Marina Rodríguez-Martín

Urea Uptake Enhances Barrier Function and Antimicrobial Defense in Humans by Regulating Epidermal Gene Expression

Urea is an endogenous metabolite, known to enhance stratum corneum hydration. Yet, topical urea anecdotally also improves permeability barrier function, and it appears to exhibit antimicrobial activity. Hence, we hypothesized that urea is not merely a passive metabolite, but a small-molecule regulator of epidermal structure and function. In 21 human volunteers, topical urea improved barrier function in parallel with enhanced antimicrobial peptide (LL-37 and β-defensin-2) expression. Urea both stimulates expression of, and is transported into keratinocytes by two urea transporters, UT-A1 and UT-A2, and by aquaporin 3, 7 and 9. Inhibitors of these urea transporters block the downstream biological effects of urea, which include increased mRNA and protein levels for: (i) transglutaminase-1, involucrin, loricrin and filaggrin; (ii) epidermal lipid synthetic enzymes, and (iii) cathelicidin/LL-37 and β-defensin-2. Finally, we explored the potential clinical utility of urea, showing that topical urea applications normalized both barrier function and antimicrobial peptide expression in a murine model of atopic dermatitis (AD). Together, these results show that urea is a small-molecule regulator of epidermal permeability barrier function and antimicrobial peptide expression after transporter uptake, followed by gene regulatory activity in normal epidermis, with potential therapeutic applications in diseased skin.

Pathogenesis-Based Therapy Reverses Cutaneous Abnormalities in an Inherited Disorder of Distal Cholesterol Metabolism

Identification of the underlying genetic, cellular, and biochemical basis of lipid metabolic disorders provides an opportunity to deploy corrective, mechanism-targeted, topical therapy. We assessed this therapeutic approach in two patients with Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD) syndrome, an X-linked dominant disorder of distal cholesterol metabolism. Based upon the putative pathogenic role of both pathway-product deficiency of cholesterol and accumulation of toxic metabolic intermediates, we assessed the efficacy of combined therapy with lovastatin and cholesterol. We also evaluated the basis for the poorly understood, unique lateralization of the cutaneous and bone malformations of CHILD syndrome by analyzing gene activation in abnormal and unaffected skin. Ultrastructural analysis of affected skin showed evidence of both cholesterol depletion and toxic metabolic accumulation. Topical treatment with lovastatin/cholesterol (but not cholesterol alone) virtually cleared skin lesions by 3 months, accompanied by histologic and ultrastructural normalization of epidermal structure and lipid secretion. The unusual lateralization of abnormalities in CHILD syndrome reflects selective clearance of keratinocytes and fibroblasts that express the mutant allele from the unaffected side. These findings validate pathogenesis-based therapy that provides the deficient end-product and prevents accumulation of toxic metabolites, an approach of potential utility for other syndromic lipid metabolic disorders.

Randomized, double-blind clinical trial to evaluate the efficacy of topical tacalcitol and sunlight exposure in the treatment of adult nonsegmental vitiligo

Background  Vitiligo is a common skin disease which is difficult to treat. Approximately half of patients acquire the disease before the age of 20 years. This disease has a high stigmatizing impact but no ideal, aetiology‐oriented, effective therapy has been found to date. Tacalcitol and other vitamin D analogues have been shown to have stimulating activity both on immunomodulatory mediators and on melanocytes in lesional skin.

Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders.

Molecular geneticists tend to conceptualize disease pathogenesis from the mutated gene outward, an approach that does not take into account the impact of barrier requirements in determining disease phenotype. An ‘outside-to-inside’ perspective, which takes full advantage of the same genetic information, has provided quite different explanations for the ichthyoses, including several of the disorders of distal cholesterol metabolism. Elucidation of responsible pathogenic mechanisms also is pointing to appropriate, pathogenesis (pathway)-based therapeutic strategies. In the case of the lipid metabolic disorders, it takes full advantage of new molecular, genetic and cellular pathogenesis information to correct or bypass the metabolic abnormality. This approach fully exploits the unique accessibility of the skin to a topical approach. Moreover, since it will utilize topical lipids and lipid-soluble, and often generic, lipid-soluble drugs, these treatments should be readily transported across the stratum corneum. If successful, this approach could initiate an entirely new departure for the therapy of the ichthyoses. Finally, because these agents are relatively safe and inexpensive, this form of treatment has the potential to be widely-deployed, even in the developing world.

Successful treatment of erosive pustular dermatosis of the scalp with topical tacrolimus

bined with topical or systemic anti-infective agents, dermabrasion, CO2 laser vaporization and Grenz ray therapy. Full-thickness excision of affected skin with repair by split-thickness grafting may reduce sweating and provide improvement. Dapsone, vitamin E, psoralen ultraviolet A, methotrexate, or thalidomide have been recommended. Infection is a common complication, and in disease exacerbation several infective causes (bacterial ⁄ fungal ⁄ viral) need to be excluded. Although our patient was treated with Fucibet ointment with no improvement, this did not exclude an underlying fungal infection. When he presented to us, apart from lesions consistent with Hailey–Hailey disease there was also evidence of tinea pedis and widespread fungal infection (tinea incognito). Our patient was commenced on oral lamisil and topical ketoconazole ointment with reduced usage of topical steroids in the infected areas, and improved after treatment.

Psychological stress regulates antimicrobial peptide expression by both glucocorticoid and β-adrenergic mechanisms

Psychological stress (PS) exerts well-known negative consequences for permeability barrier function in humans and mice, and deterioration of barrier function appears to be attributable largely to excess production of endogenous glucocorticoids (GC). More recently, PS has been shown to compromise antimicrobial defense, also by GC-dependent mechanisms. We assessed here changes in a third antimicrobial peptide (AMP); i.e., the neuropeptide, catestatin (Cst), which also is expressed in the outer epidermis, and previously shown to be regulated by changes in permeability barrier status. In these studies, PS again provoked a decline in both mouse cathelicidin (CAMP) and mouse β-defensin 3 (mBD3) expression, in a GC-dependent fashion. In contrast, Cst immunostaining instead increased after short-term PS, but then began to decline with more sustained PS. In cultured keratinocytes, we showed further that GC downregulate Cst expression, but β-adrenergic blockade increased immunostaining for Cst in the face of long-term PS. Furthermore, β-adrenergic blockade also upregulated CAMP and mBD3 expression. Together, these results suggest that both endogenous GC and β-adrenergic signaling regulate AMP expression.

Multiple verrucae vulgaris in a young woman's tattoo.

356 JEADV 2006, 20, 341–362

Coincidental presentation of vitiligo and psoriasis in a patient with polyglandular autoimmune syndrome

T.Yanagi, N. Kato, N. Yamane, R. Osawa, K. Isu* and W. Ichimura† Departments of Dermatology, *Orthopaedic Surgery and Department of †Radiology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan. Dr Teruki Yanagi, MD, Department of Dermatology, National Hospital Organization Hokkaido Cancer Center, Kikusui 4-2, Shiroishi-ku, 0030804, Sapporo, Japan. E-mail: yanagi@med.hokudai.ac.jp Conflict of interest: none declared. Accepted for publication 29 January 2007

Ziprasidone in the Treatment of Delusional Parasitosis

Delusional parasitosis is characterized by a patient’s fixed false belief of being infested with parasites or small creatures. The first-line treatment options are typical antipsychotics such as pimozide. However, the accompanying extrapyramidal side effects might limit their use. We report on a patient with a good response to pimozide combined with ziprasidone. Ziprasidone is an atypical antipsychotic drug with a lower risk of extrapyramidal symptoms; thus, it might be considered a good first or second treatment option for delusional parasitosis.

Patients with vitiligo present fewer cardiovascular risk factors: results from a case-control study.

Editor Vitiligo is a common dermatologic condition that affects 1% of the population worldwide, with no sexual predilection. Several co-morbidities have been described in association with this disorder: thyroidopathies, pernicious anaemia, diabetes, etc. However, no cardiovascular (CV) risk profile has been related so far. Several studies have analysed the relationship between other common dermatological conditions like psoriasis, lichen planus (LP) or androgenetic alopecia and CV disease or metabolic syndrome, showing a possible association based on a convergent mechanism of T-cell mediated chronic inflammation in cutaneous conditions, atherosclerosis or dyslipemia. In this study, we assessed the relationship between vitiligo and CV risk factors, and we suggest a molecular mechanism for this negative association. We performed a case–control study in the University Hospital of Canary Islands between January and August 2011. We included 200 patients, 105 with active non-segmental vitiligo and 95 healthy controls consecutively admitted to the outpatient clinic of Dermatology Department and Primary care respectively. We defined ‘cases’ as patients 14 years of age or older, diagnosed with active non-segmental vitiligo (with new lesions appearing in the last year) with no oral immunosuppressant medication, and ‘controls’ as those patients who are 14 years of age or older, with neither vitiligo nor oral immunosuppressant. Patients and controls were investigated for blood tests, including glycaemia, cholesterol HDL; LDL, triglycerides (TG), height, body weight, body mass index (BMI), abdominal perimeter (AP) and demographical data. Normal ranges for these values are recruited in Table 1. Written informed consent and the explicit approval of our Institutional Ethics Review Board were obtained. Data were analysed using the SPSS 17.0. Continuous variables were analysed using the t-test, chisquare, ANOVA or nonparametric test appropriately. P < 0.05 was considered statistically significant. Data for cases and controls are summarized in Table 2. A total of 105 patients were included in the study group (50 males and 55 females), age ranged from 14 to 85 years (average: 44.4 ± 17.4 years). Control group included 95 patients (32 males and 63 females), aged from 16 to 87 years (average: 49.1 ± 17 years). The analysis of metabolic syndrome parameters revealed a lower significant prevalence of altered AP, TG and low HDL in vitiligo patients (P < 0.05, Table 2). No significant differences could be observed in glucose levels, BMI or LDL. No significant differences could be observed between all these variables regarding gender in the study group.