Cutaneous Responses Research Articles

Early cutaneous inflammatory response at different degree of burn and its significance for clinical diagnosis and management

A complete characterization of the burn wound based on cutaneous architectural changes and inflammatory response is extremely important to provide evidence for progressive changes in the burn wound. Burn wounds are highly susceptible to conversion into deeper wounds, which need special care and attention; thereby, the complete characterization of burn wound type and their subsequent inflammatory status in the cutaneous system at the earliest is of paramount importance. Inflammatory markers at different degrees will help clinicians devise better and more specific treatment strategies for each burn type.The present study is carried out to profile pro-inflammatory gene expression along with immune cell quantification, vascular perfusion, and histopathological assessment in the cutaneous system of murine models. The study revealed that burn injury caused an immediate increase in vascular perfusion in superficial and partial-thickness burns, whereas there was a decrease in vascular perfusion in full-thickness burns. An influx of lymphocytes at the edges of burn wounds in each type of burn injury was well-orchestrated with the event of vascular perfusion. Further, pro-inflammatory gene expression profiling revealed significant upregulation vis-à-vis upregulation of TNF-α and MCP-1 genes, with an increase in the number of neutrophils following 72 h of injury that evidently cemented the conversion of superficial burn into partial-thickness burn. The molecular findings were profoundly supported by the histopathological changes.Thus, our foundational studies show distinct characteristic cutaneous changes correlated with the expression of key pro-inflammatory genes in three different types of burn injuries. Characterization of these cutaneous inflammatory responses provides a promising future for medical interventions involved with different degrees of burn injury, and it will also help in the pre-clinical testing of therapies for burn injury.

BI24 Cutaneous pseudolymphoma secondary to pembrolizumab

Abstract A 35-year-old man presented with a 7-week history of itchy, nontender, indurated erythematous plaques and nodules on his forehead and upper back, with no discriminatory clinical features. He was systemically well. Three months previously, he had completed a 12-month course of adjuvant pembrolizumab for stage IIIC melanoma. The primary melanoma had been excised from his left cheek, with involvement of left parotid and supraclavicular lymph nodes, treated with clearance via superficial parotidectomy and left neck dissection. Clinical and imaging surveillance revealed no evidence of melanoma recurrence. Incisional biopsies of the lesions on his back and forehead both demonstrated a superficial and deep dermal perivascular and periadnexal infiltrate of small- and medium-sized lymphoid cells. There was no epidermotropism and B- and T-cell clonality studies were negative. Morphological appearance and immunophenotype favoured a CD4+-reactive lymphoid process in keeping with cutaneous pseudolymphoma (CPL), secondary to pembrolizumab. The conspicuous forehead lesion was unresponsive to clobetasol propionate under occlusion. A single course of intralesional triamcinolone acetonide 10 mg mL–1 resulted in significant improvement within days, with subsequent complete resolution. The lesion on the back resolved spontaneously. Drug-induced CPL describes an adverse cutaneous drug reaction mimicking B- or T-cell lymphomas clinically and/or histologically. It has been described with anticonvulsants, antidepressants and biologic agents, often with resolution on cessation of the responsible drug (Etesami I, Kalantari Y, Tavakolpour S et al. Drug-induced cutaneous pseudolymphoma: a systematic review of the literature. Australas J Dermatol 2023; 64:41–9). It has been proposed that the drugs affect immune surveillance, leading to an abnormal cutaneous lymphocyte response. A case report (Ayoubi N, Haque A, Vera N et al. Ipilimumab/nivolumab-induced pseudolymphoma in a patient with malignant melanoma. J Cutan Pathol 2020; 47:390–3) has described drug-induced CPL secondary to ipilimumab and nivolumab in a 38-year-old man presenting with erythematous plaques on the hands and face, similar to the presentation of our patient, which responded to prednisolone. As with the other adverse effects of immunotherapy, it is likely that CPL in this cohort is due to an iatrogenic immune dysregulation leading to T-cell overactivity. We present the first reported case of CPL secondary to pembrolizumab and highlight the successful use of intralesional steroid as a treatment option. It is important to recognize CPL as an adverse cutaneous effect of immunotherapy and be aware that it can present after completing treatment due to an ongoing immune response.

Individual and sociodemographic factors associated with polysensitization at a New York City hospital

Allergic contact dermatitis (ACD) is a cutaneous delayed-type hypersensitivity response with a global prevalence estimated at over 20%.1 The gold standard for diagnosis is patch testing, in which allergens are applied to a patient's skin to elicit cutaneous responses in sensitized individuals. Many patients undergoing patch testing test positive for 3 or more unrelated allergens, termed polysensitization.2 A recent North American Contact Dermatitis Group study found that 32.1% of patients tested were positive to at least three allergens, but reported rates vary.3

A sensory signal related to left-right symmetry modulates intra- and interlimb cutaneous reflexes during locomotion in intact cats.

During locomotion, cutaneous reflexes play an essential role in rapidly responding to an external perturbation, for example, to prevent a fall when the foot contacts an obstacle. In cats and humans, cutaneous reflexes involve all four limbs and are task- and phase modulated to generate functionally appropriate whole-body responses. To assess task-dependent modulation of cutaneous interlimb reflexes, we electrically stimulated the superficial radial or superficial peroneal nerves in adult cats and recorded muscle activity in the four limbs during tied-belt (equal left-right speeds) and split-belt (different left-right speeds) locomotion. We show that the pattern of intra- and interlimb cutaneous reflexes in fore- and hindlimbs muscles and their phase-dependent modulation were conserved during tied-belt and split-belt locomotion. Short-latency cutaneous reflex responses to muscles of the stimulated limb were more likely to be evoked and phase-modulated when compared to muscles in the other limbs. In some muscles, the degree of reflex modulation was significantly reduced during split-belt locomotion compared to tied-belt conditions. Split-belt locomotion increased the step-by-step variability of left-right symmetry, particularly spatially. These results suggest that sensory signals related to left-right symmetry reduce cutaneous reflex modulation, potentially to avoid destabilizing an unstable pattern.

Homeostatic activation of aryl hydrocarbon receptor by dietary ligands dampens cutaneous allergic responses by controlling Langerhans cells migration.

Dietary compounds can affect the development of inflammatory responses at distant sites. However, the mechanisms involved remain incompletely understood. Here, we addressed the influence on allergic responses of dietary agonists of aryl hydrocarbon receptor (AhR). In cutaneous papain-induced allergy, we found that lack of dietary AhR ligands exacerbates allergic responses. This phenomenon was tissue-specific as airway allergy was unaffected by the diet. In addition, lack of dietary AhR ligands worsened asthma-like allergy in a model of 'atopic march.' Mice deprived of dietary AhR ligands displayed impaired Langerhans cell migration, leading to exaggerated T cell responses. Mechanistically, dietary AhR ligands regulated the inflammatory profile of epidermal cells, without affecting barrier function. In particular, we evidenced TGF-β hyperproduction in the skin of mice deprived of dietary AhR ligands, explaining Langerhans cell retention. Our work identifies an essential role for homeostatic activation of AhR by dietary ligands in the dampening of cutaneous allergic responses and uncovers the importance of the gut-skin axis in the development of allergic diseases.

In vivo pressure-flow relation of human cutaneous vessels following prolonged iterative exposures to hypergravity.

The study examined intra- and interlimb variations in cutaneous vessel responsiveness to acute and repeated transmural pressure elevations. In 11 healthy men, red blood cell flux was assessed via laser-Doppler flowmetry on both glabrous and nonglabrous skin regions of an arm (finger and forearm) and leg (toe and lower leg), across a wide range of stepwise increasing distending pressures imposed in the vessels of each limb separately. The pressure-flux cutaneous responses were evaluated before and after 5 wk of intermittent (40 min, 3 sessions per week) exposures to hypergravity (∼2.6-3.3 G; G training). Before and after G training, forearm and lower leg blood flux were relatively stable up to ∼210 and ∼240 mmHg distending pressures, respectively; and then they increased two- to threefold (P < 0.001). Finger blood flux dropped promptly (P < 0.001), regardless of the G training (P = 0.64). At ≤120-mmHg distending pressures, toe blood flux enhanced by ∼40% (P ≤ 0.05); the increase was augmented after the G training (P = 0.01). At high distending pressures, toe blood flux dropped by ∼70% in both trials (P < 0.001). The present results demonstrate that circulatory autoregulation is more pronounced in glabrous skin than in nonglabrous skin, and in nonglabrous sites of the leg than in those of the arm. Repetitive high-sustained gravitoinertial stress does not modify the pressure-flow relationship in the dependent skin vessels of the arm nor in the nonglabrous sites of the lower leg. Yet it may partly inhibit the myogenic responsiveness of the toe's glabrous skin.

No impact of biological sex on nitric oxide contribution to cutaneous vascular response to 39ºC local heating

Purpose: The contribution of endothelial nitric oxide (NO) to vasodilation (%NO contribution) is a significant indicator of risk of cardiovascular disease development. Local skin heating to either 42 ºC or 39 ºC is used to determine mechanisms of vasodilation in health and disease, specifically to investigate %NO contribution. Women have lower %NO contribution in the cutaneous vasculature than men in the early follicular phase of the menstrual cycle, when the circulating vasoactive reproductive hormones are at their lowest concentration. However, this phase represents only a brief portion of the menstrual cycle. We aimed to determine the overall impact of biological sex on %NO contribution to cutaneous vasodilation utilizing a 39ºC local heating protocol, which better isolates the endothelial NO-synthase pathway. We tested women randomly during any phase of the menstrual cycle. We hypothesized that women would demonstrate greater NO-dependent cutaneous vasodilation than men in response to 39ºC local heating. Methods: Data are represented as mean(SD). An intradermal microdialysis fiber was placed in the ventral forearms of 12 men and 13 women [24.2(4.6) years]. Local heaters and laser-Doppler flowmetry probes were used to measure red blood cell flux (perfusion units, PU). Cutaneous vascular conductance (CVC) was calculated as laser-Doppler PU/mean arterial pressure. A standard 39ºC local heating protocol was conducted wherein PU was continuously collected at rest (10 minutes), then the local temperature was increased to 39ºC. After PU reached a steady plateau (~40 minutes), the NO synthase inhibitor 15 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused. Maximal vasodilation was induced by heating to 43ºC and perfusing 28 mM sodium nitroprusside and normalized to %CVCmax. %NO contribution was calculated as the absolute percentage difference between %CVCmax of 39ºC plateau and %CVCmax of L-NAME steady-state. We compared both CVC and %CVCmax between groups with two-way ANOVA and the %NO contribution with unpaired t-tests. Results: The %NO contribution was not different between sexes [men 48(23)%, women 39(17)%; P = 0.26]. There was no effect of sex on either absolute CVC [men 0.717(0.29) PU, women 0.73(0.48) PU at 39ºC phase] or %CVCmax [men 69(31)%, women 54(20)% at 39ºC phase] at any stage of the 39ºC local heating protocol (main effects P ≥ 0.08). Conclusion: These data indicate there is no impact of biological sex on the vasodilatory response of the cutaneous vasculature to 39ºC local heating in young healthy adults when women are tested at random across the menstrual cycle. Funding: National Institutes of Health Grant T-32-5T32AG049676 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Seasonal Tanning-Induced Increases in Skin Pigmentation Do Not Affect Nitric Oxide-Mediated Vasodilation of the Cutaneous Microvasculature

Acute ultraviolet radiation (UVR) exposure reduces nitric oxide (NO)-dependent cutaneous vasodilation. Additionally, increased constitutive skin melanin concentrations are associated with reduced NO-dependent cutaneous vasodilation. However, the impact of seasonal tanning-induced increases in skin melanin concentration on NO-dependent cutaneous vasodilation has not been investigated. PURPOSE: To investigate the effect of seasonal tanning-induced increases in skin melanin on the NO-dependent cutaneous vasodilation response to local heating. We hypothesized that NO-dependent cutaneous vasodilation would be reduced in tanned skin relative to untanned skin. METHODS: Three intradermal microdialysis fibers were placed in the ventral upper arm (least sun exposed), ventral forearm (moderately sun exposed), and dorsal forearm (most sun exposed) of seven adults (33 ± 14 yrs; 4M/3F) with light-to-moderate constitutive skin pigmentation. Differences in sun exposure among the sites was confirmed using the melanin-index (M-index; an index of skin pigmentation), measured via skin reflectance spectrophotometry. Lactated Ringer’s solution was perfused through the microdialysis fibers while local heating to 42°C induced cutaneous vasodilation. After attaining a stable plateau in cutaneous blood flow, 15mM NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) was perfused at all sites to quantify NO-mediated vasodilation. Red cell flux was measured using laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC=LDF/mean arterial pressure) was calculated for each phase of the local heating response (i.e., baseline, initial peak, local heating plateau, post L-NAME plateau) and expressed as percent maximum (%CVCmax; 28mM sodium nitroprusside + 43°C local heating). RESULTS: M-index was highest (i.e., skin pigmentation was darkest) in the dorsal forearm (50.5 ± 11.8 a.u.) compared to the ventral forearm (37.5 ± 7.4 a.u.; p ≤ 0.03) and upper arm (30.2 ± 5.1 a.u.; p ≤ 0.001). There were no baseline (p ≥ 0.37), initial peak (p ≥ 0.22), post L-NAME plateau (p ≥ 0.12), or maximal CVC (p ≥ 0.23) differences among the three sites. Likewise, the magnitude of the local heating plateau was not different among the three sites (dorsal: 88±17%; ventral: 81±20%; upper: 90±12%; p ≥ 0.16), nor was NO-mediated vasodilation (dorsal: 59±15%; ventral: 54±13%; upper: 55±11.0%; p ≥ 0.79). CONCLUSION: These data suggest that, in contrast to the effects of acute UVR exposure or a constitutively dark skin pigmentation, seasonal tanning-induced increases in skin pigmentation do not alter NO-dependent cutaneous vasodilation responses to local heating. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites

Abstract Mosquito-borne viruses are a growing global threat. Initial viral inoculation occurs in the skin via the mosquito ‘bite’, eliciting immune responses that shape the establishment of infection and pathogenesis. Here we assess the cutaneous innate and adaptive immune responses to controlled Aedes aegypti feedings in humans living in Aedes-endemic areas. In this single-arm, cross- sectional interventional study (trial registration #NCT04350905), we enroll 30 healthy adult participants aged 18 to 45 years of age from Cambodia between October 2020 and January 2021. We perform 3-mm skin biopsies at baseline as well as 30 min, 4 h, and 48 h after a controlled feeding by uninfected Aedes aegypti mosquitos. The primary endpoints are measurement of changes in early and late innate responses in bitten vs unbitten skin by gene expression profiling, immunophenotyping, and cytokine profiling. The results reveal induction of neutrophil degranulation and recruitment of skin-resident den- dritic cells and M2 macrophages. As the immune reaction progresses T cell priming and regulatory pathways are upregulated along with a shift to Th2-driven responses and CD8+ T cell activation. Stimulation of participants’ bitten skin cells with Aedes aegypti salivary gland extract results in reduced pro-inflammatory cytokine production. These results identify key immune genes, cell types, and pathways in the human response to mosquito bites and can be leveraged to inform and develop novel therapeutics and vector- targeted vaccine candidates to interfere with vector-mediated disease. Division of Intramural Research at National Institute of Allergy and Infectious Diseases at the National Institutes of Health #1ZIAAI001066-12: J.M., F.O.; Howard Hughes Medical Institute-Wellcome #208710/Z/17/Z: T.C.; French National Research Agency #ANR-17-CE15-00029: D.M.; Calmette-Yersin PhD Scholarship: D.G.

Disease associated monocytes contribute to the inflammatory milieu in hidradenitis suppurativa and have dysregulated expression of transposable elements

Abstract Hidradenitis suppurativa (HS), an inflammatory skin-disease, manifests as painful lesions in intertriginous skin. Despite their central role in innate immunity the role of monocytes in HS is largely unknown. Here we utilized cytometry by time-of-flight (CyTOF), imaging CyTOF (IMC), cellular indexing of transcriptomes and epitopes by sequencing (CITEseq), spatial transcriptomics (ST), and our recently developed database (HSOmicsDB) to characterize the systemic and cutaneous immune response in patients with HS. CITEseq found differential genes in circulating immune cells from HS patients enriched for cellular activation and extravasation. CyTOF immune profiling of fresh whole-blood samples found decreased frequency of classical Mos (C.Mos), which had increased expression of skin homing chemokine receptors. IMC found C.Mos infiltrated lesional dermis and tunnel regions, but not perilesional (PL) skin. Patients with HS showed increased proportions of activated C.Mo subclusters and a population of SOD2+ C.Mos expressing genes downstream of viral sensing pathways. SOD2 +C.Mos expressed high levels of neutrophil attracting chemokines. ST found SOD2 +C.Mos localized to regions of active inflammation and dermal tunnels. HSOmicsDB showed Mos and Macs expressed SOD2 +C.Mo genes, which were enriched in lesions, but not PL skin. Finally, we show that SOD2 +C.mos in HS have dysregulated expression of transposable elements (TEs), which may be activating viral sensing mechanisms in patients with HS. Together our data shows monocytes in HS function to recruit neutrophils to lesional HS skin, and provides the first evidence implicating TEs as disease promoting factors in HS by leading to C.Mo dysregulation. Supported By NIH/NIAMS, R01AR078688-01A1 and R21AR079089-01A1

Coinfection with Strongyloides and SARS-CoV-2: A Systematic Review.

Treatments for COVID-19, including steroids, might exacerbate Strongyloides disease in patients with coinfection. We aimed to systematically review clinical and laboratory features of SARS-CoV-2 and Strongyloides coinfection, investigate possible interventions, assess outcomes, and identify research gaps requiring further attention. We searched two electronic databases, LitCOVID and WHO, up to August 2022, including SARS-CoV-2 and Strongyloides coinfection studies. We adapted the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment to evaluate if using corticosteroids or other immunosuppressive drugs in COVID-19 patients determined acute manifestations of strongyloidiasis. We included 16 studies reporting 25 cases of Strongyloides and SARS-CoV-2 coinfection: 4 with hyperinfection syndrome; 2 with disseminated strongyloidiasis; 3 with cutaneous reactivation of strongyloidiasis; 3 with isolated digestive symptoms; and 2 with solely eosinophilia, without clinical manifestations. Eleven patients were asymptomatic regarding strongyloidiasis. Eosinopenia or normal eosinophil count was reported in 58.3% of patients with Strongyloides reactivation. Steroids were given to 18/21 (85.7%) cases. A total of 4 patients (19.1%) received tocilizumab and/or Anakirna in addition to steroids. Moreover, 2 patients (9.5%) did not receive any COVID-19 treatment. The causal relationship between Strongyloides reactivation and COVID-19 treatments was considered certain (4% of cases), probable (20% of patients), and possible (20% of patients). For 8% of cases, it was considered unlikely that COVID-19 treatment was associated with strongyloidiasis reactivations; the relationship between the Strongyloides infection and administration of COVID-19 treatment was unassessable/unclassifiable in 48% of cases. Of 13 assessable cases, 11 (84.6%) were considered to be causally associated with Strongyloides, ranging from certain to possible. Further research is needed to assess the frequency and risk of Strongyloides reactivation in SARS-CoV-2 infection. Our limited data using causality assessment supports recommendations that clinicians should screen and treat for Strongyloides infection in patients with coinfection who receive immunosuppressive COVID-19 therapies. In addition, the male gender and older age (over 50 years) may be predisposing factors for Strongyloides reactivation. Standardized guidelines should be developed for reporting future research.

Within-limb variation in skin pigmentation does not influence cutaneous vasodilation.

Ultraviolet radiation (UVR) exposure acutely reduces nitric oxide (NO)-dependent cutaneous vasodilation. In addition, increased constitutive skin melanin is associated with attenuated NO-dependent cutaneous vasodilation. However, the impact of within-limb variation in skin melanization, associated with seasonal UVR exposure, on NO-dependent cutaneous vasodilation is unknown. We investigated the effect of within-limb variation in skin melanin on NO-dependent cutaneous vasodilation. Intradermal microdialysis fibers were placed in the inner-upper arm, ventral forearm, and dorsal forearm of seven adults (33 ± 14 yr; 4 M/3 F) with constitutively light skin pigmentation. Melanin-index (M-index; an index of skin pigmentation), measured via reflectance spectrophotometry, confirmed differences in sun exposure among sites. A standardized local heating (42°C) protocol induced cutaneous vasodilation. After attaining a stable elevated blood flow plateau, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) was infused to quantify the NO contribution. Laser-Doppler flowmetry (LDF) measured red cell flux and cutaneous vascular conductance (CVC = LDF/mean arterial pressure) and was normalized to maximal (%CVCmax; 28 mM sodium nitroprusside + 43°C local heating). Dorsal forearm M-index was higher [50.5 ± 11.8 au (arbitrary units)] compared with the ventral forearm (37.5 ± 7.4 au; P ≤ 0.03) and upper arm (30.0 ± 4.0 au; P ≤ 0.001) M-index. Cutaneous vasodilation responses to local heating were not different among sites (P ≥ 0.12). Importantly, neither the magnitude of the local heating plateau (dorsal: 85 ± 21%; ventral: 70 ± 21%; upper: 87 ± 15%; P ≥ 0.16) nor the NO-mediated component of that response (dorsal: 59 ± 15%; ventral: 54 ± 13%; upper: 55 ± 11%; P ≥ 0.79) was different among sites. These data suggest that within-limb differences in skin pigmentation secondary to seasonal UVR exposure do not alter NO-dependent cutaneous vasodilation.NEW & NOTEWORTHY Locally derived endothelial nitric oxide (NO) contributes to the full expression of cutaneous vasodilation responses. Acute ultraviolet radiation (UVR) exposure attenuates NO-mediated vasodilation of the cutaneous microvasculature. Our findings suggest that in constitutively lightly pigmented skin, variation in skin melanin due to seasonal exposure to UVR does not alter the NO contribution to cutaneous vasodilation. Seasonal UVR exposure does not impact the NO-mediated cutaneous microvascular function.

1037 Triggering receptor expressed on myeloid cells (TREM)-1 modulates cutaneous immune responses and prevents skin cancer

1037 Triggering receptor expressed on myeloid cells (TREM)-1 modulates cutaneous immune responses and prevents skin cancer

Thermographic Assessment of Skin Temperature Changes following Partial Body Cryostimulation (PBC) in Football Players

Infrared thermography has been widely used to visualize skin temperature in human science. One of the important areas of its application is the analysis of changes in body surface temperature as a result of the use of physical medicine treatments in post-exercise regeneration in sports. The aim of this study was to evaluate the cutaneous temperature response in selected body areas and the range of chosen markers of skeletal muscle damage to partial body cryostimulation (PBC) as a method of post-match regeneration. Fourteen football players underwent PBC after a match. Thermographic analyses of anterior and posterior surfaces of the body were performed before and immediately after the treatment. Before, directly after, and 24, 48, and 72 h after the match serum creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) were evaluated. After PBC, a significant (p ≤ 0.001) decrease in skin temperature (Tsk) in all analyzed areas occurred. The greatest drop was observed in the areas of the thighs (∆ = 9.96–11.02 °C); the smallest temperature drop occurred in the areas of the upper and lower part of the back (∆ = 6.18−6.70 °C) and in the area of the chest (∆ = 6.80 °C). The most significant positive relationships between the magnitude of change in Tsk of the anterior and posterior surfaces of the thighs, body fat, and systolic and diastolic blood pressure have been shown. There were no significant differences between temperatures in selected areas in relation to the sides of the body, both before and after PBC. The range of temperature changes confirms the stimulating effect of PBC. The course of changes in the concentration of CK and AST indicates a potentially beneficial effect of PBC on the course of post-workout regeneration, without side effects. Maintaining a constant body temperature during PBC comes at the expense of thermoregulatory mechanisms leading to a lower body surface temperature.

Modulation of Inflammatory Proteins in Serum May Reflect Cutaneous Immune Responses in Cancer Immunotherapy.

Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP.

Acute impact of aerobic exercise on local cutaneous thermal hyperaemia.

Little is known about the acute changes in cutaneous microvascular function that occur in response to exercise, the accumulation of which may provide the basis for beneficial chronic cutaneous vascular adaptations. Therefore, we examined the effects of acute exercise on cutaneous thermal hyperaemia. Twelve healthy, recreationally active participants (11 male, 1 female) performed 30-minute cycling at 50% (low-intensity exercise, LOW) or 75% (high-intensity exercise, HIGH) maximum heart rate. Laser Doppler flowmetry (LDF) and rapid local skin heating were used to quantify cutaneous thermal hyperaemia before (PRE), immediately following (IMM) and 1-h (1HR) after exercise. Baseline, axon reflex peak, axon reflex nadir, plateau, maximum skin blood flow responses to rapid local heating (42°C for 30-min followed by 44°C for 15-min) at each stage were assessed and indexed as cutaneous vascular conductance [CVC=flux/mean arterial blood pressure (MAP), PU·mmHg-1], and expressed as a percentage of maximum (%CVCmax). Exercise increased heart rate (HR), MAP and skin blood flow (all P<0.001), and to a greater extent during HIGH (all P<0.001). The axon reflex peak and nadir were increased immediately and 1-h after exercise (all comparisons P<0.01 vs. PRE), which did not differ between intensities (peak: P=0.34, axon reflex nadir: P=0.91). The endothelium-dependent plateau response was slightly elevated after exercise (P=0.06), with no effect of intensity (P=0.58) nor any interaction effect (P=0.55). CONCLUSION: Exercise increases cutaneous microvascular axonal responses to local heating for up to 1-h, suggesting an augmented sensory afferent function post-exercise. Acute exercise may only modestly affect endothelial function in cutaneous microcirculation.

Skin infectome of patients with a tick bite history.

Ticks are the most important obligate blood-feeding vectors of human pathogens. With the advance of high-throughput sequencing, more and more bacterial community and virome in tick has been reported, which seems to pose a great threat to people. A total of 14 skin specimens collected from tick-bite patients with mild to severe symptoms were analyzed through meta-transcriptomic sequencings. Four bacteria genera were both detected in the skins and ticks, including Pseudomonas, Acinetobacter, Corynebacterium and Propionibacterium, and three tick-associated viruses, Jingmen tick virus (JMTV), Bole tick virus 4 (BLTV4) and Deer tick mononegavirales-like virus (DTMV) were identified in the skin samples. Except of known pathogens such as pathogenic rickettsia, Coxiella burnetii and JMTV, we suggest Roseomonas cervicalis and BLTV4 as potential new agents amplified in the skins and then disseminated into the blood. As early as 1 day after a tick-bite, these pathogens can transmit to skins and at most four ones can co-infect in skins. Advances in sequencing technologies have revealed that the diversity of tick microbiome and virome goes far beyond our previous understanding. This report not only identifies three new potential pathogens in humans but also shows that the skin barrier is vital in preventing horizontal transmissions of tick-associated bacteria or virus communities to the host. It is the first research on patients' skin infectome after a tick bite and demonstrates that more attention should be paid to the cutaneous response to prevent tick-borne illness.

Exploring the roles of prostanoids, leukotriens, and dietary fatty acids in cutaneous inflammatory diseases: Insights from pharmacological and genetic approaches.

Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2 -EP4 and LTB4 -BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine-induced migration ability into the skin and play critical roles in the priming and/or activation of antigen-specific effector T cells in the skin. In addition to these ω6 fatty acid-derived metabolites, various ω3 fatty acid-derived metabolites regulate skin immune cell functions, and some exert potent anti-inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.

The peripheral vascular responses in non-freezing cold injury and matched controls.

What is the central question of this study? Does non-freezing cold injury (NFCI) alter normal peripheral vascular function? What is the main finding and its importance? Individuals with NFCI were more cold sensitive (rewarmed more slowly and felt more discomfort) than controls. Vascular tests indicated that extremity endothelial function was preserved with NFCI and that sympathetic vasoconstrictor response might be reduced. The pathophysiology underpinning the cold sensitivity associated with NFCI thus remains to be identified. The impact of non-freezing cold injury (NFCI) on peripheral vascular function was investigated. Individuals with NFCI (NFCI group) and closely matched controls with either similar (COLD group) or limited (CON group) previous cold exposure were compared (n=16). Peripheral cutaneous vascular responses to deep inspiration (DI), occlusion (PORH), local cutaneous heating (LH) and iontophoresis of acetylcholine and sodium nitroprusside were investigated. The responses to a cold sensitivity test (CST) involving immersion of a foot in 15°C water for 2min followed by spontaneous rewarming, and a foot cooling protocol (footplate cooled from 34°C to 15°C), were also examined. The vasoconstrictor response to DI was lower in NFCI compared to CON (toe: 73 (28)% vs. 91 (17)%; P=0.003). The responses to PORH, LH and iontophoresis were not reduced compared to either COLD or CON. During the CST, toe skin temperature rewarmed more slowly in NFCI than COLD or CON (10min: 27.4 (2.3)°C vs. 30.7 (3.7)°C and 31.7 (3.9)°C, P<0.05, respectively); however, no differences were observed during the footplate cooling. NFCI were more cold-intolerant (P<0.0001) and reported colder and more uncomfortable feet during the CST and footplate cooling than COLD and CON (P<0.05). NFCI showed a decreased sensitivity to sympathetic vasoconstrictor activation than CON and greater cold sensitivity (CST) compared to COLD and CON. None of the other vascular function tests indicated endothelial dysfunction. However, NFCI perceived their extremities to be colder and more uncomfortable/painful than the controls.

Assessment of Suppression of Cutaneous Allergic Responses and Pruritus by Topical Minocycline

Assessment of Suppression of Cutaneous Allergic Responses and Pruritus by Topical Minocycline