Corneobiology and corneotherapy--a final chapter.

The text obtained for this review from Professor Albert Kligman was drawn posthumously from a variety of notes that he had been planning to use to write a review on corneobiology and corneotherapy. It was a review that he had dearly hoped to complete--his final 'magnum opus' with reflections on the subject.

Barrier functions of human skin: a holistic view.

The fascinating topic of skin barrier continues to engage researchers from diverse disciplines both in academia and industry. Much of the information on the basic biology of barrier formation, its ontogeny as well as repair and homeostasis comes from studies on animal models. A smaller number of human studies have validated the usefulness of animal models, while highlighting some essential differences. We submit that the human skin barrier is unique in several ways, as much due to our adaptive ability as our control over the environment (macro and micro) that none of the other species have exerted. The human skin is not only exposed to the greatest variations of environment due to our phenomenal mobility but also to the largest number of xenobiotics, both chemical and microbial, resulting from human activity. In this overview, we attempt to evaluate the interdependent relation of skin barriers to environmental stressors hoping to raise interest in some of the lesser known or neglected aspects of human skin barriers as they relate to skin health and dysfunctions.

Experimental studies on the nature of sensitive skin.

BACKGROUND: In the USA, Europe and Japan 40 to 50% of women report that they have sensitive skin, defined as abnormal sub-clinical sensory responses to drugs, cosmetics and toiletries in the absence of visible signs of irritation. Itching, burning, stinging and tightness are the commonest complaints, which mainly afflict women. Manufacturers of skin care products have made available a large variety of products which are designed for persons with sensitive skin. Such products are not required by regulatory agencies to submit evidence of safety and efficacy, allowing marketers to make claims that are often exaggerated, irrational and even preposterous. The consumer with self-assessed sensitive skin has no way of judging which products are likely to be most beneficial and least harmful. The marketplace is awash with products for which there is no evidence that the rosy claims have been substantiated by appropriate testing procedures. There is no internationally accepted consensus regarding the criteria which define sensitive skin. Many papers have been published in the last 15 years, mainly originating from industry, which express widely differing views regarding what constitutes sensitive skin. For some, any adverse reaction to a product topically applied to sensitive skin, including breakouts, redness, scaling etc., a panoply of adverse reactions which is virtually meaningless. Others include environmental factors as causative, including cold, dry wind, heat and high humidity, solar radiation, etc., which add to the manifest complexities of the subject. METHODS: This is the first paper in a series which provides a comprehensive review of the subject, emphasizing the all too many controversies and confusions arising from the lack of a consensus regarding the identification, classification, epidemiology, prevalence and pathogenesis of sensitive skin. Sensitive skin is a biologic reality and not a psychological, fashionable fantasy on the part of impressionable women. RESULT/CONCLUSION: There is an urgent necessity to establish rigorous methodologies for estimating the quality and severity of sensitive skin, a heterogeneous condition involving multi-factorial factors. Subsequent papers in this series will describe in detail the experimental approach our group has used to bring some clarity and credibility to this querulous, but important subject.

Comparative efficacy of clindamycin and benzoyl peroxide for in vivo suppression of Propionibacterium acnes.

BACKGROUND: Benzoyl peroxide and clindamycin are the two most widely prescribed topical antimicrobials in the treatment of acne. AIM: To compare the antimicrobial efficacy, in vivo, of benzoyl peroxide and clindamycin against Propionibacterium acnes. METHODS: Two groups of 10 subjects each, with comparable mean P. acnes baseline counts of log 5.75 to 5.85, underwent twice daily application of benzoyl peroxide or clindamycin for 14 days. RESULTS: The results of quantitatively sampling P. acnes after 3, 7 and 14 days of treatment showed that Triaz 6% benzoyl peroxide special gel produced faster and significantly greater reductions in P. acnes than did the 1% clindamycin phosphate in Cleocin-T lotion (p < 0.01). These results were paralleled by the greater reductions produced by Triaz versus Cleocin (p < 0.05) in P. acnes fluorescence. CONCLUSION: Benzoyl peroxide formulations suppress the follicular population of P. acnes more rapidly and to a greater degree than topical antibiotics such as clindamycin.

What is the 'true' function of skin?

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

Corticosteroid-induced atrophy and barrier impairment measured by non-invasive methods in human skin.

BACKGROUND/AIMS: Atrophy is a distressing side effect of potent corticosteroids. After open application of a high potency steroid, we monitored atrophogenicity by a variety of non-invasive methods. METHODS: Volar forearms were treated twice daily for 3 or 4 weeks, with clobetasol propionate cream (Temovate). The following methods were used: 1) confocal microscopy, 2) transepidermal water loss (TEWL), 3) dimethyl sulfoxide whealing, 4) sodium hydroxide erosions, 5) analysis of stratum corneum lipids, and 6) B-scan ultrasound. RESULTS: Confocal microscopy revealed thinning of the epidermis, decreased microvasculature and decreased size of keratinocytes. Evaporimetry demonstrated transepidermal water loss. Whealing to dimethyl sulfoxide was enhanced. Sodium hydroxide erosions formed more quickly. The amount of ceramides, cholesterol, and free fatty acids was reduced. Ultrasound showed thinning of the dermis. CONCLUSION: Non-invasive methods are very useful for quantifying the atrophogenicity of topical corticosteroids.

Structural diversity of mast cell granules in black and white skin.

BACKGROUND: There are conflicting reports of structural differences between black and white skin, other than pigmentary differences. OBJECTIVES: To evaluate differences in mast cells between black and white skin. METHODS: Biopsies of normal buttock skin were obtained from four African-American males (29.2 +/- 3.0 years old) and four Caucasian males (29.4 +/- 1.2 years old) and processed routinely for electron microscopy. For the quantitative assessment of mast cell granules, five electron micrographs at a final magnification of x 53,700 were analysed for each individual, using a computer-assisted image analyser. More than 10 granules per cell, and a total of 1210 granules, were evaluated for their internal structures. RESULTS: Mast cells in black skin contained larger granules than those in white skin (P < 0.0001). In black skin, fusion of granules seemed to account for the larger sizes. The percentage of granule matrix occupied by curved lamellae was higher in white skin, whereas parallel-linear striations were more frequent in black skin (P < 0.05). The subgranular distribution of the mast cell proteases, tryptase and cathepsin G, were evaluated by immunoelectron microscopy. Tryptase reactivity was localized preferentially over the parallel-linear striations and partially over the dark amorphous subregions within granules of black skin, whereas it was confined to the peripheral area of granules, including curved lamellae, in white skin. Cathepsin G reactivity was more intense over the electron-dense amorphous areas in both groups, while parallel-linear striations in black skin and curved lamellae in white skin were negative. CONCLUSIONS: This study has confirmed ultrastructural differences in mast cell granules between black and white skin, which may be of functional importance.

New photographic techniques for clinical evaluation of acne.

Clinical evaluation of acne is usually based on direct visual assessment and ordinary flash photography, both of which are compromised by viewer subjectivity. It is difficult to accurately assess individual acne lesions and to observe early response to therapy. Standard flash photography has inherent limitations owing to the physics of light; it does not permit consistent visualization of subtle cutaneous characteristics like erythema or microcomedones, and it tends to blur distinctions between active inflammatory lesions and older hyperpigmented macules. Over the last decade there has been increasing interest in newer techniques aimed at increasing the accuracy and objectivity of acne evaluation. These include parallel-polarized light photography, cross (or perpendicular)-polarized light photography, videomicroscopy, and fluorescence photography. This article will review the advances of the past decade and summarize new techniques to evaluate acne lesions. Moreover, findings of a study that evaluated the course of individual acne lesions and the effects of adapalene gel 0.1% on inflammatory and non-inflammatory acne lesions will be viewed. In this study, the use of parallel-polarized and cross-polarized photography, in combination with videomicroscopy and sebum production measurement, provided objective, detailed information on the evolution of different variable acne lesions and their response to adapalene gel 0.1%. Adapalene treatment produced rapid resolution of inflammatory and non-inflammatory lesions, and inhibited formation of new lesions. Sebum secretion rates also declined during treatment. Use of the new assessment techniques proved to be a valuable, non-invasive and reliable method of assessing acne vulgaris and its response to treatment.

Polarized light photography and videomicroscopy greatly enhance the capability of estimating the therapeuic response to a topical retinoid (adapalene) in acne vulgaris.

Assessment of improvement in acne lesions following treatment is often based on clinical evaluation and photographs. However, limitations are associated with this sublective evaluation, making it difficult to accurately review individual acne lesions and to observe early response to therapy. Conventional photographs do not allow us to visualize small lesions, and it can be difficult to differentiate inflammatory lesions as papules or small nodules. Our objective was to evaluate a new standardized method for tracking individual acne lesions based on photographs. The effect of adapalene gel 0.1% on both inflammatory and noninflammatory acne lesions was evaluated using this technique. Polarized light photography and videomicroscopy were used to record the evolution of acne lesions over a 16-week period in 5 volunteers with moderate acne vulgaris. During the first 4 weeks before treatment, acne lesions were evaluated on a 3-times weekly basis to establish a pattern of progression and determine the length of time to resolution. Sebum secretion rates were monitored using Sebutape adhesive patches applied to the forehead and both cheeks for 1 hour. After 4 weeks, adapalene gel 0.1% was used once daily at bedtime for 8 weeks; polarized light photography, videomicroscopy, and assessment of sebum production followed treatment response. This treatment period was followed by a further 4-week phase, after which acne lesions and sebum secretion rates were evaluated. Our results showed that the new methodology was appropriate to track acne lesions and allowed an accurate and more oblective evaluation of individual lesions. Using this methodology demonstrated that adapalene gel 0.1% causes rapid resolution of inflammatory and noninflammatory lesions. The probability of clearing inflammatory and noninflamma tory lesions during the treatment period increased, and the probability of new lesions appearing decreased. Sebum secretion rates declined in patients while on study drug, returning to near pretreatment levels following therapy cessation. Using sophisticated photography and videomicroscopy every other day proved to be a valuable, noninvasive, and reliable method of following response to adapalene treatment in patients with moderate acne vulgaris.

Collagen loss in photoaged human skin is overestimated by histochemistry.

It is well known that photoaged skin is characterized by increases in dermal matrix components that include glycosaminoglycans, proteoglycans and masses of abnormal elastic fibers accompanied by substantial collagen loss. Histochemical staining of such tissue gives the impression of "massive" loss of collagen and its replacement by these other matrix components. Early biochemical studies have lent support to this notion with a reported decrease in total collagen of approximately 45% compared to protected skin. More recent studies report considerably less, but varying, amounts of collagen loss. Rarely have the two approaches, histochemistry and biochemical analysis, been used in the same study to examine the same tissue. In this study, collagen loss was quantified biochemically in paired biopsies from sun-protected and sun-exposed arm skin of moderately photoaged female subjects (age 51-77 years). The values obtained were compared with histochemical and immunochemical findings. Quantitatively, collagen loss on a per mg protein basis was small compared to the histochemical appearance.

Cosmetics. A dermatologist looks to the future: promises and problems.

The skin-care industry has created myriad new products to meet the needs of an aging population. Novel "bioactive" ingredients are derived from the sea, the earth, and the plant kingdom. Popular ingredients include Chinese herbs, vitamins, minerals, antioxidants, enzymes, hormones, and a multitude of "naturals". For academic medicine, this avalanche of new products poses the task of establishing international safety standards for determining how much product efficacy is science-based and how much is marketing hype.

Photodamage pilot study: a double-blind, vehicle-controlled study to assess the efficacy and safety of tazarotene 0.1% gel.

BACKGROUND: Tazarotene, a potent acetylenic retinoid for topical use, might be expected to benefit photodamaged skin, including improving the classical signs of fine wrinkles, mottled hyperpigmentation, and roughness. OBJECTIVE: Our purpose was to determine the efficacy and safety of tazarotene 0.1% gel in the treatment of photodamaged dorsal forearm skin. METHODS: Ten healthy female volunteers, aged 45 to 65 years, with moderately photodamaged forearm skin applied tazarotene 0.1% gel to one arm and vehicle gel to the other once daily for 12 weeks. The study was a double-blind, randomized, paired-comparison evaluation conducted at a single site. RESULTS: Tazarotene showed beneficial effects for several efficacy variables. It was more efficacious than vehicle in reducing skin roughness and fine wrinkling based on objective measurements. Tazarotene also corrected epidermal atrophy and atypia and improved skin hydration properties. CONCLUSION: In this 12-week pilot study tazarotene redressed abnormalities associated with photo-damaged skin.

Biophysical assessment of persistent effects of moisturizers after their daily applications: evaluation of corneotherapy.

BACKGROUND: Although effective moisturizers can improve xerotic skin changes immediately, their effects are only transient, because the materials applied to the stratum corneum (SC) are easily shed from the skin surface by the daily desquamation process. However, there are a few lines of clinical as well as experimental evidence suggesting that, once application of effective moisturizers is repeated daily, they may produce persistent effects without being influenced by the desquamation of the skin surface. If we can expect such pharmacological effects by simple repeated applications of moisturizers on the skin surface, it will provide a great motivation for the introduction of corneotherapy into the treatment of xerotic skin problems. OBJECTIVE: This study was designed not only to confirm the feasibility of corneotherapy but to propose a practical method to assess such long-lasting effects of moisturizers by using biophysical methods. METHODS: We conducted applications of various moisturizers twice daily to different areas of the flexor surface of the forearms for the initial 5 days of the first week. Thereafter, we performed biophysical measurements of the SC of these areas in the second week, namely 3, 5 and 7 days after their last applications. RESULTS: Daily repeated applications of moisturizers did not induce any change in the water barrier function of the SC or in the size of desquamating corneocytes, a parameter for turnover rate of the SC. However, they substantially increased high-frequency conductance, a parameter for the hydration state of the skin surface, for several days in both normal individuals and patients with atopic xerosis, although the lasting effects were shorter in the latter. The obtained data enabled us to rank the efficacy of moisturizers either according to the duration of the lasting effects or the magnitude of an increase in the hydration levels of the SC. CONCLUSION: The present results confirmed the feasibility of corneotherapy, in which even simple application of moisturizers targeted at the SC can produce unexpected persistent clinical effects after their repeated treatments. The method described in this study constitutes a practical assay system to evaluate the efficacy of topical agents used for dry skin problems objectively and quantitatively.

Hairless guinea pig skin: anatomical basis for studies of cutaneous biology.

In order to characterize the microscopic anatomy of hairless guinea pig (HL-GP) skin, we utilized light microscopy with a computer-assisted image analysis system, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). SEM revealed that the hair shafts of HL-GPs were thin, short, extremely irregular in diameter and often twisted and curled. The HL-GP epidermis was of similar thickness to that of human skin with distinct strata, serrated/non-serrated basal keratinocytes and shallow dermal papillae. The density of Langerhans cells in epidermal sheets, visualized by adenosine-s-triphosphatase staining, was similar to that of normal-haired guinea pigs (HD-GPs), although the dendrites of HL-GPs were thicker and shorter than those of HD-GPs. The dermal vasculature of HL-GPs was well-developed and similar to that of humans, demonstrating a network of vertically oriented capillary loops. HL-GPs had significantly more dendritic or spindle-shaped dermal interstitial cells than humans and HD-GPs. Collectively, these data suggest that HL-GP skin is more similar to human skin than to the skin of HD-GPs and other rodents and, therefore, the HL-GP may be a useful animal for studying cutaneous biology, experimental pathology, pharmacology and toxicology.

Digital fluorescence photography can assess the suppressive effect of benzoyl peroxide on Propionibacterium acnes.

BACKGROUND: Porphyrins produced by Propionibacterium acnes exhibit an orange-red fluorescence under UVA light. The amount of fluorescence can be estimated by digital fluorescence photography. OBJECTIVE: We thought that digital fluorescence photography would be a quicker and simpler method than bacteriologic culture to demonstrate depopulation of P acnes in sebaceous follicles. We used benzoyl peroxide to bring about rapid suppression of P acnes. METHODS: Benzoyl peroxide 10% was applied twice daily for 7 days to the faces of 9 subjects. Five subjects were untreated controls. Digital fluorescence photographs of cheek and nose, and scrub samples for quantitative recovery of P acnes from the cheek were taken at baseline, day 3, day 7 (end of treatment), and day 16 (regression phase). RESULTS: The effect of benzoyl peroxide against P acnes was clearly demonstrated both by culture and by fluorescence photography after only 3 days. Image analysis of porphyrin fluorescence correlated well with the decrease in P acnes density from scrub cultures. No further decrease was observed at day 7 (end of therapy). Ten days later there was a return to baseline values, although in some subjects these remained lower. CONCLUSION: Digital fluorescence photography is a reliable, fast, and easy screening technique to demonstrate the suppressive effect of topical antibacterial agents on P acnes.

Quantitative and ultrastructural analysis of inflammatory infiltrates in male pattern alopecia.

In order to determine whether lymphocytic inflammation around the lower infundibula in male pattern alopecia is incidental or a general phenomenon, we performed morphometric and ultrastructural analysis of inflammatory infiltrates in the transitional zones of the vertex and occipital hairy scalps of 19 patients with male pattern alopecia. Six normal subjects served as controls. The number of inflammatory infiltrates around the follicular infundibula of the alopecic vertices and non-alopecic occiputs of male pattern alopecia patients was significantly greater than the corresponding control value. The number of mast cells in the widened fibrous tracts in the vertices of male pattern alopecia patients was significantly greater than those in the adventitial fibrotic sheaths of control subjects and the non-alopecic occiputs of male pattern alopecia patients. These data support the idea that the inflammatory process may be, at least in part, responsible for the development of male pattern alopecia.