Biofeedback,cognitive‐behavioral methods,and hypnosis in dermatology: Is it all in your mind?

Biofeedback can improve cutaneous problems that have an autonomic nervous system component. Examples include biofeedback of galvanic skin resistance (GSR) for hyperhidrosis and biofeedback of skin temperature for Raynaud's disease. Hypnosis may enhance the effects obtained by biofeedback. Cognitive-behavioral methods may resolve dysfunctional thought patterns (cognitive) or actions (behavioral) that damage the skin or interfere with dermatologic therapy. Responsive diseases include acne excoriée, atopic dermatitis, factitious cheilitis, hyperhidrosis, lichen simplex chronicus, needle phobia, neurodermatitis, onychotillomania, prurigo nodularis, trichotillomania, and urticaria. Hypnosis can facilitate aversive therapy and enhance desensitization and other cognitive-behavioral methods. Hypnosis may improve or resolve numerous dermatoses. Examples include acne excoriée, alopecia areata, atopic dermatitis, congenital ichthyosiform erythroderma, dyshidrotic dermatitis, erythromelalgia, furuncles, glossodynia, herpes simplex, hyperhidrosis, ichthyosis vulgaris, lichen planus, neurodermatitis, nummular dermatitis, postherpetic neuralgia, pruritus, psoriasis, rosacea, trichotillomania, urticaria, verruca vulgaris, and vitiligo. Hypnosis can also reduce the anxiety and pain associated with dermatologic procedures.     

Impaired keratinocyte proliferative and clonogenic potential in transgenic mice overexpressing 14-3-3σ in the epidermis

The 14-3-3 protein family controls diverse biochemical processes through interaction with phosphorylated consensus sequences in protein targets. Its epithelial specific member, 14-3-3σ, also known as stratifin, is highly expressed in differentiated keratinocytes, and in vitro evidence indicates that 14-3-3σ downregulation leads to keratinocyte immortalization. To define the role of 14-3-3σ in skin homeostasis in vivo, we generated transgenic mice overexpressing 14-3-3σ in proliferating keratinocytes of the epidermis and hair follicle. Transgenic animals show decreased epidermal thickness and hair follicle density associated with reduced number of proliferating keratinocytes and decreased levels of keratins 14, 5, and 15. Primary keratinocytes isolated from transgenic mice manifest reduced proliferation and migration. Moreover, clonogenicity assessment and label-retaining analysis reveal a reduction in keratinocyte progenitor cell number in transgenic mice. Response to IGF-1 is strongly impaired in cultured transgenic keratinocytes compared with wild-type cells. Consistently, activation of phosphoinositol 3-kinase (PI3K), AKT, and Rac1, all IGF-1 downstream mediators, is reduced. Our results demonstrate that 14-3-3σ controls the in vivo epidermal proliferation-differentiation switch by reducing proliferative potential and forcing keratinocytes to exit the cell cycle, and that this effect associates with inhibition of the IGF-1 pathway.     

Experimental study of δ-ALA-PDT in the treatment in BXSB lupus-prone mice

Extracorporeal photochemotherapy can correct immune disease and treat many autoimmune diseases. The aim of this study was to investigate the effects of delta-aminolevulinic acid photodynamic therapy (δ-ALA-PDT) on BXSB mouse. The 24-h urine protein, titers of serum antinuclear antibodies, peripheral blood lymphocyte apoptosis and deposition of immune complex in renal glomeruli were determined in BXSB mice after δ-ALA-PDT treatment. Results showed that δ-ALA-PDT treatment could reduce 24-h urine protein, titers of serum antinuclear antibodies, and deposition of immune complex in renal glomeruli. The δ-ALA-PDT treatment could also lead to significant increase in the rate of peripheral blood lymphocytes.     

Human Langerhans cells in epidermal cell culture,in vitro skin explants and skin grafts onto “nude” mice

Summary In order to find a model system which best preserves human Langerhans cells (LC) outside of the human body, three possibilities were examined: epidermal cell culture, skin explants, and skin grafts onto nude mice. Using OKT-6 and anti-HLA-DR monoclonal antibodies, we quantified LC in epidermal sheets or epidermal cell cultures. All observations were carried out over a period of 4 weeks. We found that under epidermal cell culture conditions, LC rapidly disappeared, to the extent that after 10 days only rare HLA-DR-positive cells could be observed. In contrast, in the presence of intact dermis (explants and grafts), 60%–80% of the original number of LC, morphologically unchanged, dendritic and OKT-6 and HLA-DR-positive, were seen. These findings suggest that human LC are either a long-lived cell population or else can proliferate locally. The systems studied may be a useful tool for future investigation of LC function.     

Galvanic zinc–copper microparticles produce electrical stimulation that reduces the inflammatory and immune responses in skin

The human body has its own innate electrical system that regulates the body’s functions via communications among organs through the well-known neural system. While the effect of low-level electrical stimulation on wound repair has been reported, few studies have examined the effect of electric potential on non-wounded, intact skin. A galvanic couple comprised of elemental zinc and copper was used to determine the effects of low-level electrical stimulation on intact skin physiology using a Dermacorder device. Zn–Cu induced the electrical potential recorded on intact skin, enhanced H₂O₂ production and activated p38 MAPK and Hsp27 in primary keratinocytes. Treatment with Zn–Cu was also found to reduce pro-inflammatory cytokines, such as IL-1α, IL-2, NO and TNF-α in multiple cell types after stimulation with PHA or Propionibacterium acnes bacteria. The Zn–Cu complex led to a dose-dependent inhibition of TNF-α-induced NF-κB levels in keratinocytes as measured by a dual-luciferase promoter assay, and prevented p65 translocation to the nucleus observed via immunofluorescence. Suppression of NF-κB activity via crosstalk with p38 MAPK might be one of the potential pathways by which Zn–Cu exerted its inflammatory effects. Topical application of Zn–Cu successfully mitigated TPA-induced dermatitis and oxazolone-induced hypersensitivity in mice models of ear edema. Anti-inflammatory activity induced by the Zn–Cu galvanic couple appears to be mediated, at least in part, by production of low level of hydrogen peroxide since this activity is reversed by the addition of Catalase enzyme. Collectively, these results show that a galvanic couple containing Zn–Cu strongly reduces the inflammatory and immune responses in intact skin, providing evidence for the role of electric stimulation in non-wounded skin.     

Trends in HIV sexual prevention: Attitudinal beliefs and behavioral intention in Spanish young people over the past two decades (1999–2020)

Despite preventive efforts, HIV exposure is still a concern for public health. The current prevalence is related to unsafe sex, which is based on socio-cognitive variables. Therefore, information about these variables is required to verify whether the past preventive strategies have been effective and improve the future ones. However, there is not updated information to adjust future preventive interventions. For this reason, this study analyzes trends by gender in Spanish young people over the past two decades in perceived susceptibility to HIV, severity perceived to HIV, condom confidence and the intention of condom use, from 1999 to 2020. For this purpose, 11,665 Spanish young people (from 17 to 40 years old) completed the AIDS Prevention Questionnaire in each year. Following our results, in general, the socio-cognitive variables have revealed an unsatisfactory trend: a low perceived susceptibility to HIV and a behavioral intention that have remained stable or even declined slightly over the past years. Particularly, men are more likely to report a riskier level in socio-cognitive variables although, in the latest evaluations, women would decrease condom use intention largely than men. In general, regarding age, young adult would report better levels of condom confidence, but early youth would get higher results in perceived severity, as well as better scores in the latest evaluations of condom use intention. Considering these results, policies should make an effort in HIV prevention programs, and emphasize the attention to attitudinal beliefs and behavioral intention to improve their effectiveness.     

Potentiation of histamine-induced itch and flare responses in human skin by the enkephalin analogue FK 33-824, β-endorphin and morphine

Summary The effect of various opioid or putative neurotransmitter peptides on histamine-induced itch and flare responses was studied in humans after intradermal injection. Significant enhancement of the histamine responses was induced by the stable methionine-enkephalin analogue FK 33-824, -endorphin and morphine. The putative neurotransmitters substance P and vasoactive intestinal polypeptide (VIP) — which moreover are potent histamine liberators — had no enhancing effect. The potentiation induced by FK 33-824 was induced neither by local pretreatment with Compound 48/80 to deplete the local stores of mast-cell-bound histamine, nor by oral pretreatment with indomethacin to inhibit prostaglandin formation in the skin. Thus, the enhancement did not seem to be due to histamine release or to prostaglandin formation and the mechanism of the effect remains to be shown. The specific morphine antagonist naloxone did not inhibit the potentiation by FK 33-824, which might indicate that ordinary opiate receptors were not involved. The results support the idea that pain and itch are qualitatively separate processes, and suggest possible mechanisms of morphine-induced pruritus. The findings are of particular interest in view of recent reports on the presence of methionineenkephalin in Merkel cells.A preliminary report on this investigation was presented at the Annual Meeting of the European Society for Dermatological Research, Amsterdam, The Netherlands, May 1980 [10]     

Skin responses to topical dehydroepiandrosterone: implications in antiageing treatment?

Background  Although low dehydroepiandrosterone (DHEA) is suspected to have a role in skin ageing, little information is available on the mechanisms potentially involved. Objectives  To obtain information on androgen receptor (AR) and procollagen expression in ageing skin during DHEA treatment. Methods  A placebo‐controlled, randomized, prospective study was performed with 75 postmenopausal women aged 60–65 years. The women were treated twice daily for 13 weeks with 3·0 mL of placebo or 0·1%, 0·3%, 1% or 2% DHEA cream applied on the face, arms, back of hands, upper chest and right thigh where 2‐mm biopsies were collected before and after treatment. Results  Although the overall structure of the epidermis was not significantly affected at the light microscopy level, AR expression examined by immunocytochemistry was markedly increased by DHEA treatment. In the dermis, the expression levels of procollagen 1 and 3 mRNA estimated by in situ hybridization were increased by DHEA treatment. In addition, the expression of heat shock protein (HSP) 47, a molecule believed to have chaperone‐like functions potentially affecting procollagen biosynthesis, was also found by immunocytochemistry evaluation to be increased, especially at the two highest DHEA doses. Conclusion  These data suggest the possibility that topical DHEA could be used as an efficient and physiological antiageing skin agent.     

Induction by tumour necrosis factor α of dose-related changes in Langerhans cell frequency in mice

Abstract It has been demonstrated previously that tumour necrosis factor α (TNF-α) provides an important signal for the migration of epidermal Langerhans cells (LC) from the skin. Intradermal administration to mice of homologous recombinant TNF-α induces both a rapid reduction in the frequency of LC local to the site of exposure and, somewhat later, an accumulation of dendritic cells in draining lymph nodes. It has been proposed recently, however, that the influence of TNF-α on LC function may be dose-dependent in nature with lower concentrations inducing migration, but higher concentrations immobilizing LC in the epidermis. To investigate this proposal we examined the kinetics and dose-response relationships of TNF-α-induced LC migration in mice. At all concentrations tested (50, 150 or 300 ng/ear), intradermal exposure to TNF-α caused within 30 min a significant reduction in the frequency of MHC class II (Ia)⁺ LC within epidermal sheets. With the lower concentrations of TNF-α this effect was still apparent when LC were enumerated in the epidermis up to 4 h following cytokine treatment. In contrast, however, exposure of mice to 300 ng of TNF-α was consistently associated with a considerably less marked, and statistically insignificant, reduction in LC frequency by 4 h. These data indicate that at all concentrations of the cytokine examined here, TNF-α was able to stimulate a rapid (within 30 min) reduction in epidermal LC numbers, but that the rapidity with which the epidermis was repopulated following the initiation of LC migration was influenced by the concentration of TNF-α administered. It is suggested that TNF-α may influence not only the tempo of LC migration, but also the kinetics of epidermal repopulation. Received: 18 June 1998 / Received after revision: 25 February 1999 / Accepted: 19 March 1999     

The α-melanocyte-stimulating hormone-melanocortin receptor system influences the effects of ultraviolet A on skin and intestinal immunity in mice

Irradiation by ultraviolet (UV) A is known to decrease Langerhans cells (LCs) in the skin and increase IgA expression in the intestine, specifically the jejunum. These changes were induced in C57BL/6j mice by exposure of the ear or the eyes to 11 J/cm² UVA radiation, then a melanocortin receptor agonist (Agouti‐related protein; AgRP) was introduced either intracerebrally or intracerebroventricularly. The degree of change in both LC number and IgA expression induced by UVA eye irradiation was reduced more by intracerebral than by intraperitoneal injection of AgRP. α‐Melanocyte‐stimulating hormone and melanocortin receptors in the brain seem to contribute to immunomodulation after UVA irradiation of the eye or the ear in mice.     

Ultrastructural observations of skin lesions in MRL mice —dermoepidermal junction

Summary The MRL-lpr/lpr (MRL/1) mouse, a new animal model for the study of human systemic lupus erythematosus (SLE), shows characteristic skin manifestations in addition to several systemic autoimmune phenomena. The ultrastructural changes observed in the dermoepidermal junction (DEJ) and in the uppermost dermis were: (1) infolding of the DEJ; (2) deformities of the basal lamina, — partial disappearance, thickening, hanging down, duplication, and separation from the basal cell membrane; (3) basal laminalike dense material in the uppermost dermis and increased anchoring fibrils; (4) particles composed of circulated half-desmosomes between the basal cells and the basal lamina, and in the uppermost dermis with or without an enclosing basal lamina; (5) cell processes of the basal cells; and (6) invagination of the basal lamina in the basal cells. Most of these findings were similar to the ultrastructural changes observed in the skin lesions of human SLE. The skin eruptions of MRL/l mice might be a new aid in the investigation of the pathogenesis of the skin lesions of human SLE.This is the third part of a series of papers entitled pathogénesis of lupus dermatoses in autoimmune mice.     

The 21st century renaissance of the basophil? Current insights into its role in allergic responses and innate immunity

Basophils and mast cells express all the three subchains of the high-affinity immunoglobulin E (IgE) receptor Fc epsilon RI and contain preformed histamine in the cytoplasmic granules. However, it is increasingly clear that these cells play distinct roles in allergic inflammatory disease. Despite their presence throughout much of the animal kingdom, the physiological function of basophils remains obscure. As rodent mast cells are more numerous than basophils, and generate an assortment of inflammatory cytokines, basophils have often been regarded as minor players in allergic inflammation. In humans, however, basophils are the prime early producers of interleukin (IL)-4 and IL-13, T helper (Th)2-type cytokines crucial for initiating and maintaining allergic responses. Basophils also express CD40 ligand which, in combination with IL-4 and IL-13, facilitates IgE class switching in B cells. They are the main cellular source for early IL-4 production, which is vital for the development of Th2 responses. The localization of basophils in various tissues affected by allergic inflammation has now been clearly demonstrated by using specific staining techniques and the new research is shedding light on their selective recruitment to the tissues. Finally, recent studies have shown that basophil activation is not restricted to antigen-specific IgE crosslinking, but can be caused in non-sensitized individuals by a growing list of parasitic antigens, lectins and viral superantigens, binding to non-specific IgE antibodies. This, together with novel IgE-independent routes of activation, imparts important new insights into the potential role of basophils in both adaptive and innate immunity.     

Differential distribution of haematopoietic and nonhaematopoietic progenitor cells in intralesional and extralesional keloid: do keloid scars provide a niche for nonhaematopoietic mesenchymal stem cells?

Background Keloid disease is a benign, quasineoplastic disease with a high recurrence rate. Mesenchymal‐like stem cells (MLSC) have previously been demonstrated in keloid scars and may be involved in keloid pathobiology. However, as these cells have only been examined by single colour fluorescence activated cell sorting (FACS) alone, they need to be more comprehensively characterized so that the key cellular contributors to keloid scars can be better understood. Objectives To identify and characterize MLSC in intralesional and extralesional keloid, and to distinguish haematopoietic stem cells (HSC) from mesenchymal stem cells (MSC). Methods and patients Punch biopsies from intralesional (top, middle and margin) and extralesional keloid scar sites were obtained from 17 patients with a keloid. Multicolour FACS analysis using antibodies specific for HSC markers CD34 and CD117 and MSC markers CD13, CD29, CD44 and CD90 was performed on freshly isolated keloid scar cells and on passage 0 and 1 cells. This was complemented by real‐time quantitative polymerase chain reaction (PCR) and immunohistological in situ analyses. Results Keloid scars contain distinct subpopulations of MLSCs. Cells positive for CD13, CD29, CD44 and CD90 were found to be significantly (P < 0·05) higher in the top and middle compartments of keloid scars compared with extralesional skin, where cells positive for CD34, CD90 and CD117 (representing HSCs) predominated. A unique population of CD34+ cells (cells positive for CD13, CD29, CD34, CD44 and CD90) were found in keloid scars and in extralesional skin. FACS and quantitative PCR analysis showed that many of the MSC markers were progressively downregulated and all HSC markers were lost during extended keloid fibroblast culture up to passage 1. Conclusion We have found distinct subpopulations of haematopoietic and nonhaematopoietic MSC in keloid scars, whereby HSC accumulate extralesionally, while keloids seem to provide a niche environment for nonhaematopoietic MSC. Future therapy of keloids may have to target differentially both stem cell populations in order to deprive these tumours of their regenerative cell pools.     

Differential Expression of TGF-β Isoforms in Human Kerationocytes by Narrow Band UVB

Background

Transforming growth factor-β (TGF-β), a multifunctional growth factor, has three isoforms: TGF-β1, TGF-β2, and TGF-β3. Different isoforms of TGF-β are associated with different proliferation and differentiation states of the epidermis. Narrow band ultraviolet B (NBUVB) emits a concentrated UVB source of 311 nm. NBUVB 1,000 mJ/cm² induces apoptosis in approximately 50% of keratinocytes.

Objective

The purpose of this study was to evaluate whether irradiation with NBUVB would alter the expression and production of TGF-β1, 2, and 3.

Methods

We measured TGF-β1, 2, and 3 mRNA and TGF-β1 and 2 protein levels at 800, 1,000, and 1,200 mJ/cm² for 24 hours and 48 hours.

Results

TGF-β1 mRNA levels were increased at both 24 hr and 48 hr, TGF-β2 mRNA levels were decreased at both 24 hr and 48 hr, and TGF-β3 mRNA levels were increased at 24 hr and similar to control at 48 hr. TGF-β1 protein levels were increased at 48 hr but decreased at 24 hr. TGF-β2 protein levels were decreased at both 24 hr and 48 hr.

Conclusion

The results suggest a possible role for TGF-β1 after NBUVB irradiation and opposing roles for TGF-β1 and TGF-β2 isoforms in NBUVB irradiation.