Anxiety, Depression, and Suicidal Ideation amongst Patients with Facial Dermatoses (Acne, Rosacea, Perioral Dermatitis, and Folliculitis) in Lithuania.

BACKGROUND/OBJECTIVE: Skin diseases, especially those with visible manifestation, are considered to cause a major influence on global mental health. Therefore, we determined the prevalence and severity of anxiety, depression, and suicidal ideation in a large sample of patients with facial dermatoses, namely acne, rosacea, folliculitis, and perioral dermatitis. METHODS: The mental health of patients with facial dermatoses and respective controls was assessed using the Hospital Anxiety and Depression Scale and questions concerning suicidal ideation. RESULTS: The study included 543 patients with facial dermatoses and 497 healthy individuals. Anxiety was present in 37.6% of the patients (14.9% of controls), depression in 21.7% (6.8%), and suicidal thoughts in 9.8% (3.2%) (p < 0.001). Acne patients demonstrated the highest anxiety and depression subscale scores (mean ± standard deviation: 7.1 ± 0.25, 95% confidence interval (CI): 6.58-7.56; controls: 5 ± 0.23, 95% CI: 4.57-5.49). In rosacea 30% of the patients had depression symptoms (adjusted odds ratio (OR): 7.216, 95% CI: 4.122-12.632, p < 0.001), while in folliculitis patients 15.4% (OR: 3.138, 95% CI: 1.241-7.936, p = 0.016) had suicidal thoughts. Patients with anxiety symptoms and suicidal thoughts were on average younger than those without (28.3 ± 0.76 vs. 31.2 ± 0.66 years, p = 0.001 and 25.3 ± 0.98 vs. 30.5 ± 0.55 years, p = 0.007, respectively). CONCLUSION: Acne and rosacea are associated with anxiety, depression, and suicidal ideation in Lithuanian patients. Younger patients are more prone to report such symptoms than older ones.

Aesthetic aspects of skin aging, prevention, and local treatment.

Skin aging is a complex biologic process influenced by a combination of intrinsic and extrinsic factors. Aging skin shows wrinkles, uneven tone, loss of elasticity, and thinning. Skin health is considered one of the principal factors representing overall well-being and the perception of health in humans; therefore, anti-aging strategies to combat aging signs and dysfunction have been developed over the last decades. Understanding the mechanism behind skin aging is required for elucidation of the mechanism of action and, hence, the potential benefits of the claimed anti-aging products. In this review, preventive measurements, cosmetologic strategies, and photoprotection (systemic antioxidants, ultraviolet and filters), as well as the mechanisms of action and the effectiveness of topical pharmaceutical agents, such as antioxidants (vitamins, polyphenols, and flavonoids) and cell regulators (retinols, peptides, hormones, and botanicals), are presented.

No evidence for follicular keratinocyte hyperproliferation in acne lesions as compared to autologous healthy hair follicles.

Abnormal hyperkeratinization in sebaceous hair follicles has long been believed to play an important role in acne pathogenesis. Several early reports purported to provide histological evidence for hyperproliferation of keratinocytes in acne lesions by showing a higher expression of the Ki67 as well as certain keratins. The evidence is, however, not robust, and a number of methodological and technical limitations can be identified in these studies. In this study, we looked at the expression of proliferation, mitosis and apoptosis markers directly at acne skin lesions in 66 patients with acne vulgaris. Ki67 was assessed using immunohistochemistry and α-tubulin, phospho-histone H3 and cleaved-PARP with immunofluorescence microscopy. Allogenic unaffected hair follicles from the same acne patients were used as an internal control. In both acne and control hair follicles, the α-tubulin staining was universal, approaching 100% cells and showed no signs of changed assembly. Expression of cleaved-PARP-the apoptosis marker-was a rare event. Cell proliferation rate measured by the expression of Ki67 and phospho-histone H3 was virtually identical between acne and the two control groups. Our findings show the absence of increased keratinocyte proliferation in acne vulgaris. Alternative mechanisms are likely responsible for infundibular hyperkeratinization in acne pathogenesis.

Acne vulgaris.

Acne vulgaris is a chronic inflammatory disease - rather than a natural part of the life cycle as colloquially viewed - of the pilosebaceous unit (comprising the hair follicle, hair shaft and sebaceous gland) and is among the most common dermatological conditions worldwide. Some of the key mechanisms involved in the development of acne include disturbed sebaceous gland activity associated with hyperseborrhoea (that is, increased sebum production) and alterations in sebum fatty acid composition, dysregulation of the hormone microenvironment, interaction with neuropeptides, follicular hyperkeratinization, induction of inflammation and dysfunction of the innate and adaptive immunity. Grading of acne involves lesion counting and photographic methods. However, there is a lack of consensus on the exact grading criteria, which hampers the conduction and comparison of randomized controlled clinical trials evaluating treatments. Prevention of acne relies on the successful management of modifiable risk factors, such as underlying systemic diseases and lifestyle factors. Several treatments are available, but guidelines suffer from a lack of data to make evidence-based recommendations. In addition, the complex combination treatment regimens required to target different aspects of acne pathophysiology lead to poor adherence, which undermines treatment success. Acne commonly causes scarring and reduces the quality of life of patients. New treatment options with a shift towards targeting the early processes involved in acne development instead of suppressing the effects of end products will enhance our ability to improve the outcomes for patients with acne.

IL-1ß drives inflammatory responses to propionibacterium acnes in vitro and in vivo.

Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1ß mRNA and the active processed form of IL-1ß are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1ß processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1ß and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1ß as possible therapeutic targets in acne.

Skin anti-aging strategies.

Skin aging is a complex biological process influenced by a combination of endogenous or intrinsic and exogenous or extrinsic factors. Because of the fact that skin health and beauty is considered one of the principal factors representing overall "well-being" and the perception of "health" in humans, several anti-aging strategies have been developed during the last years. It is the intention of this article to review the most important anti-aging strategies that dermatologists have nowadays in hand, including including preventive measurements, cosmetological strategies, topical and systemic therapeutic agents and invasive procedures.

An update on the role of the sebaceous gland in the pathogenesis of acne.

The pathogenesis of acne, a disease of the pilosebaceous follicle and one of the most common chronic skin disorders, is attributed to multiple factors such as increased sebum production, alteration of the quality of sebum lipids, inflammatory processes, dysregulation of the hormone microenvironment, interaction with neuropeptides, follicular hyperkeratinisation and the proliferation of Propionibacterium acnes within the follicle. In particular, the sebaceous gland plays an exquisite role in the initiation of the disease as it possesses all the enzyme machinery for the production of hormones and cytokines. In addition, in response to the altered tissue environment in the pilosebaceous follicle as well as in answer to emotional fret, stress response system mechanisms with induction of central and local expression of neuropeptides, are also initiated. This review summarises the latest advances in understanding the role of sebaceous gland cells in the pathomechanism of acne.

Isotretinoin: state of the art treatment for acne vulgaris.

Summary Isotretinoin (13-cis retinoic acid) is the most potent known inhibitor of sebum production. The multiple modes of action for isotretinoin, including suppression of sebaceous gland activity, normalization of the pattern of keratinization within the sebaceous gland follicle, inhibition of inflammation, reduction of growth of Propionibacterium acnes in a secondary manner and, as currently shown, normalization of the expression of matrix tissue metalloproteinases and their inhibitors make this compound the single most effective in the treatment of severe recalcitrant nodulocystic acne, and in the prevention of acne scarring. Several generic formulations for oral use have recently been introduced, in addition to the brand formulations Roaccutane and Accutane (Roche). This development, considering the high risk of teratogenicity associated with oral isotretinoin use, has led the European Commission and the European Medicines Agency (EMEA) to release a directive towards the harmonization of the Summary of Product Characteristics (SPC). This has similarities to US FDA regulations, a matter that caused the reaction of the Forum for the Improvement of Clinical Trials in Acne. Physician's experience, coupled with proper patient selection, dose adjustment or discontinuation of treatment, and routine monitoring for potential toxicity, has allowed the successful prevention and management of most adverse effects associated with isotretinoin.

New developments in our understanding of acne pathogenesis and treatment.

Interest in sebaceous gland physiology and its diseases is rapidly increasing. We provide a summarized update of the current knowledge of the pathobiology of acne vulgaris and new treatment concepts that have emerged in the last 3 years (2005-2008). We have tried to answer questions arising from the exploration of sebaceous gland biology, hormonal factors, hyperkeratinization, role of bacteria, sebum, nutrition, cytokines and toll-like receptors (TLRs). Sebaceous glands play an important role as active participants in the innate immunity of the skin. They produce neuropeptides, excrete antimicrobial peptides and exhibit characteristics of stem cells. Androgens affect sebocytes and infundibular keratinocytes in a complex manner influencing cellular differentiation, proliferation, lipogenesis and comedogenesis. Retention hyperkeratosis in closed comedones and inflammatory papules is attributable to a disorder of terminal keratinocyte differentiation. Propionibacterium acnes, by acting on TLR-2, may stimulate the secretion of cytokines, such as interleukin (IL)-6 and IL-8 by follicular keratinocytes and IL-8 and -12 in macrophages, giving rise to inflammation. Certain P. acnes species may induce an immunological reaction by stimulating the production of sebocyte and keratinocyte antimicrobial peptides, which play an important role in the innate immunity of the follicle. Qualitative changes of sebum lipids induce alteration of keratinocyte differentiation and induce IL-1 secretion, contributing to the development of follicular hyperkeratosis. High glycemic load food and milk may induce increased tissue levels of 5alpha-dihydrotestosterone. These new aspects of acne pathogenesis lead to the considerations of possible customized therapeutic regimens. Current research is expected to lead to innovative treatments in the near future.

The role of neuropeptides in the multifactorial pathogenesis of acne vulgaris.

BACKGROUND: Central or peripheral stress may induce the development of clinical inflammation in the pilosebaceous unit (PSU) leading to the development or to exacerbation of preexisting acne. The presence of a complete corticotropin-releasing hormone (CRH) system has been confirmed in human sebocytes in vitro. CRH is capable to induce lipid synthesis, steroidogenesis and interact with testosterone and growth hormone. alpha-Melanocyte-stimulating hormone (alpha-MSH) and its receptors can regulate melanogenesis as well as affect inflammation, apoptosis and sebogenesis. OBJECTIVES: The purpose of the study was to investigate by immunohistochemistry if changes of CRH/CRH-binding protein (CRHBP)/CRH receptors (CRHR) as well as melanocortin-1 receptor (MC-1R) expression are detectable in acne lesions vs. normal skin, especially in the sebaceous gland (SG). RESULTS: Very strong expression of CRH was observed in acne-involved skin in SG cells comparing with weaker expression in non-involved and normal skin SG. The strongest reaction for CRHBP in acne-involved SG was in differentiating sebocytes. CRHR-1 and -2 exhibited the strongest expression in sweat glands and SG, respectively. Sebocytes and cells of the ductus seboglandularis (DSG) of acne-involved and non-involved skin showed very intense MC-1R expression in contrast to less intense scattered immunoreactivity in normal skin samples. METHODS: 33 patients with acne vulgaris and 8 age-matched volunteers without acne participated in the study. Skin biopsies were taken from acne-involved face, the non-involved thigh skin of the same patients and from normal human skin. CONCLUSIONS: These data suggest that NP, such as the complete CRH system and MC-1R, are involved in the pathogenesis of acne.

Receptors of eccrine, apocrine, and holocrine skin glands.

Skin glands are highly active miniorgans of skin that fulfill a diversity of functions. To coordinate metabolic and secretory activity, they express specific receptors. Recent investigations reveal expression of nuclear hormone receptors, neuropeptide receptors, cytokine receptors, and receptors for peptides of the transforming growth factor superfamily. There is evidence of not only central control, but also autocrine mechanisms of skin glands activity. The knowledge of ligand receptor interactions in these specialized skin structures might offer not only a better understanding of their pathology, but also new therapeutic options.

Increased in situ expression of melanocortin-1 receptor in sebaceous glands of lesional skin of patients with acne vulgaris.

Central or peripheral stress may induce the development of clinical inflammation in the pilosebaceous unit, leading to the development of acne lesions or to exacerbation of pre-existing acne. Melanocortin peptides such as alpha-melanocyte-stimulating hormone and its receptors do not only regulate melanogenesis but can also affect non-pigmentary processes, such as inflammation, apoptosis and sebogenesis. The purpose of the study was to investigate by immunohistochemistry if changes of melanocortin-1 receptor expression exist in acne lesions versus normal skin. In all, 33 patients with acne vulgaris and seven age-matched volunteers without acne participated in the study. Skin biopsies were taken from acne-involved faces, the non-involved thigh skin of the same patients and from normal human skin. Melanocortin-1 receptor immunoreactivity was most prominently detectable in adnexal structures. Sebocytes and keratinocytes of the ductus seboglandularis of acne-involved and non-involved skin showed very intense melanocortin-1 receptor expression in contrast to less intense scattered immunoreactivity in normal skin samples. These data suggest that melanocortin-1 receptor is involved in the pathogenesis of acne.

Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands.

The expression of enzymes involved in leukotriene and prostaglandin signalling pathways, of interleukins 6 and 8 and of peroxisome proliferator-activated receptors in sebaceous glands of acne-involved facial skin was compared with those of non-involved skin of acne patients and of healthy individuals. Moreover, 5-lipoxygenase and leukotriene A(4) hydrolase were expressed at mRNA and protein levels in vivo and in SZ95 sebocytes in vitro (leukotriene A(4) hydrolase > 5-lipoxygenase), while 15-lipoxygenase-1 was only detected in cultured sebocytes. Cyclooxygenase-1 and cyclooxygenase-2 were also present. Peroxisome proliferator-activated receptors were constitutively expressed. Enhanced 5-lipoxygenase, cyclooxygenase 2 and interleukin 6 expression was detected in acne-involved facial skin. Arachidonic acid stimulated leukotriene B(4) and interleukin 6 release as well as prostaglandin E(2) biosynthesis in SZ95 sebocytes, induced abundant increase in neutral lipids and down-regulated peroxisome proliferator-activated receptor-alpha, but not receptor-gamma1 mRNA levels, which were the predominant peroxisome proliferator-activated receptor isotypes in SZ95 sebocytes. In conclusion, human sebocytes possess the enzyme machinery for functional leukotriene and prostaglandin pathways. A comprehensive link between inflammation and sebaceous lipid synthesis is provided.