Plantar Skin Research Articles

Clinical application of free super-thin anterolateral femoral perforator lobulated skin flap with nerve for repair of tissue defect of the foot and ankle

Objective To explore the clinical outcome of free super-thin anterolateral femoral perforator lobulated skin flap with nerve for repairing the tissue defect of the foot and ankle. Methods Free super-thin anterolateral femoral perforator lob-ulated skin flap with nerve was transferred to repair soft tissue defects of the foot and ankle in 32 cases. There were 20 males and 12 females with an average age of 35.5 years(range, 21-50 years). The wounds located in dorsal and plantar ankle skin with ten-don, bone and/or internal fixation exposed. The defect area was from 12 cm×10 cm to 20 cm×15 cm. At first the site of perforator vessels were determined by Doppler, according to the wound shape and size, the flaps were designed and harvested with the site as center; the femoral lateral cutaneous nerve was carried and most tensor fascia was reserved. During flap harvesting trimming of the flap was carried out, the flap was freed and only connected with its vascular pedicle. A step-wise defatting was done from the periphery of the flap towards the vascular pedicle with 1.0 to 2.0 cm tissue around the perforator preserved. Flap circulation was carefully observed to prevent damage to the perforators. The vascular pedicle was disconnected and formed a split leaf skin flap, and then the flap was transferred to the foot and ankle to cover the defect. Results All the 32 flaps were survived. No vascular crisis happened and all skin grafts were survived in donor sites. Necrosis of 1.5 cm×1.0 cm of the distal flap occurred in 1 case five days after surgery and it was healed by dress changing. All the 32 cases were followed-up for 6 to 24 months(average, 13 months). The flaps were supple and elastic with near normal color. There was no bulkiness. Sensory function was recovered well and two point discrimination(2-PD)was about 3.0-5.0 mm. The function and appearance of the foot and ankle were good. According to the Chinese Medical Association of hand surgery upper limb function evaluation of upper limb, the results were excellent in 22 cases, good in 9, fair in 1, with 97%(31/32)overall excellent and good rate. Conclusion The free super-thin anterolateral femoral perforator lobulated skin flap with nerve is an improvement of the traditional anterolateral thigh flap. The survived flaps are ideal in terms of covering foot and ankle defects and restore function. Key words: Foot; Ankle; Surgical flaps; Soft tissue injuries; Microsurgery

Effects of hypothermically reduced plantar skin inputs on anticipatory and compensatory balance responses.

BackgroundAnticipatory and compensatory balance responses are used by the central nervous system (CNS) to preserve balance, hence they significantly contribute to the understanding of physiological mechanisms of postural control. It is well established that various sensory systems contribute to the regulation of balance. However, it is still unclear which role each individual sensory system (e.g. plantar mechanoreceptors) plays in balance regulation. This becomes also evident in various patient populations, for instance in diabetics with reduced plantar sensitivity. To investigate these sensory mechanisms, approaches like hypothermia to deliberately reduce plantar afferent input have been applied. But there are some limitations regarding hypothermic procedures in previous studies: Not only plantar aspects of the feet might be affected and maintaining the hypothermic effect during data collection. Therefore, the aim of the present study was to induce a permanent and controlled plantar hypothermia and to examine its effects on anticipatory and compensatory balance responses. We hypothesized deteriorations in anticipatory and compensatory balance responses as increased center of pressure excursions (COP) and electromyographic activity (EMG) in response to the hypothermic plantar procedure. 52 healthy and young subjects (23.6 ± 3.0 years) performed balance tests (unexpected perturbations). Subjects’ foot soles were exposed to three temperatures while standing upright: 25, 12 and 0 °C. COP and EMG were analyzed during two intervals of anticipatory and one interval of compensatory balance responses (intervals 0, 1 and 2, respectively).ResultsSimilar plantar temperatures confirmed the successful implementation of the thermal platform. No significant COP and EMG differences were found for the anticipatory responses (intervals 0 and 1) under the hyperthermia procedure. Parameters in interval 2 showed generally decreased values in response to cooling.ConclusionNo changes in anticipatory responses were found possibly due to sensory compensation processes of other intact afferents. Decreased compensatory responses may be interpreted as the additional balance threat, creating a more cautious behavior causing the CNS to generate a kind of over-compensatory behavior. Contrary to the expectations, there were different anticipatory and compensatory responses after reduced plantar inputs, thereby, revealing alterations in the organization of CNS inputs and outputs according to different task difficulties.

Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes.

Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16-/- mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16-/- footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment.

Minor foot amputations in diabetic foot syndrome

The treatment strategy for diabetic foot syndrome must take into account protective sensibility of the foot, open wounds, infection status, and the rules of septic bone surgery. Interventions are classified as elective, prophylactic, curative, or emergency. Amputations in the forefoot and midfoot region are performed as ray amputations (including metatarsal), which can often be carried out as "inner" amputations. Gentle tissue treatment mandatory because of greater risk of revision with re-amputation compared to classical amputation. Good demarcation of infection, acute osteomyelitis, osteolytic lesions, neurotropic ulcer, arterial and venous blood flow to the other toes, gangrene of other toes with metatarsal affection. Arterial occlusive disease, infection of neighboring areas, avoidable amputations, poorly healing ulcers on the lower leg. Primary dorsal approach; minimal incisional distance (5cm) to minimize skin necrosis risk. Atraumatic preparation, minimize hemostasis to not compromise the borderline perfusion situation. In amputations, plantar skin preparation and longer seams placed as dorsal as possible, either disarticulated and maintain cartilage, or round the cortical metatarsal bone after resection. Diabetes control. Braun splint, mobilization in a shoe with forefoot decompression and hindfoot support, physiotherapy. Antibiotics based on resistance testing. If no complications, dressing change on postoperative day1. Optimal wound drainage by lowering foot several times a day; drainage removal after 12-24h. Insoles and footwear optimization. Amputations require continued attention and if necessary treatment to avoid sequelae. Insufficient treatment associated with recurrent ulceration and altered anatomy.

The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling That Requires NGF and TRPV1.

The complement cascade is a principal component of innate immunity. Recent studies have underscored the importance of C5a and other components of the complement system in inflammatory and neuropathic pain, although the underlying mechanisms are largely unknown. In particular, it is unclear how the complement system communicates with nociceptors and which ion channels and receptors are involved. Here we demonstrate that inflammatory thermal and mechanical hyperalgesia induced by complete Freund's adjuvant was accompanied by C5a upregulation and was markedly reduced by C5a receptor (C5aR1) knock-out or treatment with the C5aR1 antagonist PMX53. Direct administration of C5a into the mouse hindpaw produced strong thermal hyperalgesia, an effect that was absent in TRPV1 knock-out mice, and was blocked by the TRPV1 antagonist AMG9810. Immunohistochemistry of mouse plantar skin showed prominent expression of C5aR1 in macrophages. Additionally, C5a evoked strong Ca(2+) mobilization in macrophages. Macrophage depletion in transgenic macrophage Fas-induced apoptosis mice abolished C5a-dependent thermal hyperalgesia. Examination of inflammatory mediators following C5a injection revealed a rapid upregulation of NGF, a mediator known to sensitize TRPV1. Preinjection of an NGF-neutralizing antibody or Trk inhibitor GNF-5837 prevented C5a-induced thermal hyperalgesia. Notably, NGF-induced thermal hyperalgesia was unaffected by macrophage depletion. Collectively, these results suggest that complement fragment C5a induces thermal hyperalgesia by triggering macrophage-dependent signaling that involves mobilization of NGF and NGF-dependent sensitization of TRPV1. Our findings highlight the importance of macrophage-to-neuron signaling in pain processing and identify C5a, NGF, and TRPV1 as key players in this cross-cellular communication. This study provides mechanistic insight into how the complement system, a key component of innate immunity, regulates the development of pain hypersensitivity. We demonstrate a crucial role of the C5a receptor, C5aR1, in the development of inflammatory thermal and mechanical sensitization. By focusing on the mechanisms of C5a-induced thermal hyperalgesia, we show that this process requires recruitment of macrophages and initiation of macrophage-to-nociceptor signaling. At the molecular level, we demonstrate that this signaling depends on NGF and is mediated by the heat-sensitive nociceptive channel TRPV1. This deeper understanding of how immune cells and neurons interact to regulate pain processing is expected to facilitate mechanism-based approaches in the development of new analgesics.

Involvement of c-Myc-mediated transient receptor potential melastatin 8 expression in oxaliplatin-induced cold allodynia in mice.

Oxaliplatin, a platinum-based chemotherapeutic agent, induces acute cold allodynia and dysesthesia. Cold-sensitive transient receptor potential channels (TRPM8 and TRPA1) have been implicated as candidates to mediate oxaliplatin-induced cold allodynia and hyperalgesia, but precise roles of these channels remain unclear. In this study, we investigated the role of TRPM8 in oxaliplatin-induced cold allodynia. Oxaliplatin was injected intraperitoneally in mice. Cold allodynia was evaluated by the acetone test. Expression levels of TRPM8 mRNA and protein were measured using reverse transcription-polymerase chain reaction and Western blotting, respectively. Oxaliplatin-induced cold allodynia was alleviated by the TRPM8 blockers N-(2-aminoethyl)-N-[4-(benzyloxy)-3-methoxybenzyl]-N'-(1S)-1-(phenyl) ethyl] urea and TC-I 2014. Oxaliplatin increased the expression levels of TRPM8 mRNA and protein in the dorsal root ganglia and plantar skin, respectively. Prophylactic administration of the c-Myc inhibitor 10058-F4 prevented cold allodynia and the increase of TRPM8 mRNA after oxaliplatin injection. These results suggest that oxaliplatin induces cold allodynia through the increase of c-Myc-mediated TRPM8 expression in primary sensory neurons.

Adaptation of Plantar Skin to Palmar Skin

Adaptation of Plantar Skin to Palmar Skin

The diagnostic accuracy of Sudoscan in transthyretin familial amyloid polyneuropathy.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an axonal sensory-motor and autonomic neuropathy. Reliable quantification of sudomotor function could prove essential in the diagnosis and early treatment management. We aim to assess the diagnostic value of a new sudomotor test (Sudoscan) in TTR-FAP. One hundred and thirty-three TTR-FAP Val30Met carriers, divided in asymptomatic and symptomatic stage 1, were compared with 37 healthy controls. We analyzed the right sural sensory nerve action potential (SNAP), the plantar sympathetic skin response (SSR) and the electrochemical skin conductance (ESC) measured by Sudoscan in both hands and feet. All neurophysiological measures were significantly worse in the symptomatic group. However, feet ESC was the only test distinguishing symptomatic patients with autonomic dysfunction from those without autonomic dysfunction, and both groups from asymptomatic subjects and healthy controls. Feet ESC was a significant independent predictor for the presence of symptoms and autonomic failure, after adjusting for demographic characteristics, sural SNAP and SSR amplitudes (p<0.05). Feet ESC showed 76% sensitivity and 85% specificity for detection of dysautonomia. Feet ESC is a sensitive test to assess early autonomic dysfunction in TTR-FAP subjects. This investigation should be considered for routine assessment in this population. Abnormal feet responses on Sudoscan support early diagnosis in TTR-FAP.

The prokineticin Bv8 sensitizes cutaneous terminals of female mice to heat

Injection of the noxious peptide Bv8 has previously been shown to induce a biphasic thermal hyperalgesia in rodents, the first peak presumably due to peripheral sensitization. This hypothesis has never been directly confirmed. We have assessed whether Bv8 can indeed sensitize peripheral nerve fibres in the mouse to heat. We used recordings from single cutaneous fibres, cutaneous calcitonin gene-related peptide (CGRP) release and immunostaining in nerves and plantar skin to evaluate the Bv8 effects on cutaneous nerves. Application of Bv8 at nanomolar concentrations (30-310nmol/L) to skin preparations significantly increased the heat-induced discharge, the heat-induced afterdischarge and reduced threshold temperature of single unmyelinated polymodal fibres. Furthermore, application of Bv8 to hind-paw skin flaps or trigeminal ganglia significantly elevated their heat-induced CGRP release. Capsaicin-induced and to a lesser extent also KCl-induced CGRP releases were also augmented after Bv8 treatment. Immunohistochemistry revealed co-localization of prokineticin 2 (Bv8 ortholog in rodents) and CGRP in both plantar skin and nerve tissues. These results confirm that Bv8 sensitizes cutaneous nerve endings to heat, partly, although not exclusively through TRPV1 activation. Our results thus support the hypothesis that the first hyperalgesic phase to follow Bv8 injection to hind paws of intact animals is due to peripheral sensitization of nociceptors. WHAT DOES THIS STUDY ADD?: Our data provide mechanistic insights into the effect Bv8 application exerts on afferent nerve endings and into the concomitant development of thermal hyperalgesia.

Anatomical and histological study to determine the border of sole skin.

Transfer of a free skin graft from the submalleolar or plantar instep area to the palmoplantar area and finger defects is widely performed; however, the sites and the border of plantar skin have yet to be examined in detail. The aim of this study was to determine the border of sole skin. Twelve paraformaldehyde-fixed cadavers were examined. Skin specimens were harvested from an area from the top of the medial malleolus extending to the top of the lateral malleolus of the right foot. The paraffin-embedded skin specimens were analyzed using histological (hematoxylin and eosin, Fontana-Masson, and elastica van Gieson stains) and immunohistochemical (cytokeratin 9) techniques. CK9-positive cells were present at the points between 21 and 78% of the intermalleolar distance measured from the tops of the medial and lateral malleoli. The melanin index abruptly changed at the points 25±7.1 and 75±4.2%. The skin thickness and amount of elastic fibers changed greatly at the points between 20 and 30% and between 70 and 80% of the intermalleolar distance. Submalleolar skin is quite different from sole skin. The border of sole skin lies at the points between 20 and 25% of the intermalleolar distance from the medial malleolus, which macroscopically corresponds to the border of skin maceration. It would be better to use the submalleolar area for grafts for the dorsum of the fingers or toes, and the plantar instep area for the ventral areas of the fingers or toes.

Investigating Foot-sock Friction: A Comparison of Two Different Methodologies

Two different methodologies for assessing the friction between plantar skin and sock textiles are compared in this study. The first approach uses a custom-built friction plate rig. The rig consists of sock material mounted on a test plate attached to two load cells that measure normal and shear loads at the skin-sock textile interface. With this methodology, participants are required to slide their foot over the test plate whilst maintaining a targeted normal load and a relatively consistent sliding speed. The second approach uses a pneumatically-driven foot probe loading device. The device includes an instrumented probe with sock material on its contact surface. Participants are instructed to stand on a platform whilst the probe is applied to, and then driven across, the plantar aspect of foot. The cyclic motion of the probe is displacement-controlled and normal and shear loads are measured using load cells. Both approaches allow friction coefficients to be calculated from load data collected during the sliding phase of movement. Data from both approaches was examined, collected from friction tests using the same six participants and sliding contact between the first metatarsal head (1MTH) region and textiles from two commercially available running socks. Both approaches were capable of measuring the friction between 1MTH skin and sock materials and good agreement was found between them. In the dry conditions tested, the cotton-rich sock was found to provide lower friction that the anti-blister sock material.

EXPRESS: Methylcobalamin ameliorates neuropathic pain induced by vincristine in rats: Effect on loss of peripheral nerve fibers and imbalance of cytokines in the spinal dorsal horn.

BackgroundVincristine, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and there are currently no effective drugs to prevent or treat this side effect. Previous studies have shown that methylcobalamin has potential analgesic effect in diabetic and chronic compression of dorsal root ganglion model; however, whether methylcobalamin has effect on vincristine-induced painful peripheral neuropathy is still unknown.ResultsWe found that vincristine-induced mechanical allodynia and thermal hyperalgesia, accompanied by a significant loss of intraepidermal nerve fibers in the plantar hind paw skin and an increase in the incidence of atypical mitochondria in the sciatic nerve. Moreover, in the spinal dorsal horn, the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the protein expression of p-p65 as well as tumor necrosis factor α was increased, whereas the protein expression of IL-10 was decreased following vincristine treatment. Furthermore, intraperitoneal injection of methylcobalamin could dose dependently attenuate vincristine-induced mechanical allodynia and thermal hyperalgesia, which was associated with intraepidermal nerve fibers rescue, and atypical mitochondria prevalence decrease in the sciatic nerve. Moreover, methylcobalamin inhibited the activation of NADPH oxidase and the downstream NF-κB pathway. Production of tumor necrosis factor α was also decreased and production of IL-10 was increased in the spinal dorsal horn following methylcobalamin treatment. Intrathecal injection of Phorbol-12-Myristate-13-Acetate, a NADPH oxidase activator, could completely block the analgesic effect of methylcobalamin.ConclusionsMethylcobalamin attenuated vincrinstine-induced neuropathic pain, which was accompanied by inhibition of intraepidermal nerve fibers loss and mitochondria impairment. Inhibiting the activation of NADPH oxidase and the downstream NF-κB pathway, resulting in the rebalancing of proinflammatory and anti-inflammatory cytokines in the spinal dorsal horn might also be involved. These findings might provide potential target for preventing vincristine-induced neuropathic pain.

Simultaneous Reconstruction of Forefoot and Hindfoot Defects with a Thoracodorsal-Axis Chimeric Flap.

Simultaneous Reconstruction of Forefoot and Hindfoot Defects with a Thoracodorsal-Axis Chimeric Flap.

Keratins K2 and K10 are essential for the epidermal integrity of plantar skin

BackgroundK1 and K2 are the main type II keratins in the suprabasal epidermis where each of them heterodimerizes with the type I keratin K10 to form intermediate filaments. In regions of the ears, tail, and soles of the mouse, only K2 is co-expressed with K10, suggesting that these keratins suffice to form a mechanically resilient cytoskeleton. ObjectiveTo determine the effects of the suppression of both main keratins, K2 and K10, in the suprabasal plantar epidermis of the mouse. MethodsKrt2−/− Krt10−/− mice were generated by crossing Krt2−/− and Krt10−/− mice. Epidermal morphology of soles of hind-paws was examined macroscopically and histologically. Immunofluorescence analysis and quantitative PCR analysis were performed to analyze the expression of keratins in sole skin of wildtype and Krt2−/− Krt10−/− mice. Highly abundant proteins of the sole stratum corneum were determined by electrophoretic and chromatographic separation and subsequent mass spectrometry. ResultsK2 and K10 are the most prominent suprabasal keratins in normal mouse soles with the exception of the footpads where K1, K9 and K10 predominate. Mice lacking both K2 and K10 were viable and developed epidermal acanthosis and hyperkeratosis in inter-footpad epidermis of the soles. The expression of keratins K1, K9 and K16 was massively increased at the RNA and protein levels in the soles of Krt2−/− Krt10−/− mice. ConclusionsThis study demonstrates that the loss of the main cytoskeletal components of plantar epidermis, i.e. K2 and K10, can be only partly compensated by the upregulation of other keratins. The thickening of the epidermis in the soles of Krt2−/− Krt10−/− mice may serve as a model for pathomechanistic aspects of palmoplantar keratoderma.

Skin Perfusion Pressure and the Prevalence of Atherothrombosis in Hemodialysis Patients.

End-stage renal disease is associated with atherothrombosis (ATIS), which, in turn, can promote peripheral arterial occlusive disease (PAOD), coronary artery disease (CAD), and/or cerebrovascular disease (CVD). The aim of this study was to determine whether low plantar skin perfusion pressure (SPP) was related to ATIS among 122 patients receiving maintenance hemodialysis (HD) from March to November 2013 at our outpatient facility. We routinely measured SPP and used the value for analysis. In addition, we retrospectively evaluated the prevalence of ATIS with patients categorized to CAD, CVD, or PAOD groups. Of the 122 outpatients, ATIS was diagnosed in about half (N = 60, 49.2% vs. 62, 50.8%; average SPP, 56.6 vs. 72.9 mm Hg, respectively). These data show that SPP was significantly lower in patients with ATIS (difference, 16.3 mm Hg; P < 0.001) and there was a negative relationship between average SPPs and past history of ATIS complications. When the patients were stratified by the presence of diabetes mellitus, this trend was stronger. Particularly, receiver operating characteristic analysis of HD patients with diabetes revealed a cutoff point of 53.0 mm Hg and an area under the curve value of 0.84, with a sensitivity of 77.0% and specificity of 91.3%. Therefore, we concluded that SPP enables the evaluation of not only local PAOD, but also systemic ATIS. Moreover, we found that a cutoff point of 53.0 mm Hg was useful for detection of ATIS in HD patients.

Medial plantar island flap for soft tissue reconstruction of the heel after excision of melanoma

Objective To study the efficacy of medial plantar island flap for repairing soft tissue defect of the heel after excision of melanoma. Methods Five patients (including 3 males and 2 females) with malignant melanoma were treated. All lesions were located in the heel and were proved by pathological examination. Local extensive resection was performed in all cases. The surgical margin used for excision of melanoma was 2 cm, and the depth used was deep into periosteum of the calcaneus. Plantar medial artery island skin flaps were applied in the reparation according to the size of heel soft tissue defect and anatomic study. The postoperative follow-up was 8 to 14 months. Results The surgical reparation was successful in all 5 cases. The plantar medial artery was very suitable to cover the surgical wound surface and to recover the function and sense. Before 3 months the sense of flaps remained on the donor area and later went to the heel gradually. All patients remained alive and no tumor recurrence was observed. All the patients were walking normally and had protective sensation in the new heel pad comparable to the opposite normal heel. Two patients with more than 10 years follow-up were reported. Conclusions Plantar medial island flap can be used to repair the wound after malignant melanoma resection in the heel, which is an effective method. Key words: Malignant melanoma; Heel; Island flap; Medial plantar artery

Foot Lesions in Farmed Mink (Neovison vison): Pathologic and Epidemiologic Characteristics on 4 Danish Farms.

The aim of this study was to evaluate gross and histologic lesions and epidemiologic factors of foot lesions in farmed mink. The feet of 1159 mink from 4 Danish farms were examined and lesions described. Swabs from the lesions were taken from 27 mink for microbiology, and tissue samples from a representative spectrum of feet with and without lesions (n= 22) were examined histologically. Feet were grouped according to gross inspection: no lesions (55.1%), hair loss (7.1%), hyperkeratosis (35.8%), and crusting (5.3%). Lesions were predominantly located in plantar metatarsal skin (98.1%). Staphylococci were the most prevalent microorganisms cultured from the lesions. There was a significant association between presence of lesions and sex (P< .0001), age (P< .0001), and color type (P= .023). Lesion size was significantly different between hair loss and crusts and between hyperkeratosis and crusts (P< .0001). Histologically, lesions included varying degrees of orthokeratotic to parakeratotic hyperkeratosis and granulomatous to pyogranulomatous dermatitis with trichogranulomas as a dominant feature in all mink. The gross and microscopic lesions were comparable to physically induced changes in other species that develop as a response to repetitive friction or pressure. The condition may have an impact on animal welfare in mink production.

Pituitary Adenylate Cyclase-Activating Polypeptide Is Upregulated in Murine Skin Inflammation and Mediates Transient Receptor Potential Vanilloid-1-Induced Neurogenic Edema

Although pituitary adenylate cyclase-activating polypeptide (PACAP) was described as a key vasoregulator in human skin, little is known about its expression in mouse skin. As it is important to investigate PACAP signaling in translational mouse dermatitis models, we determined its presence, regulation, and role in neurogenic and non-neurogenic cutaneous inflammatory mechanisms. The mRNA of PACAP and its specific receptor PAC1 was detected with real-time PCR in several skin regions at comparable levels. PACAP-38-immunoreactivity measured with radioimmunoassay was similar in plantar and dorsal paw skin and the ear but significantly smaller in the back skin. PACAP and PAC1 mRNA, as well as PACAP-38 and PAC1 protein expression, significantly increased in the plantar skin after intraplantar administration of capsaicin (50 μl, 100 μg ml(-1)), an agonist of the transient receptor potential vanilloid 1 (TRPV1) receptor, evoking chiefly neurogenic inflammation without inflammatory cell accumulation. Intraplantar complete Freund's adjuvant (CFA; 50 μl, 1 mg ml(-1)) also increased PACAP/PAC1 mRNA but not the PACAP peptide. Capsaicin-induced neurogenic paw edema, but not CFA-evoked non-neurogenic swelling, was significantly smaller in PACAP-deficient mice throughout a 24-hour period. To our knowledge, we provide previously unreported evidence for PACAP and PAC1 expression upregulation during skin inflammation of different mechanisms and for its pro-inflammatory function in neurogenic edema formation.

Sympathetic fibre sprouting in the skin contributes to pain-related behaviour in spared nerve injury and cuff models of neuropathic pain.

BackgroundCuff and spared nerve injury (SNI) in the sciatic territory are widely used to model neuropathic pain. Because nociceptive information is first detected in skin, it is important to understand how alterations in peripheral innervation contribute to pain in each model. Over 16 weeks in male rats, changes in sensory and autonomic innervation of the skin were described after cuff and SNI using immunohistochemistry to label myelinated (neurofilament 200 positive—NF200+) and peptidergic (calcitonin gene-related peptide positive—CGRP+) primary afferents and sympathetic fibres (dopamine β-hydroxylase positive—DBH+)ResultsCuff and SNI caused an early loss and later reinnervation of NF200 and CGRP fibres in the plantar hind paw skin. In both models, DBH+ fibres sprouted into the upper dermis of the plantar skin 4 and 6 weeks after injury. Despite these similarities, behavioural pain measures were significantly different in each model. Sympathectomy using guanethidine significantly alleviated mechanical allodynia 6 weeks after cuff, when peak sympathetic sprouting was observed, having no effect at 2 weeks, when fibres were absent. In SNI animals, mechanical allodynia in the lateral paw was significantly improved by guanethidine at 2 and 6 weeks, and the development of cold hyperalgesia, which roughly paralleled the appearance of ectopic sympathetic fibres, was alleviated by guanethidine at 6 weeks. Sympathetic fibres did not sprout into the dorsal root ganglia at 2 or 6 weeks, indicating their unimportance to pain behaviour in these two models.ConclusionsAlterations in sympathetic innervation in the skin represents an important mechanism that contributes to pain in cuff and SNI models of neuropathic pain.

The Use of Glabrous Skins Grafts in the Treatment of Pediatric Palmar Hand Burns

An often overlooked, yet useful, technique in the treatment of palmar hand burns is the use of glabrous skin grafting, particularly in dark-skinned individuals. Pediatric palmar burns are a particularly unique subset of burns. The typical split-thickness or full-thickness skin grafts leave a notably different skin texture and pigmentation. It is also known that the psychological aspects of a pediatric burn can be quite burdensome for a child as he or she progresses through childhood and adolescence. For a dark-skinned patient the placement a standard full-thickness skin graft in a nonpigmented palm provides for a constant reminder of a traumatic event. We report a case series of pediatric patients who were managed with glabrous skin grafting from the plantar aspect of the foot. A retrospective review of palmar skin burns requiring grafting at a single pediatric burn center experience over a 2 and a half year time period was performed. Seventeen patients were identified. Our treatment algorithm for deep partial thickness burns first relies on a combination of operative and nonoperative measures to expedite the demarcation of the burn injury. If the burn is full thickness in nature or if a lack of progression of healing is identified within the first 14 days of injury, then skin grafting is recommended. Our technique for performing the graft is described. The average age at time of surgery was 2.05 years (6 months to 6.8 years). Fourteen of the 17 patients had darker skin types (Fitzpatrick Type III-VI) and identified themselves as either Hispanic or African American. The average size of the area requiring skin graft after debridement was 0.94% total body surface area (0.5%-2.0%). Of the patients that were not lost to follow-up, 1 patient required additional grafting after developing a finger contracture for splint noncompliance. Aesthetically, the wounds went on to heal with an excellent pigment match and an inconspicuous donor site. In the management of deep-partial or full-thickness palmar skin burns in the pediatric population that require grafting, the use of plantar glabrous skin grafts offers a reliable option for coverage. The aesthetic and functional results are improved over standard techniques.