Position statement: Recommendations on the diagnosis and treatment of Malassezia folliculitis.

Malassezia is a lipophilic yeast that is a part of the human mycobiome. Malassezia folliculitis appears when the benign colonization of the hair follicles, by the Malassezia yeasts, becomes symptomatic with pruritic papules and pustules. Although Malassezia folliculitis is common in hospital departments, diagnosing and treating it varies among dermatologists and countries. The European Academy of Dermatology and Venereology Mycology Task Force Malassezia folliculitis working group has, therefore, sought to develop these recommendations for the diagnosis and management of Malassezia folliculitis. Recommendations comprise methods for diagnosing Malassezia folliculitis, required positive findings before starting therapies and specific treatment algorithms for individuals who are immunocompetent, immunocompromised or who have compromised liver function. In conclusion, this study provides a clinical strategy for diagnosing and managing Malassezia folliculitis.

Emerging antifungal treatment failure of dermatophytosis in Europe: take care or it may become endemic.

BACKGROUND: Dermatophytosis is a world-wide distributed common infection. Antifungal drug resistance in dermatophytosis used to be rare, but unfortunately the current Indian epidemic of atypical widespread recalcitrant and terbinafine-resistant dermatophytosis is spreading and has sporadically been reported in Europe. OBJECTIVES: To explore the occurrence of clinical and mycological proven antifungal drug resistance in dermatophytes in Europe. METHODS: A standardized questionnaire was distributed through the EADV Task Force of Mycology network to dermatologists in Europe. RESULTS: Representatives from 20 countries completed the questionnaires of which 17 (85 %) had observed clinical and/or mycological confirmed antifungal resistance, two countries published cases of antifungal resistance and one country had no known cases. CONCLUSIONS: This pilot study confirms that both clinical and mycological antifungal resistance exist in Europe.

A survey among dermatologists: diagnostics of superficial fungal infections - what is used and what is needed to initiate therapy and assess efficacy?

BACKGROUND: Superficial fungal infections are common. It is important to confirm the clinical diagnosis by mycological laboratory methods before initiating systemic antifungal treatment, especially as antifungal sensitivity and in vitro susceptibility may differ between different genera and species. For many years, the gold standard for diagnosis of superficial fungal infections has been direct fungal detection in the clinical specimen (microscopy) supplemented by culturing. Lately, newer molecular based methods for fungal identification have been developed. OBJECTIVE: This study was initiated to focus on the current usage of mycological diagnostics for superficial fungal infections by dermatologists. It was designed to investigate whether it was necessary to differentiate between initial diagnostic tests and those used at treatment follow-up in specific superficial fungal infections. METHODS: An online questionnaire was distributed among members of the EADV mycology Task Force and other dermatologists with a special interest in mycology and nail disease. RESULTS: The survey was distributed to 62 dermatologists of whom 38 (61%) completed the whole survey, 7 (11%) partially completed and 17 (27%) did not respond. Nearly, all respondents (82-100%) said that ideally they would use the result of direct microscopy (or histology) combined with a genus/species directed treatment of onychomycosis, dermatophytosis, Candida- and Malassezia-related infections. The majority of the dermatologists used a combination of clinical assessment and direct microscopy for treatment assessment and the viability of the fungus was considered more important at this visit than when initiating the treatment. Molecular based methods were not available for all responders. CONCLUSION: The available diagnostic methods are heterogeneous and their usage differs between different practices as well as between countries. The survey confirmed that dermatologists find it important to make a mycological diagnosis, particularly prior to starting oral antifungal treatment in order to confirm the diagnose and target the therapy according to genus and species.

Application of cosmetic nail varnish does not affect the antifungal efficacy of amorolfine 5% nail lacquer in the treatment of distal subungual toenail onychomycosis: results of a randomised active-controlled study and in vitro assays.

As onychomycosis is unsightly, this study clinically evaluated whether the antifungal efficacy of amorolfine 5% nail lacquer (NL) was affected by a masking, natural-coloured, cosmetic nail varnish applied 24 h later; in vitro investigations were also performed. Subjects with mild-to-moderate distal subungual toenail onychomycosis were randomised to receive amorolfine 5% NL once weekly with or without cosmetic nail varnish applied 24 h later. After 12-week treatment, antifungal activity of affected toenail clippings was assessed by measurement of zones of inhibition (ZOIs) on Trichophyton mentagrophytes seeded agar plates. Mean diameters were 53.5 mm for the amorolfine 5% NL-alone group (n = 23) and 53.6 mm for amorolfine 5% NL plus cosmetic nail varnish group (n = 25). Also, mycological cultures of subungual debris at week 12 were negative for all subjects in both groups. Most subjects (88%) reported that cosmetic nail varnish masked their infected toenails. Additionally, cadaver human nails coated in vitro with or without cosmetic nail varnish 10 min or 24 h post amorolfine NL application all gave ZOIs on Trichophyton rubrum agar plates representing potent antifungal activity. In conclusion, cosmetic nail varnish applied post amorolfine had no effect on the subungual antifungal activity of amorolfine 5% NL or its penetration through toenails.

Cutaneous melanoma in Iceland: changing Breslow's tumour thickness.

BACKGROUND: The incidence of cutaneous melanoma increased dramatically in Iceland during the last two decades of the 20th century. OBJECTIVE: The aim of this study was to investigate the trend in Breslow's tumour thickness during the years 1980-2009. METHODS: The population-based Icelandic Cancer Registry provided information on all cutaneous melanomas diagnosed in the country during the study period, a total of 854 cases. Incidence rates were stratified according to gender, age at diagnosis, year of diagnosis and Breslow's tumour thickness. RESULTS: When stratified by gender and age, the incidence of thin (≤1.0 mm) melanomas increased dramatically in all subgroups. The increase in thin (≤1.0 mm) melanomas was more apparent in women or 2.6 per 100,000 in 1980-1989 to 13.3 in 2000-2009 and especially in young (<50 years) women or from 1.6 to 12.2 per 100,000 during the same period compared to an increase from 0.2 to 3.4 per 100,000 for young (<50 years) men (P < 0.05). In intermediate thickness (1.01-4.0 mm) tumours, the incidence increased only in men over the age of 50 from 2.1 in 1980-1989 to 11.3 per 100,000 in 2000-2009 (P < 0.05). The incidence of thick melanomas (>4 mm) did not increase. The median Breslow's thickness declined from 2.15 mm in 1980-1989 to 0.9 mm in 2000-2009 in males and from 1.0 to 0.6 mm in females for the same period (P < 0.001). CONCLUSION: The rise in melanoma incidence in individuals under 50 years and in women over 50 years was confined to thin tumours. However, among older males there was also an increased incidence of tumours of an intermediate thickness. This could indicate that future melanoma educational campaigns in Iceland should be directed at older individuals, and that older men may need special attention regarding suspicious nevi.

The prevalence of onychomycosis in the global population: a literature study.

BACKGROUND: Onychomycosis is a common disorder, and high prevalence figures are commonly cited in the literature. OBJECTIVES: Evaluate the prevalence of onychomycosis based on published studies. METHODS: Relevant studies were identified in Medline by using specific search criteria. RESULTS: Eleven population-based and 21 hospital-based studies were identified. The mean prevalence in Europe and North America was 4.3% [95% Confidence Interval (CI): 1.9-6.8] in the population-based studies, but it was 8.9% (95% CI: 4.3-13.6) for the hospital-based studies. Both population-based and hospital-based studies showed that onychomycosis is more common in toenails and is seen more frequently in males. The main causative agent was a dermatophyte in 65.0% (95% CI: 51.9-78.1) of the cases. Trichophyton rubrum was the single most common fungus and was cultured on average in 44.9% of the cases (95% CI: 33.8-56.0). Moulds were found on average in 13.3% (95% CI: 4.6-22.1) and yeasts in 21.1% (95% CI: 11.0-31.3). LIMITATIONS: We may not have been able to locate all studies. CONCLUSIONS: Onychomycosis is a common disorder, but it may not be as common as cited in the literature, because hospital-based studies might overestimate the prevalence of onychomycosis. It is more frequent in males, and toenails are more commonly affected. Dermatophytes, particularly T. rubrum, are the main causative agents.

The role of Th17/Tc17 peripheral blood T cells in psoriasis and their positive therapeutic response.

It is known that NB-UVB therapy can suppress a broad range of immune cells, but the additional effect of bathing in geothermal seawater still remains unclear. To study the influence of treatment on the expression of circulating immune cells contributing to the pathogenesis of psoriasis, six patients with psoriasis were treated with bathing in geothermal seawater two times daily combined with NB-UVB five times/week for 2 weeks and six patients were treated with NB-UVB therapy three times/week for 8 weeks. Disease severity (Psoriasis Area and Severity Index, PASI), chemokines, inflammatory cytokines, T cells and Toll-like receptors in the blood and skin samples were evaluated on enrolment (W0) and at 1 (W1), 3 (W3) and 8 (W8) weeks. Compared with healthy controls, psoriasis patients with active disease had significantly higher proportion of peripheral CLA+ T cells expressing CCR10 and CD103 and T cells with both Th1/Tc1 (CD4+/CD8+ IFN-γ+ or TNF-α+ cells) and Th17/Tc17 (CD4+CD45R0+IL-23R+, CD4+/CD8+ IL-17A+ or IL-22+ cells) phenotypes. Both treatments gave a significant clinical effect; however, bathing in geothermal seawater combined with NB-UVB therapy was more effective than NB-UVB therapy alone. This clinical improvement was reflected by a reduction in circulating CLA+ peripheral blood T cells and by a decreased Th1/Th17 and Tc1/Tc17 inflammatory response. These findings suggest that the inflammatory response in psoriasis is predominantly driven by both CD4+ and CD8+ skin-homing tissue retaining T cells of the Th17/Tc17 lineages.

Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study.

BACKGROUND: Interleukin (IL)-17A has major proinflammatory activity in psoriatic lesional skin. OBJECTIVES: To assess the efficacy and safety of secukinumab, a fully human IgG1κ monoclonal anti-IL-17A antibody, in moderate-to-severe plaque psoriasis in a phase II regimen-finding study. METHODS: A total of 404 patients were randomized to subcutaneous placebo (n = 67) or one of three secukinumab 150 mg induction regimens: single (week 0; n = 66), early (weeks 0, 1, 2, 4; n = 133) and monthly (weeks 0, 4, 8; n = 138 patients). The primary outcome was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75) at week 12. PASI 75 responders from active treatment arms at week 12 were rerandomized to either a fixed-interval (secukinumab 150 mg at weeks 12 and 24; n = 65) or a treatment-at-start-of-relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed; n = 67). RESULTS: At week 12, early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54·5% and 42·0% vs. 1·5%; P < 0·001 for both). Among PASI 75 responders at week 12 entering the maintenance period, PASI 75 and PASI 90 achievement at least once from week 20 to week 28 was superior with the fixed-interval regimen [85% (n = 55) and 58% (n = 38), respectively] vs. the start-of-relapse regimen [67% (n = 45), P = 0·020, and 21% (n = 14), respectively]. Fifteen weeks after last study drug administration, < 10% of patients in the fixed-interval and start-of-relapse groups experienced a start of relapse. No immunogenicity was observed, and no injection-site reactions were reported. Reported cases of neutropenia were mild-to-moderate (≤ grade 2); none was associated with clinically significant adverse events or resulted in study discontinuation. Due to the brief duration of the safety assessment, no firm conclusions can be drawn regarding long-term safety. CONCLUSIONS: Secukinumab shows efficacy for induction and maintenance treatment of moderate-to-severe plaque psoriasis.

Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study.

BACKGROUND: Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long-term safety. Interleukin (IL)-17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. OBJECTIVES: To assess the efficacy and safety of different doses of secukinumab, a fully human anti-IL-17A IgG1κ monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12-week treatment period, patients entered a follow-up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator's Global Assessment (IGA) and PASI 90 and 50 response rates. RESULTS: After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow-up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow-up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort. CONCLUSIONS: Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate-to-severe psoriasis.

Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs.

BACKGROUND: Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis. OBJECTIVE: To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer. METHODS: Subjects with mild-to-moderate toe onychomycosis (25% to ≤75% nail-involvement, matrix uninvolved) were randomized to receive either TNS or vehicle in two double-blind studies, and to TNS or amorolfine in an active-controlled, open-label study. Primary endpoint was complete cure (no residual clinical involvement and negative mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH microscopy and negative culture) and clinical effectiveness (≤10% residual-involvement and negative mycology) at week 52. RESULTS: Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well-tolerated. CONCLUSION: Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of nail involvement of study population.

The zebrafish brain in research and teaching: a simple in vivo and in vitro model for the study of spontaneous neural activity.

Recently, the zebrafish (Danio rerio) has been established as a key animal model in neuroscience. Behavioral, genetic, and immunohistochemical techniques have been used to describe the connectivity of diverse neural circuits. However, few studies have used zebrafish to understand the function of cerebral structures or to study neural circuits. Information about the techniques used to obtain a workable preparation is not readily available. Here, we describe a complete protocol for obtaining in vitro and in vivo zebrafish brain preparations. In addition, we performed extracellular recordings in the whole brain, brain slices, and immobilized nonanesthetized larval zebrafish to evaluate the viability of the tissue. Each type of preparation can be used to detect spontaneous activity, to determine patterns of activity in specific brain areas with unknown functions, or to assess the functional roles of different neuronal groups during brain development in zebrafish. The technique described offers a guide that will provide innovative and broad opportunities to beginner students and researchers who are interested in the functional analysis of neuronal activity, plasticity, and neural development in the zebrafish brain.

Prognostic factors for cure following treatment of onychomycosis.

OBJECTIVE: To examine if host baseline factors and week 24 mycology results are associated with mycological and clinical cure in patients with onychomycosis treated with oral terbinafine. DESIGN: Open pilot study to determine prognostic factors in the treatment of onychomycosis. SETTING: Outpatient dermatology clinic. PATIENTS: A total of 199 patients from the Icelandic arm of a trial comparing continuous terbinafine with intermittent terbinafine in onychomycosis were recruited for additional observation. MAIN OUTCOME MEASURES: Mycological, clinical and complete cure of the target toenail 72 weeks after treatment was initiated. RESULTS: Patients with matrix involvement or slow nail growth were less likely to reach mycological, clinical and complete cure. Lateral involvement affected complete and mycological cure rates negatively. Patients with a dermatophytoma were less likely to reach mycological cure. Patients with a history of prior infection, men and older patients were less likely to reach clinical cure. Positive culture at 24 weeks affected mycological and clinical cure at 72 weeks negatively. LIMITATIONS: Only patients treated with terbinafine were considered. CONCLUSIONS: Several host-related factors at baseline and positive culture at 24 weeks had negative effects on cure of onychomycosis 72 weeks after treatment was initiated. This finding merits a large study on prognostic outcome factors in onychomycosis.

Efficacy of amorolfine nail lacquer for the prophylaxis of onychomycosis over 3 years.

BACKGROUND: Standard treatment for onychomycosis often results in less than half of subjects achieving disease-free nails. Onychomycosis is even more challenging to treat as relapses and re-infections are common. OBJECTIVE: To determine if a prophylactic effect exists when a treatment with amorolfine nail lacquer (ANL), with half the frequency of the standard regimen, is instituted following successful treatment of dermatophytic toenail onychomycosis with matrix involvement. METHODS: Efficacy and safety of a group treated with ANL (once every 2 weeks) were compared with that of an untreated group in a 36-month (3 years), single-centre, randomized, open-label, comparison study. Subjects to be included in the study were required to be cured of confirmed onychomycosis with matrix involvement after an initial treatment with either ANL + oral terbinafine or oral terbinafine alone in a previous study. Prophylaxis of onychomycosis was assessed by global recurrence rate, confirmed onychomycosis, clinical recurrence and mycological recurrence. RESULTS: A total of 52 subjects were enrolled (26 in each group) in the study. Throughout the study, recurrences occurred more quickly in the untreated group compared with that in the ANL group. Statistically significant differences were observed at month 12 (ANL, 8.3%; untreated, 31.8%; P = 0.047). At endpoint, 70.8% of the subjects treated with ANL remained cured compared to 50% in the untreated group (P = 0.153). Recurrence was delayed by nearly 200 days for the ANL group compared with that of the untreated group. Amorolfine was safe and well tolerated during the study, with no treatment-related adverse events. CONCLUSION: These results suggest that amorolfine nail lacquer may be effective and is safe for use as a prophylactic treatment for the recurrence of onychomycosis.

CDKN2A mutations and melanoma risk in the Icelandic population.

BACKGROUND: Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls. METHODS: We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. RESULTS: We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma. CONCLUSIONS: This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.

Effectiveness and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis.

OBJECTIVE: This study was performed to investigate the efficacy and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in children and adolescents with atopic dermatitis (AD). METHODS: A 26-week multi-centre, randomized, double-blind, vehicle-controlled study was conducted in 521 patients aged 2-17 years, with a history of mild or moderate AD, who were clear/almost clear of disease before randomization to pimecrolimus cream 1% (n = 256) or vehicle cream (n = 265). Twice-daily treatment with study medication was started at the first signs and/or symptoms of recurring AD. If, despite the application of study medication for at least 3 days, AD worsened (as confirmed by the investigator), treatment with a moderately potent topical corticosteroid (TCS) was allowed in both groups. The primary efficacy end point was the number of days on study without TCS use for a flare. RESULTS: The mean number of TCS-free days was significantly higher (P < 0.0001) in the pimecrolimus cream 1% group (160.2 days) than in the control group (137.7 days). On average, patients on pimecrolimus cream 1% experienced 50% fewer flares requiring TCSs (0.84) than patients on vehicle cream (1.68) (P < 0.0001). Patients on pimecrolimus cream 1% also had fewer unscheduled visits (87) than patients on vehicle cream (246). CONCLUSIONS: In children and adolescents with a history of mild or moderate AD but free/almost free of signs or symptoms of the disease, early treatment of subsequent AD exacerbations with pimecrolimus cream 1% prevented progression to flares requiring TCS, leading to fewer unscheduled visits and reducing corticosteroid exposure.

Acute thoracic inlet obstruction in achalasia with adenoid cystic and squamous cell carcinoma.

Respiratory symptoms due to compression of the trachea by the dilated esophagus in achalasia are extremely rare. A patient is presented whose respiratory manifestations included engorged neck veins and a neck swelling that fluctuated with respiration. He also had two malignant tumors in his dilated esophagus, a squamous cell carcinoma and an adenoid cystic carcinoma.