Commentary

In explaining the “world of psychosomatics”—where there is still so much to explore—I ask my colleagues who read these pages to try to do so without prejudice for the topic, even in the parts that are “less usual” or more “imaginative” or in some way “different” from what we are familiar with in the applied medical sciences. My experience as a practicing clinical dermatologist, together with long years of teaching and research in other areas of dermatology (biochemistry and immunopathology, in particular), compel me to make a recommendation: try to think of these ideas in the “magic” moments of our work—the moments of contact with the patient. Reflection and practical clinical-therapeutic results, the only great tests, will verify whether or not our “psychosomatic path” should be followed.     

Topical therapy--risks and unwanted effects

The kinetics of substances topically applied are different from those parenterally or orally applied. Chronic damage difficult to be recognized may be caused by long-term therapy, the high "reservoir effect" of an intact horny layer or the lack of barrier in a damaged horny layer, low substance concentration peaks, or lang diffusion periods in the circulation with very low plasma concentrations. Acute systemic damage is rare with percutaneously applied substances such as salicylic acid; it usually occurs under special conditions. Chronic damage to the skin is more often observed and usually judged by a dermatologist. These changes may not only be caused by active substances but also by excipients including apparently inert supplementary therapies such as the use of surfactants. Because of percutaneous absorption, the changes are either of systemic nature with no relationship to the skin or primarily affecting the skin.     

Quantitative analysis of contact sites between mast cells and sensory nerves in cutaneous psoriasis and lichen planus based on a histochemical double staining technique

Summary The aim of the present study was to test further our previous hypothesis that the inflammatory reaction in psoriasis is neurogenic. For this purpose, contact sites between mast cells and sensory nerves were morphometrically analysed in the basement membrane zone, papillary dermis and three dermal zones of lesional/non-lesional psoriatic and lichen planus skin as well as in healthy control skin. The analyses were made on sections stained with a histochemical double stain developed for this study. With the double stain, active mast cell tryptase was stained blue enzyme histochemically, and the sensory nerves black using specific monoclonal anti-neurofilament antibodies with immunogold. In psoriatic lesions, both mast cells and mast cell — nerve contacts were markedly more frequent in the basement membrane zone and in the papillary dermis when compared with the corresponding areas in the other groups. Mast cell numbers were increased in both lesional and symptom-free skin in lichen planus, but no increase was found in the mast cell — nerve contacts. Increased contacts between mast cells and sensory nerves indicate that the elements exist for neurogenic inflammation in psoriatic lesions. These increased contacts are not due to the extensive inflammatory reaction only, because they were not observed in lichen planus lesions.     

Psychosomatic dermatology

Overthrowing the traditional obligating positivistic “scientific” method, we assert that no disease—particularly no cutaneous affection—can be considered surely exempt from psychological influences, even in the absence of any strictly scientific demonstration in this regard. Even an infectious disease that does not seem to offer any space for interpretations other than the etiologically specific biotic noxae can be influenced by psychosocial factors. This has been known for some time, but has been reconfirmed by recent documentation¹ in which the authors even attribute to a “typical mother” the common phrase “If you don't get some rest you are going to get sick.”     

Diagnosis in psychosomatic dermatology

Franz Alexander¹ proposed that the term “psychosomatic” should be used only to indicate an investigative method for diagnosis and therapy with simultaneous and coordinated application of somatic (ie, physiologic, anatomic, pharmacologic, surgical, and dietetic) and psychological concepts and methods. Correct diagnostic methodology in psychosomatic dermatology could not, therefore, avoid subverting some of the procedures habitually used in medicine. In fact, in a traditional somatic approach the fundamental points are the progressive evaluation of the data resulting from the anamnesis, objective clinical examination of the patient, and the laboratory findings, from which diagnosis is deduced, by exclusion.² Dermatology—the science of evidence—has not subtracted itself from this interest aimed, above all, at “the apparent,” sometimes with scarce propensity for “what lies underneath,” what is not immediately in the foreground, what is not concretely evaluable.     

Holistic approach to diagnosis in psychosomatic dermatology

Three decades ago, two psychosomatic skin clinics were established by this author—one at the Hadassah University Hospital (1955) in Jerusalem, Israel, and one at the Cincinnati General Hospital (1957) in the United States, with the close cooperation and assistance of their Department of Dermatology (headed by Dr. Leon Goldman) and the Department of Psychiatry (headed by Dr. Maurice Levine and Dr. W. Donald Ross.) Postgraduate dermatologists, residents, medical students, and nurses were trained in the close relationship and possible interaction of organic and emotional factors in certain dermatoses. The teaching was conducted by the author, a dermatologist trained in psychiatry and psychosomatic dermatology.A psychiatrist was only occasionally consulted in specifically psychiatric cases.The aim was to enable the dermatologist to gain sufficient knowledge and experience in psychosomatic dermatology that he could directly handle his own patients by a holistic approach. Thus, this method was on a one-to-one (dermatologist-patient) basis, as opposed to the conventional two-to-one (dermatologist-psychiatrist-patient) relationship. This led to interesting seminar sessions with the residents, as well as special conferences with the hospital patients, and case presentations.Long experience in teaching convinced us that the greatest difficulty of postgraduate and resident dermatologists was in making the correct diagnosis of psychosomatic dermatosis. The aim of this paper is to guide the dermatologist in achieving this goal. To be able to make a proper diagnosis of psychosomatic skin disorder, the dermatologist must free himself of some misconceptions relating to the term “psychosomatic.”     

Influences of retinoic acid and retinoid on skin metabolism

Summary All-trans retinoic acid and its derivative retinoid, two new compounds with expanding therapeutic spectrum in dermatology, were investigated in biochemical assays. Both substances provoke an increase in oxygen consumption of rat skin whereas in human skin only retinoid was found active in this respect. In resting yeast cells, both substances failed to exert any significant influence on oxygen consumption. — Pure G-6-PDH was inhibited by retinoic acid and retinoid in concentrations as low as 5 µg/ml. In human skin homogenates, LDH-, GAPDH-, and G-6-PDH-activities were inhibited by retinoic acid whereas GOT-, LAP-, and ALD-acitivites remained practically unchanged following an incubation with retinoic acid in concentrations between 1 and 100 µg/ml for 60 min. — The data collected in this study were briefly discussed with regard to the use of retinoic acid and its derivatives in psoriasis.

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Zusammenfassung All-trans-Retinsäure und ihr Derivat Retinoid, zwei neue Substanzen mit zunehmender Bedeutung für die dermatologische Therapie, wurden in ihrer Auswirkung auf den Sauerstoffverbrauch von Zellen und von überlebenden Hautschnitten und auf Enzymaktivitäten (Reinenzym G-6-PDH; Hauthomogenat) untersucht. Sowohl Retinsäure als auch Retinoid bewirkten eine Steigerung des Sauerstoffverbrauches der Rattenhaut. Der Sauerstoffverbrauch menschlicher Haut erfuhr nur in Gegenwart von Retinoid eine signifikante Steigerung. An ruhenden Hefen verursachte keine der beiden untersuchten Substanzen einen Anstieg des Sauerstoffverbrauchs. — Schon in Konzentrationen von 5 µg/ml (etwa 15 µmol/l) hemmen Retinsäure und Retinoid die G-6-PDH-Aktivität (Reinenzym). Im Hauthomogenat (menschliche Haut) hemmte Retinsäure die Aktivitäten der LDH, GAPDH und G-6-PDH, während GOT-, LAP- und ALD-Aktivitäten unbeeinflußt blieben, zumindest durch Konzentrationen zwischen 1 und 100 µg/ml. (Retinoid wurde in diesen Versuchen nicht geprüft.) — Die Untersuchungsergebnisse werden im Hinblick auf die Anwendung von Retinsäure und Retinoid zur Behandlung der Psoriasis kurz diskutiert.

     

Cosmeceuticals and active ingredients

Cosmetic ingredients previously considered “inert” have potential to provide a biologic effect to skin. In a cosmeceutical formulation, the boundary between an “active” and “inert” ingredient may be obscured. For this reason, the cosmeceutical distributor must find a nonambiguous method to demonstrate the efficacy of a new ingredient. For a product to be successful in the marketplace, the benefits of the product must clearly be communicated to the consumer, and the consumer must be satisfied with product performance.     

Abnormal epidermal barrier in the pathogenesis of contact dermatitis

A crucial role of the epidermal permeability barrier is obvious in contact dermatitis. An intact skin barrier prevents the penetration of harmful substances into the skin. Irritants and allergens that stay on the skin surface and come into contact with the stratum corneum only do not harm the skin. After disruption of the skin barrier, however, irritants may penetrate into the living epidermal layers, injure the keratinocyte membrane, and release cytokines, which leads to inflammation and to irritant contact dermatitis. The skin barrier is often disrupted by chronic exposure to water plus detergents, solvents, or other irritants. A disrupted barrier in irritant contact dermatitis also allows for the penetration of allergens. Allergens may come into contact with Langerhans and T cells, induce immunological reactions, and cause inflammation, which results in allergic contact dermatitis. Treatments in contact dermatitis should restore the skin barrier to prevent relapse of the disease. Topical corticosteroids, most often used in treating contact dermatitis, reduce immunological reactions and inflammation but do not lead to a complete barrier repair. Skin barrier repair is more complete after treatment with calcineurin inhibitors and bland lipid-based emollient; therefore, these preparations should be preferred for long-term treatment of contact dermatitis.     

Viral and Nonviral Uses of Imiquimod: A Review

Background Imiquimod is a topical immunomodulator that is indicated for the treatment of external genital and perianal warts. This drug has been recently approved for the treatment of actinic keratoses and superficial basal cell carcinoma. There is a growing body of evidence for its effectiveness in treating a variety of other skin conditions.Objective This review examines the role of imiquimod 5% cream in the treatment of skin diseases such as actinic keratoses, basal cell carcinoma, Bowen’s disease, lentigo maligna, and extramammary Paget’s disease.Methods Published literature containing the words “Imiquimod” or “Aldara” was reviewed and summarized.Results This agent has demonstrated indirect antiviral and antitumor effects in animal models. Although the exact mechanism of action is unknown, imiquimod is an agonist for toll-like receptor (TLR) 7 and is thought to act by inducing cytokines, such as interferon alpha (IFN-α), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-α). These cytokines trigger the immune system to recognize the presence of a viral infection or tumor and the associated lesion is ultimately eradicated. Side effects are generally well tolerated with local skin reactions reported most frequently.Conclusion Imiquimod has been shown to be a safe and effective treatment for a variety of skin conditions.

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SommaireAntécédents Imiquimod est un immunomodulateur topique prescri dans le traitement des verrues génitales et périanales externes. Ce médicament a été récemment approuvé pour le traitement des kératoses actiniques et des carcinomes basocellulaires. Il y a de plus en plus de preuves soulignant son efficacité dans le traitement d’une variété d’autres troubles cutanés.Objectif Cette revue examine le rôle de la crème d’imiquimod à 5 % dans le traitement des troubles cutanés tels que les kératoses actiniques, les carcinomes basocellulaires, la maladie de Bowen, le mélanome malin à type de lentigo et la maladie de Paget extramammaire.Méthode Les textes publiés contenant les termes «Imiquimod» ou «Aldara» ont été revus et résumés.Résultats Cet agent a des effets antiviraux et antinéoplastiques chez les modéles animaux. Bien que le mécanisme d’action exact soit inconnu, l’imiquimod est un agoniste pour le récepteur TLR (Toll-like) 7. On pense qu’il agit en induisant des cytokines, telles que l’interféron alpha (IFN-α), l’interleukine-12 (IL-12), ainsi que les facteurs de nécrose tumorale alpha (TNF-α). Ces cytokines déclenchent la réaction du système immunitaire à la présence d’une infection virale ou d’une tumeur et la lésion connexe s’en trouve éradiquée. Les effets secondaires sont généralement bien tolérés, les réactions cutanées étant les plus fréquentes.Conclusion L’innocuité et l’efficacité de Limiquimod dans le traitement d’une varité de troubles cutanés ont été démontrées.

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This work was supported in part by 3M Pharmaceuticals, London, Ontario, Canada.     

Human papillomaviruses biochemical and biologic properties

The viral origin of warts and condylomas was established at the beginning of this century by experiments on the transmission of warts by means of cell-free tissue extracts.¹ For a long time, a single virus—the human wart virus—was considered responsible for these lesions,¹ although the multiplicity of human papillomaviruses (HPVs) was suspected on the basis of epidemiologic,² serologie,³ and histologic^4,5 data. It was, thus, generally thought that “the clinical type is determined by the local conditions at the site of infection and not by the virus”¹ and that the clinical evolution of the lesions—in particular, the rare malignant transformation^6,7 of genital condylomas and that of the cutaneous lesions of patients suffering from epidermodysplasia verruciformis (EV)—depended on immunologic, genetic, or extrinsic factors.^1,6,8

The characterization of HPVs and the study of their pathogenic properties have long been hindered by the absence of a cellular system permitting the in vitro replication of these viruses.⁹ During the last few years, new methods of analysis of the viral DNA—in particular, the molecular cloning of viral genomes in a plasmid or in the DNA of a bacteriophage—have permitted considerable improvement in our knowledge of HPVs.^10–12 At least 28 HPV types now are recognized^13–29 (Ostrow, R. personal communication). It seems likely that the different clinical types of lesions classically associated with an HPV are, in fact, distinct diseases caused by specific viruses.^23,30–34 Finally, the discovery of the high frequency of infection of the uterine cervix by an HPV,^36,36 as well as the frequent detection of HPV DNA sequences in neoplasias of the skin,^{16,32,37–39} the external genitalia,^40–46 and the uterine cervix^24,25 have broadened the spectrum of the pathogenicity of PVs for human beings and imposed the idea that infection by specific HPV types is a risk factor for the development of these neoplasias.

After reviewing the physicochemical and biologic characteristics of HPVs and the methods used for their study, we will present recent data on the nomenclature, the pathogenicity, and the oncogenic potential of HPVs.     

Cryosurgery of malignant and premalignant diseases of the skin: A simple approach

Cryosurgical treatment of skin cancer and premalignant conditions of the skin has been in widespread use for 20 years. Data accumulated over this period suggest that if attention is paid to the treatment technique and to lesion selection, then cure rates equivalent to radiotherapy, simple surgical excision, and curettage and cautery can be achieved reliably. Moh's micrographic surgery offers a higher cure rate for skin cancer, but is not suitable for the vast majority of lesions seen in clinical practice. The decision to use cryosurgery to treat any particular lesion will therefore be influenced by a number of other considerations. Cryosurgery competes well on morbidity and cosmetic outcome and is the quickest, easiest, cheapest and most readily available of the treatment options. As such it has earned its place among the recognized treatment modalities for skin cancers as well as premalignant conditions of the skin. Cryosurgery is commonly delivered empirically without record of the dose delivered and without audit of the outcome. The aim of this review is to describe in detail one standard technique of therapy that is easily reproduced and has been audited; the timed spot freeze technique. This technique can be used, even by those inexperienced in cryosurgery, to achieve predictable success rates. Many other techniques do exist, but either have not been audited or are unnecessarily cumbersome.     

Topical vitamin A acid in the treatment of acne vulgaris

Summary A controlled non-blind multicenter trial was conducted in 211 acne patients to test the activity of topical retinoic acid against sulfur-resorcinol—salicylic acid and placebo. Uniform evaluation criteria were used. After 8 weeks' treatment in comparable groups of patients, retinoic acid proved to be superior to the standard and to the placebo. The difference was statistically significant.Side effects were present in a number of patients treated with the active substances and with the placebo (mainly erythema), but rarely was the treatment discontinued.

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Zusammenfassung Um die lokale Wirksamkeit von Retinoic Säure im Vergleich zu Schwefel-Resorzin — Salizylsäure und Placebo zu testen, wurde im Rahmen einer multizentrischen Prüfung bei 211 Acne-Patienten eine kontrollierte Untersuchung durchgeführt. Es kamen einheitliche Auswertungskriterien zur Anwendung. Nach einer 8wöchigen Behandlung mit vergleichbaren Patientengruppen hat sich die Retinoic-Säure dem Vergleichspräparat und dem Placebo als überlegen gezeigt. Der Unterschied war statistisch signifikant.Nebenwirkungen waren in einer Anzahl von Patienten sei es unter der Behandlung mit den Wirksubstanzen als auch mit Placebo vorhanden (hauptsächlich Erytheme); eine Unterbrechung der Behandlung war jedoch nur selten notwendig.

     

Cannabinoid system in the skin – a possible target for future therapies in dermatology

Abstract:  Cannabinoids and their derivatives are group of more than 60 biologically active chemical agents, which have been used in natural medicine for centuries. The major agent of exogenous cannabinoids is Δ⁹-tetrahydrocannabinol (Δ⁹-THC), natural psychoactive ingredient of marijuana. However, psychoactive properties of these substances limited their use as approved medicines. Recent discoveries of endogenous cannabinoids (e.g. arachidonoylethanolamide, 2-arachidonoylglycerol or palmithyloethanolamide) and their receptors initiated discussion on the role of cannabinoid system in physiological conditions as well as in various diseases. Based on the current knowledge, it could be stated that cannabinoids are important mediators in the skin, however their role have not been well elucidated yet. In our review, we summarized the current knowledge about the significant role of the cannabinoid system in the cutaneous physiology and pathology, pointing out possible future therapeutic targets.     

Zur Ökologie von Staphylococcus aureus auf der menschlichen Hautoberfläche

Zusammenfassung Durch die der Einsaat von Staphylococcus aureus vorhergehende Ätherextraktion der Haut wird die Vermehrung im Vergleich zur normalen Haut der Gegenseite deutlich begünstigt. Bei denjenigen Probanden, die auf normaler Haut keine Vermehrung zulassen, scheint auf der ätherextrahierten Haut eine Vermehrung möglich zu sein, jedoch in geringerem Maße als bei den übrigen Versuchspersonen. — Durch das nicht mit mechanischer Einwirkung verbunden Ätherbad wird die hautansässige Flora deutlich vermindert; die Keimzahlen sind auch 24 Std später noch niedriger als auf der nicht vorbehandelten Haut.Auf krankhaft veränderten, eine vermehrte Schuppenbildung aufweisenden Versuchsfeldern, wie z. B. psoriatischen, ekzematösen oder narbigen Partien, kann sich der Staphylococcus aureus — günstige Feuchtigkeitsbedingungen vorausgesetzt — stark vermehren. Auf klinisch gesunden Arealen von Ekzematikern bieten sich dem Staphylococcus aureus offenbar wesentlich günstigere Bedingungen zur Vermehrung als bei Hautgesunden.Während einer innerlichen Antibioticagabe (Penicillin i.m., Chloramphenicol per os) ist die Vermehrung des Staphylococcus aureus auf der Hautoberfäche meistens unterbunden und der Testkeim nach 24 Std nicht mehr nachweisbar. Dagegen ist auf der Abrißfläche beim größeren Teil der Versuchspersonen nur eine teilweise Hemmung der Vermehrung festzustellen.

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Ecology of staphylococcus aureus on the human skin surfaceV. Staphylococcus aureus, artificially inoculated upon the skin surface after extraction with ether, of patients with dermatoses and during systemic administration of antibiotics

Summary An ether extraction of the skin surface prior to the inoculation of Staphylococcus aureus supports the multiplication in the following hours. This support is evident also in persons which on untreated normal skin do not exhibit a multiplication of Staphylococcus aureus. — The ether extraction reduces the resident flora of the skin very distinctly; up to 24 hours later the number of microbes is smaller than on untreated skin.On pathologically altered skin with increased scaling, f.i. psoriatic, eczematous or scarred areas, the multiplication of Staphylococcus aureus is supported, provided that the evaporation of the perspiratio insensibilis is impeded. Clinically healthy skin areas of patients with eczema are obviously more suitable for the multiplication of Staphylococcus aureus than normal skin.During systemic administration of antibiotics (penicillin, chloramphenicol) the multiplication of Staphylococcus aureus is mostly stopped on the normal skin surface. In contrast with the normal skin surface there is on the stripped skin only a partial inhibition of the multiplication.

     

The public health approach to the burden of common skin diseases in the community.

The vast majority of work performed by dermatologists in clinical practice is managing common skin conditions including eczema, psoriasis, acne, tinea, warts and in some countries skin cancer and in others skin infections. Governments and other health organisations rely on data to plan medical services. Dermatologists seek the same data to justify their existence. In Australia, we have been studying the frequency of these conditions showing that they are very common, with particular conditions occurring at particular ages. Our data show also that less than 50% of people seek advice from the medical practitioner, with pharmacists being the most common of the other sources of advice. People are frequently misinformed about their conditions and may be using treatment that is of no value. These data suggest the need for both public and professional education programs informing the public where to seek correct advice and teaching those who provide it to ensure that they have the knowledge to do so.     

Distribution and arrangement of multiple lesions in the anogenital region

A series of skin diseases may affect the anogenital region with unusual presentations; therefore, a careful clinical approach is needed to make a correct diagnosis. Diseases of the anogenital area include inflammatory dermatoses, infectious lesions, and neoplastic conditions. Inflammatory dermatoses are frequently not restricted to the anogenital area and often occur on other sites. Infectious anogenital lesions can be easily confused with other benign or malignant processes. Tumors that arise on the anogenital skin are similar to those that occur on the skin elsewhere. The differential diagnosis of all of these lesions often depends upon the distribution and arrangement of the skin lesions.     

Identification and classification of skin sensitizers: identifying false positives and false negatives

The first step in regulatory evaluation of substances involves the identification of their intrinsic hazards, including the potential for skin sensitization. This is, quite properly, entirely different from assessment of the risks to human health, which might arise from incorporation of substances in products. EU guidance on regulations concerning the classification of skin sensitizers suggests a range of sources of information be deployed in the hazard identification process. These include chemical structure, predictive animal tests, and various types of human data. Where the information is clear-cut, then uncertainties rarely arise. However, for some materials, discordant information arises, perhaps because the substance is on the borderline of test sensitivity and classification (sensitizing materials of insufficient potency do not classified according to the EU scheme), due to conflicting results in predictive tests or for other reasons. In this study, we review data on a number of substances where a classification decision is complicated by such discordances and seek to use these examples to demonstrate how best to make a weight of evidence decision on whether a substance should, or should not, be classified as a skin sensitizer.     

Heat Shock Protein-70 Expression in Vitiligo and its Relation to the Disease Activity

Background:Vitiligo is a progressive depigmenting disorder characterized by the loss of functional melanocytes from the epidermis. The etiopathogenesis of vitiligo is still unclear. Heat shock proteins (HSPs) are prime candidates to connect stress to the skin. HSPs were found to be implicated in autoimmune diseases such as rheumatoid arthritis and other skin disorders as psoriasis.Results:Our analysis revealed a significantly higher expression of HSP-70 mRNA in lesional skin biopsies from vitiligo patients compared to nonlesional skin biopsies from vitiligo patients (P < 0.001) and compared to skin biopsies from healthy controls (P < 0.001). The level of HSP-70 was not found to be correlated with age, sex, or disease duration. The expression of HSP-70 was correlated with the disease activity and patients with active vitiligo showed higher mean HSP-70 level compared to those with inactive disease.Conclusions:HSP-70 plays a role in the pathogenesis of vitiligo and may enhance the immune response in active disease.