Proximal peroneal perforator flap, cadaveric study, and clinical applications for shallow defect reconstructions.

PURPOSE: Peroneal artery perforator offers a versatile range of microvascular tissue transfer methods from local flaps to vascularized osteocutaneous fibula flaps. It is one of the few flaps that can cover shallow defects that require thin and pliable skin paddles, such as in hands and feet (Han et al., 2018). The proximal region of the lower leg offers such flexible and thin flap compared to the middle and distal lower leg (Winters & de Jongh, 1999). However, the anatomy of the proximal peroneal artery perforator is relatively unknown in literature and its proximity to the common peroneal nerve (CPN) has not yet been studied. This study conducted a cadaveric study and put it in application into clinical settings. METHODS: Twenty lower leg specimens were dissected according to the methods of clinical proximal peroneal artery perforator flap harvest. Perforators arising in the proximal lower leg area of between 20 and 40 percentile of fibular length were inspected. Perforator length, location from fibular head, course, and location of CPN were recorded. Clinical reconstruction cases using the proximal lateral lower leg were analyzed. Six patients between the ages of thirty and seventy were included. Five cases were due to trauma, and one from mass excision, but all required thin and pliable flaps for reconstructions in hands or feet. Flaps were designed concentrical oval shapes, and harvest was done similarly to cadaveric perforator dissection, but perforator dissection was done only up to the required pedicle length. Perforator length, flap size, thickness, and long-term complications were recorded. RESULTS: Among 20 specimens, a total of 20 perforators were found in 18 cadavers (90%). Two specimens showed no perforators while two specimens showed multiple perforators. The perforators were located at an average of 101 mm from fibular head, with an average length of 55 mm ranging from 20 to 153 mm. The average size of perforator at origin was 2.0 mm, ranging from 1.0 to 3.6 mm. 45% showed septocutaneous course and 55% intramuscular course. Two out of 20 perforators were shown to arise from source vessels other than the peroneal artery. All clinical cases were successful without complications or debulking for contour shaping. Flap sizes ranged from 15 to 40 cm2 . Largest flap width was 5 cm, and all donor sites were primarily closed without complications. One year of follow-up showed no complications. CONCLUSION: Proximal peroneal artery perforator flap provides a reliable pedicle for a versatile tissue transfer. This study shows that the perforators of the proximal lateral lower leg often arise from vessels other than the peroneal artery, such as the anterior tibial artery or popliteal artery, as had been previously reported (Winters & de Jongh, 1999). Although the source vessel varies, perforator anatomy is at a safe distance from CPN. This variation of source vessels suggests a change in nomenclature to "proximal peroneal perforator flap." The clinical applications of this flap showed that it can be effectively used for reconstructions of shallow defects, such as in the hands and feet without secondary procedures for debulking.

Novel, user-friendly landmarks for localizing Baxter's nerve: A cadaveric study.

INTRODUCTION: Identification of Baxter's nerve (BN) has proven challenging for less experienced practitioners using ultrasonography due to a lack of adequate landmarks. This study aimed to establish novel, user-friendly anatomical landmarks and to describe useful structures to localize BN. MATERIALS AND METHODS: We examined 10 fresh cadaveric feet and identified the interobserver agreement of measuring three surface landmarks: the most medially protruded point on the medial malleolus (P), the navicular tuberosity (Q), and the center of the calcaneus (B). Next, 24 fresh cadaveric feet were used to identify the point of BN entry into the quadratus plantae (QP) muscle, which corresponds to the proximal BN impingement site. The rectangular coordinate system consisted of the origin (point P), X-axis, extension line P-Q, and Y-axis (the perpendicular line to the X-axis). To consider various foot sizes, the X and Y values were divided by the P-Q length and were designated as the ratios X and Y. RESULTS: Points P and Q showed smaller interobserver differences than that of point B. Ratios X and Y were 61.25 and 99.80%, respectively, for the QP. BN arose from the lateral plantar nerve in 20 of 24 specimens. The adjacent vessel was <3 mm from the entrapment site of BN in 20 of 24 specimens. CONCLUSION: New landmarks will improve the precision of localizing the entrapment site of BN and will provide advanced guidelines for podiatric patients.

Ligand-Activated Peroxisome Proliferator-Activated Receptor δ Attenuates Vascular Oxidative Stress by Inhibiting Thrombospondin-1 Expression.

Thrombospondin-1 (TSP-1) is implicated in vascular diseases associated with oxidative stress, such as abdominal aortic aneurysms, ischemia-reperfusion injury, and atherosclerosis. However, the regulatory mechanisms underlying TSP-1 expression are not fully elucidated. In this study, we found that peroxisome proliferator-activated receptor δ (PPARδ) inhibited oxidative stress-induced TSP-1 expression and migration in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly attenuated hydrogen peroxide (H2O2)-induced expression of TSP-1 in VSMCs. Small interfering RNA-mediated knockdown of PPARδ and treatment with GSK0660, a selective PPARδ antagonist, reversed the effect of GW501516 on H2O2-induced expression of TSP-1, suggesting that PPARδ is associated with GW501516 activity. Furthermore, JNK (c-Jun N-terminal kinase), but not p38 and ERK (extracellular signal-regulated kinase), mediated PPARδ-dependent inhibition of TSP-1 expression in VSMCs exposed to H2O2. GW501516- activated PPARδ also reduced the H2O2-induced generation of reactive oxygen species, concomitant with inhibition of VSMC migration. In particular, TSP-1 contributed to the action of PPARδ in the regulation of H2O2-induced interleukin-1ß expression. These results suggest that PPARδ-modulated downregulation of TSP-1 is associated with reduced cellular oxidative stress, thereby inhibiting H2O2-induced pheno-typic changes in vascular cells.

Curcumin longa extract-loaded nanoemulsion improves the survival of endotoxemic mice by inhibiting nitric oxide-dependent HMGB1 release.

BACKGROUND: High mobility group box 1 (HMGB1) is a well-known damage-related alarmin that participates in cellular inflammatory responses. However, the mechanisms leading to HMGB1 release in inflammatory conditions and the therapeutic agents that could prevent it remain poorly understood. This study attempted to examine whether the Curcumin longa herb, which is known to have anti-inflammatory property, can modulate cellular inflammatory responses by regulating HMGB1 release. METHODS: The murine macrophage RAW264.7 cells were treated with lipopolysaccharide (LPS) and/or a C. longa extract-loaded nanoemulsion (CLEN). The levels of released HMGB1, nitric oxide (NO) production, inducible NO synthase (iNOS) expression, and phosphorylation of mitogen-activated protein kinases were analyzed in RAW264.7 macrophages. The effects of CLEN on survival of endotoxemic model mice, circulating HMGB1 levels, and tissue iNOS expression were also evaluated. RESULTS: We have shown that a nanoemulsion loaded with an extract from the C. longa rhizome regulates cellular inflammatory responses and LPS-induced systemic inflammation by suppressing the release of HMGB1 by macrophages. First, treatment of RAW264.7 macrophages with the nanoemulsion significantly attenuated their LPS-induced release of HMGB1: this effect was mediated by inhibiting c-Jun N-terminal kinase activation, which in turn suppressed the NO production and iNOS expression of the cells. The nanoemulsion did not affect LPS-induced p38 or extracellular signal-regulated kinase activation. Second, intraperitoneal administration of the nanoemulsion improved the survival rate of LPS-injected endotoxemic mice. This associated with marked reductions in circulating HMGB1 levels and tissue iNOS expression. DISCUSSION: The present study shows for the first time the mechanism by which C. longa ameliorates sepsis, namely, by suppressing NO signaling and thereby inhibiting the release of the proinflammatory cytokine HMGB1. These observations suggest that identification of agents, including those in the herb C. longa, that can inhibit HMGB1 production and/or activity may aid the treatment of endotoxemia.

Subcritical water-hydrolyzed fish collagen ameliorates survival of endotoxemic mice by inhibiting HMGB1 release in a HO-1-dependent manner.

To investigate potential mechanisms underlying the bioactivity of hydrolyzed fish collagen, we examined the anti-inflammatory actions of subcritical water-hydrolyzed fish collagen (SWFC) in lipopolysaccharide (LPS)-triggered inflammation and endotoxemia. SWFC markedly inhibited LPS-stimulated release of high mobility group box 1 (HMGB1) in murine RAW264.7 macrophages, along with decreased cytosolic translocation of HMGB1. Both the protein and mRNA levels of heme oxygenase-1 (HO-1) were significantly upregulated in SWFC-treated RAW 264.7 cells in an Nrf2-dependent manner. In line with these effects of SWFC, both HO-1 siRNA and ZnPPIX (zinc protoporphyrin IX) actually attenuated the effects of SWFC on HMGB1 release stimulated by LPS, indicating a possible mechanism by which SWFC modulates HMGB1 release through HO-1 signaling. Notably, administration of SWFC improved the survival rates of LPS-injected endotoxemic mice, in which the serum level of HMGB1 was significantly reduced. Taken together, these results indicate that the anti-inflammatory activities of SWFC are achieved by inhibiting HMGB1 release induced by LPS in a HO-1-sensitive manner.

Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate.

Sphingosine 1-phosphate (S1P) influences heart rate, coronary artery caliber, endothelial integrity, and lymphocyte recirculation through five related high affinity G-protein-coupled receptors. Inhibition of lymphocyte recirculation by non-selective S1P receptor agonists produces clinical immunosuppression preventing transplant rejection but is associated with transient bradycardia. Understanding the contribution of individual receptors has been limited by the embryonic lethality of the S1P(1) knock-out and the unavailability of selective agonists or antagonists. A potent, S1P(1)-receptor selective agonist structurally unrelated to S1P was found to activate multiple signals triggered by S1P, including guanosine 5'-3-O-(thio)triphosphate binding, calcium flux, Akt and ERK1/2 phosphorylation, and stimulation of migration of S1P(1)- but not S1P(3)-expressing cells in vitro. The agonist also alters lymphocyte trafficking in vivo. Use of selective agonism together with deletant mice lacking S1P(3) receptor reveals that agonism of S1P(1) receptor alone is sufficient to control lymphocyte recirculation. Moreover, S1P(1) receptor agonist plasma levels are causally associated with induction and maintenance of lymphopenia. S1P(3), and not S1P(1), is directly implicated in sinus bradycardia. The sustained bradycardia induced by S1P receptor non-selective immunosuppressive agonists in wild-type mice is abolished in S1P(3)-/- mice, whereas S1P(1)-selective agonist does not produce bradycardia. Separation of receptor subtype usage for control of lymphocyte recirculation and heart rate may allow the identification of selective immunosuppressive S1P(1) receptor agonists with an enhanced therapeutic window. S1P(1)-selective agonists will be of broad utility in understanding cell functions in vitro, and vascular physiology in vivo, and the success of the chemical approach for S1P(1) suggests that selective tools for the resolution of function across this broad lipid receptor family are now possible.