43 [+ or -] 4% (ischemic control) to 24 [+ or -] 2 and 19 [+ or -] 3%, respectively (P < 0.05, n = 8). Intravenous injection of the S[K.sub.ATP] channel inhibitor HMR 1098 (6 mg/kg) or the nonspecific [K.sub.ATP] channel inhibitor glibenclamide (Glib; 1 mg/kg) at 10 min before remote IPC completely blocked the infarctprotective effect of remote [PC in LD muscle flaps subjected to 4 h of sustained ischemia at 24 h after remote IPC. Intravenous bolus injection of the mitochondrial [K.sub.ATP] (N[K.sub.ATP]) channel inhibitor 5-hydroxydecanoate (5-HD; 5 mg/kg) immediately before remote IPC and 30-min intravenous infusion of 5-HD (5 mg/kg) during remote IPC did not affect the infarct-protective effect of remote IPC in LD muscle flaps. However, intravenous Glib or 5-HD, but not HMR 1098, given 24 h after remote IPC completely blocked the late infarct-protective effect of remote IPC in LD muscle flaps. None of these drug treatments affected the infarct size of control LD muscle flaps. The late phase of infarct protection was associated with a higher (P < 0.05) muscle content of ATP at the end of 4 h of ischemia and 1.5 h of reperfusion and a lower (P < 0.05) neutrophilic activity at the end of 1.5 h of reperfusion compared with the time-matched control. In conclusion, these findings support our hypothesis that hindlimb remote IPC induces an uninterrupted long (48 h) late phase of infarct protection, and S[K.sub.ATP] and m[K.sub.ATP] channels play a central role in the trigger and mediator mechanism, respectively. late phase protection; adenosine 5'-triphosphate; myeloperoxidase; muscle ischemia/reperfusion injury

We previously demonstrated in the pig that instigation of three cycles of 10 min of occlusion and reperfusion in a hindlimb by tourniquet application (~300 mmHg) elicited protection against ischemia-reperfusion injury (infarction) in multiple distant skeletal muscles subsequently subjected to 4 h of ischemia and 48 h of reperfusion, but the mechanism was not studied. The aim of this project was to test our hypothesis that mitochondrial ATP-sensitive potassium ([K.sub.ATP]) (m[K.sub.ATP]) channels play a central role in the trigger and mediator mechanisms of hindlimb remote ischemic preconditioning (IPC) of skeletal muscle against infarction in the pig. We observed in the pig that hindlimb remote IPC reduced the infarct size of latissimus dorsi (LD) muscle flaps (8 x 13 cm) from 45 [+ or -] 2% to 22 [+ or -] 3% (n = 10; P < 0.05). The nonselective [K.sub.ATP], channel inhibitor glibenclamide (0.3 mg/kg) or the selective m[K.sub.ATP] channel inhibitor 5-hydroxydecanoate (5-HD, 5 mg/kg), but not the selective sarcolemmal [K.sub.ATP] (s[K.sub.ATP]) channel inhibitor HMR-1098 (3 mg/kg), abolished the infarct-protective effect of hindlimb remote IPC in LD muscle flaps (n = 10, P < 0.05) when these drugs were injected intravenously at 10 min before remote IPC. In addition, intravenous bolus injection of glibenclamide (1 mg/kg) or 5-HD (10 mg/kg) at the end of hindlimb remote IPC also abolished the infarct protection in LD muscle flaps (n = 10; P < 0.05). Furthermore, intravenous injection of the specific m[K.sub.ATP] channel opener BMS-191095 (2 mg/kg) at 10 min before 4 h of ischemia protected the LD muscle flap against infarction to a similar extent as hindlimb remote IPC, and this infarct-protective effect of BMS-191095 was abolished by intravenous bolus injection of 5-HD (5 mg/kg) at 10 min before or after intravenous injection of BMS-191095 (n = 10; P < 0.05). The infarct protective effect of BMS-191095 was associated with a higher muscle content of ATP at the end of 4 h of ischemia and a decrease in muscle neutrophilic myeloperoxidase activity at the end of 1.5 h of reperfusion compared with the time-matched control (n = 10, P < 0.05). These observations led us to conclude that m[K.sub.ATP] channels play a central role in the trigger and mediator mechanisms of hindlimb remote IPC of skeletal muscle against infarction in the pig, and the opening of m[K.sub.ATP] channels in ischemic skeletal muscle is associated with an ATP-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion. pig skeletal muscle; remote ischemic preconditioning; trigger and mediator mechanism

Acute local subcutaneous [VEGF.sub.165] injection for augmentation of skin flap viability: efficacy and mechanism. Am J Physiol Regul Integr Comp Physiol 287: R1219-R1229, 2004. First published June 24, 2004; doi:10.1152/ajpregu.00143.2004.--Distal skin ischemic necrosis is a common complication in skin flap surgery. The pathogenesis of skin flap ischemic necrosis is unclear, and there is no clinical treatment available. Here, we used the 4 x 10 cm rat dorsal skin flap model to test our hypothesis that subcutaneous injection of vascular endothelial growth factor 165 ([VEGF.sub.165]) in skin flaps at the time of surgery is effective in augmentation of skin flap viability, which is associated with an increase in nitric oxide (NO) production, and the mechanism involves 1) an increase in skin flap blood flow in the early stage after surgery and 2) enhanced angiogenesis subsequently to sustain increased skin flap blood flow and viability. We observed that subcutaneous injection of [VEGF.sub.165] in skin flaps at the time of surgery increased skin flap viability in a dose-dependant manner. Subcutaneous injection of [VEGF.sub.165] at the dose of 2 [micro]g/flap increased skin flap viability by 28% (P < 0.05; n = 8). Over 80% of this effect was blocked by intramuscular injection of the NO synthase (NOS) inhibitor [N.sup.[omega]]-nitro-L-arginine (13 mg/kg) 45 min before surgery (P < 0.05; n = 8). The [VEGF.sub.165] treatment also increased skin flap blood flow (2.68 [+ or -] 0.63 ml*[min.sup.-1]*100 [g.sup.-1]) compared with the control (1.26 [+ or -] 0.10 ml*[min.sup.-1]*100 [g.sup.-1]; P < 0.05, n = 6) assessed 6 h postoperatively. There was no change in skin flap capillary density at this time point. [VEGF.sub.165]-induced increase in capillary density (32.2 [+ or -] 1.1 capillaries/[mm.sup.2]; p < 0.05, n = 7) compared with control (24.6 [+ or -] 1.4 capillaries/[mm.sup.2]) was seen 7 days postoperatively. There was also evidence to indicate that [VEGF.sub.165]-induced NO production in skin flaps was stimulated by activation of NOS activity followed by upregulation of NOS protein expression. These observations support our hypothesis and for the first time provide an important insight into the mechanism of acute local [VEGF.sub.165] protein therapy in mitigation of skin flap ischemic necrosis. rat skin flaps; ischemic necrosis; nitric oxide; vasorelaxation; angiogenesis; vascular endothelial growth factor

Various laboratories have reported that local subcutaneous or subdermal injection of VEG[F.sub.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 VEG[F.sub.165] is a potent vasodilator and acute VEG[F.sub.165] treatment increases skin perfusion; and 2) investigate the mechanism of VEG[F.sub.165]-induced skin vasorelaxation. We observed that VEG[F.sub.165] (5 x [10.sup.16] -5 x [10.sup.-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 VEG[F.sub.165]-induced skin vasorelaxation was confirmed using a dermofluorometry technique for assessment of skin perfusion. The vasorelaxation potency of VEG[F.sub.165] in NE-preconstricted skin flaps (p[D.sub.2] = 13.57 [+ or -] 0.31) was higher (P < 0.05) than that of acetylcholine (p[D.sub.2] = 7.08 [+ or -] 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 [micro]g/ml) or a specific VEGF receptor-2 inhibitor (5 x [10.sup.-6] M SU-1498) blocked the vasorelaxation effect of VEG[F.sub.165] in NE-preconstricted skin flaps. These observations indicate that the potent vasorelaxation effect of VEG[F.sub.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 VEG[F.sub.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 intracellular [Ca.sub.2+] store, and synthesis/release of endothelial nitric oxide, which predominantly triggered the effector mechanism of VEG[F.sub.165]-induced vasorelaxation. This information provides, for the first time, an important insight into the mechanism of VEG[F.sub.165] protein or gene therapy in the prevention/treatment of ischemia in skin flap surgery and skin ischemic diseases. VEG[F.sub.165] receptors; signaling pathways; nitric oxide; prostacyclin; skin flap

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].sub.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 [adenosine.sub.1] 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. ischemic preconditioning; humoral mediator; ATP; lactate; myeloperoxidase