Recalcitrant cutaneous fungal infections-A growing problem.

The incidence and prevalence of recalcitrant cutaneous fungal infections is on the rise. Terbinafine-resistant Trichophyton has not only been widespread in India, but has also been reported in countries spread throughout the globe. Strains of yeasts such as Malassezia and Candida, which exist both as commensals and as pathogens to the human skin, have also been found to develop resistance to antifungals. Non-dermatophyte moulds which can colonize and infect damaged nails are especially difficult to treat, not only due to resistance, but also because of poor drug penetration of hard keratin. Psychosocial factors such as the indiscriminate broad-spectrum antifungal use in agriculture and in medicine, and poor adherence to hygienic measures to break the chain of infection contribute to the development of antifungal resistance. Such environments encourage fungi to develop various resistance mechanisms to withstand antifungal treatment. These include: (a) alteration of the drug target, (b) increasing efflux of drug/metabolites, (c) inactivation of drug, (d) bypass mechanisms or substitution of the pathway affected by the drug, (e) stress adaptation mechanisms and (f) biofilm formation. Understanding of such mechanisms and how they arise are crucial for development of new ways to prevent or overcome resistance. Novel antifungal treatments have recently been approved in the United States of America for treatment of vulvovaginal candidiasis. Ibrexafungerp (enfumafungin derivative) and oteseconazole (tetrazole) differ from their respective related drug classes of echinocandins and triazoles by having different structures, which lend these medicines advantage compared to traditional treatment by having a different binding site and more selectivity for fungi respectively. Other drugs designed to circumvent the known mechanisms of antifungal resistance are also at various phases of development. Concurrent measures at an institutional and individual level to address and limit inappropriate antifungal use to reduce development of antifungal resistance should be undertaken in a concerted effort to address this epidemic.

N-WASP Attenuates Cell Proliferation and Migration through ERK2-Dependent Enhanced Expression of TXNIP.

Neural Wiskott-Aldrich Syndrome Protein (N-WASP) regulates actin cytoskeleton remodeling. It has been known that reduced N-WASP expression in breast and colorectal cancers is associated with poor prognosis. Here, we found reduced N-WASP expression in squamous cell carcinoma (SCC) patient samples. The SCC cell line HSC-5 with reduced N-WASP expression was used to generate HSC-5CN (control) and HSC-5NW (N-WASP overexpression) cells. HSC-5NW cells had reduced cell proliferation and migration compared to HSC-5CN cells. HSC-5NW cells had increased phospho-ERK2 (extracellular signal-regulated kinase 2), phosphorylated Forkhead box protein class O1 (FOXO1) and reduced nuclear FOXO1 staining compared to HSC-5CN cells. Proteasome inhibition stabilized total FOXO1, however, not nuclear staining, suggesting that FOXO1 could be degraded in the cytoplasm. Inhibition of ERK2 enhanced nuclear FOXO1 levels and restored cell proliferation and migration of HSC-5NW to those of HSC-5CN cells, suggesting that ERK2 regulates FOXO1 activity. The expression of thioredoxin-interacting protein (TXNIP), a FOXO1 target that inhibits thioredoxin and glucose uptake, was higher in HSC-5NW cells than in HSC-5CN cells. Knockdown of TXNIP in HSC-5NW cells restored cell proliferation and migration to those of HSC-5CN cells. Thus, we propose that N-WASP regulates cell proliferation and migration via an N-WASP-ERK2-FOXO1-TXNIP pathway.

The Quadrivalent Human Papillomavirus Vaccine in Recalcitrant Non-genital Warts: A Retrospective Study.

INTRODUCTION: The human papillomavirus (HPV) vaccine has been reported to lead to clinical clearance of lesions when used as an off-label treatment for recalcitrant extragenital warts. The aim of the study is to evaluate the therapeutic and adverse effects of HPV vaccine as an adjunctive therapy for treatment-resistant acral warts. METHODS: Patients with persistent warts despite first and second line therapies, and subsequently receiving the quadrivalent HPV vaccine between July 2013 and June 2016 as an adjunctive treatment for recalcitrant warts at the National Skin Centre, were included. RESULTS: Twenty-six patients with a median age of 34 years (range 8 to 77 years) were treated with the HPV vaccine. Nineteen (73.1%) patients completed 3 doses of the vaccine, of whom 5 (26%) achieved complete clearance, 8 (42%) had partial clearance and 6 (32%) did not respond to the vaccine. Among the 4 patients who received 2 doses of the vaccine, 3 (75%) had complete clearance whereas 1 (25%) had partial improvement of their warts. None of the patients reported adverse reactions. CONCLUSION: Our study suggests a potential adjunctive role of the HPV vaccine in the treatment of acral warts recalcitrant to conventional therapy.

New idea for hair transplantation to preserve more donor hair follicles.

Higher risk of rapid progression in alopecia or male pattern baldness was observed in men who had family history. This could result from accumulation of DHT in hair follicles. Hair follicles on frontal region are more vulnerable to DHT. With development of minimal invasive hair transplantation surgery, hair follicles transplantation could be performed from frontal or occipital region to frontal region. However, limited hair follicles remained a problem. With development of technology of vitrification, we suggested extracting hair follicles from frontal region without affecting the appearance and preserving them with vitrification when the patient was young. When alopecia progressively developed, these extracted hair follicles would increase the donor number of hair follicles used for transplantation, which could extend longer dense hair appearance.

Overexpression of CDC42SE1 in A431 Cells Reduced Cell Proliferation by Inhibiting the Akt Pathway.

Cell division cycle 42 (CDC42), a small Rho GTPase, plays a critical role in many cellular processes, including cell proliferation and survival. CDC42 interacts with the CRIB (Cdc42- and Rac-interactive binding) domain of CDC42SE1, a small effector protein of 9 kDa. We found that the expression of CDC42SE1 was reduced in human skin cancer samples relative to matched perilesional control. Exogenous expression of CDC42SE1 but not CDC42SE1H38A (mutation within CRIB domain) in A431 cells (A431SE1, A431SE1-H38A) reduced cell proliferation. Antibody microarray analysis of A431Ctrl and A431SE1 lysate suggested that reduced A431SE1 cells proliferation was due to inhibition of Akt pathway, which was confirmed by the reduced P-Akt and P-mTOR levels in A431SE1 cells compared to A431Ctrl cells. This suggests that CDC42SE1 modulates the CDC42-mediated Akt pathway by competing with other effector proteins to bind CDC42. A431SE1 cells formed smaller colonies in soft agar compared to A431Ctrl and A431SE1-H38A cells. These findings correlate with nude mice xenograft assays, where A431SE1 cells formed tumors with significantly-reduced volume compared to the tumors formed by A431Ctrl cells. Our results suggest that CDC42SE1 is downregulated in skin cancer to promote tumorigenesis, and thus CDC42SE1 might be an important marker of skin cancer progression.

Looking back to move forward: a twenty-year audit of herpes zoster in Asia-Pacific.

BACKGROUND: Herpes zoster (HZ) is a prevalent viral disease that inflicts substantial morbidity and associated healthcare and socioeconomic burdens. Current treatments are not fully effective, especially among the most vulnerable patients. Although widely recommended, vaccination against HZ is not routine; barriers in Asia-Pacific include long-standing neglect of adult immunisation and sparse local data. To address knowledge gaps, raise awareness, and disseminate best practice, we reviewed recent data and guidelines on HZ from the Asia-Pacific region. METHODS: We searched PubMed, Scopus, and World Health Organization databases for articles about HZ published from 1994 to 2014 by authors from Australia, China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, New Zealand, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. We selected articles about epidemiology, burden, complications, comorbidities, management, prevention, and recommendations/guidelines. Internet searches retrieved additional HZ immunisation guidelines. RESULTS: From 4007 retrieved articles, we screened-out 1501 duplicates and excluded 1264 extraneous articles, leaving 1242 unique articles. We found guidelines on adult immunisation from Australia, India, Indonesia, Malaysia, New Zealand, the Philippines, South Korea, and Thailand. HZ epidemiology in Asia-Pacific is similar to elsewhere; incidence rises with age and peaks at around 70 years - lifetime risk is approximately one-third. Average incidence of 3-10/1000 person-years is rising at around 5% per year. The principal risk factors are immunosenescence and immunosuppression. HZ almost always causes pain, and post-herpetic neuralgia is its most common complication. Half or more of hospitalised HZ patients have post-herpetic neuralgia, secondary infections, or inflammatory sequelae that are occasionally fatal. These disease burdens severely diminish patients' quality of life and incur heavy healthcare utilisation. CONCLUSIONS: Several countries have abundant data on HZ, but others, especially in South-East Asia, very few. However, Asia-Pacific countries generally lack data on HZ vaccine safety, efficacy and cost-effectiveness. Physicians treating HZ and its complications in Asia-Pacific face familiar challenges but, with a vast aged population, Asia bears a unique and growing burden of disease. Given the strong rationale for prevention, most adult immunisation guidelines include HZ vaccine, yet it remains underused. We urge all stakeholders to give higher priority to adult immunisation in general and HZ in particular.

Anxiety and Depression in Patients with Atopic Dermatitis in a Southeast Asian Tertiary Dermatological Centre.

INTRODUCTION: This study aimed to assess the frequency of anxiety and depression in a cohort of adult patients with atopic dermatitis (AD) in a tertiary dermatological centre, using the Hospital Anxiety and Depression Scale (HADS). We looked for any correlation between anxiety and depression with skin disease severity. MATERIALS AND METHODS: Patients with AD were recruited from the National Skin Centre, Singapore, from 2008 to 2009 for a prospective cross-sectional study. The scoring atopic dermatitis (SCORAD) grade was determined and the HADS was administered via interviews. RESULTS: A total of 100 patients (78 males, 22 females) were enrolled (92% Chinese, 4% Malays and 4% Indians). Their average age was 25.7 years. Sixty-five percent used topical steroids, 14% had previously taken oral prednisolone for the control of disease flares, and 20% were on concurrent systemic therapy. The mean SCORAD was 55.0, with 99% of patients having moderate or severe AD. The mean HADS anxiety score was 7.2 and the mean depression score was 5.0. The level of anxiety correlated well with that of depression (Spearman's rank correlation coefficient, ρ = 0.59, P <0.05); 18% were considered as cases of anxiety and 5% as cases of depression. These patients also had higher SCORAD values compared to other patients with lower scores for anxiety or depression (P <0.05). Linear regression demonstrated a statistically significant positive relationship between anxiety and depression scores, and SCORAD scores. CONCLUSION: Our study identified, by means of the HADS, the frequency of anxiety and depression amongst a cohort of Singaporean patients with AD. More severe skin disease correlated to greater psychological burden. The HADS is a useful screening tool that can constitute part of the overall holistic management of patients with AD so as to improve patient care.

Two Episodes of Cutaneous Non-Tuberculous Mycobacterial Infection in a Patient with Psoriasis.

Non-tuberculous mycobacteria (NTM) are a group of environmental pathogens, which cause a broad spectrum of disease. The incidence of NTM infection is increasing, especially in immunocompromized patients. The past three decades also saw a rapid increase in the incidence of NTM infection involving otherwise healthy subjects. We report a case of cutaneous NTM infection in a 79-year-old Chinese woman, who was receiving methotrexate for psoriasis. Mycobacterial culture grew Mycobacterium abscessus, and the lesions cleared with a combination of oral clarithromycin, ciprofloxacin and doxycycline. Interestingly, she then developed a second episode of cutaneous NTM infection with Mycobacterium haemophilum over the same body region, five years after stoppage of methotrexate. Both episodes were separated in time and involved different species, indicating that they were independent from each other. We further discuss the risk factors for cutaneous NTM infection, treatment, and highlight the need for diagnostic vigilance.

Cutaneous protothecosis in a patient with previously undiagnosed HIV infection.

Protothecosis is an uncommon condition resulting from infection by achlorophyllous algae of the Prototheca species. Immunocompromised individuals are generally most susceptible to protothecal infection and tend to develop severe and disseminated disease. However, the association between protothecosis and HIV-induced immunosuppression is not clear, with only a handful of cases having been described to date. Here we report a case of cutaneous protothecosis in a Chinese man with previously undiagnosed HIV infection that responded well to oral itraconazole.

Eccrine syringofibroadenomatosis of the reactive subtype occurring in chronic poorly-controlled psoriasis.

Eccrine syringofibroadenomatosis (ESFA) is a rare adnexal tumor with acrosyringeal differentiation. Clinically, it can be mistaken for granulomatous infections or malignancies such as squamous cell carcinoma. Despite the rarity of the condition, we recently encountered two cases of the reactive subtype, which occurred in patients with poorly controlled chronic psoriasis. Both patients presented with long-standing, thick verrucous lesions on the lower legs. The diagnosis was made after histological examination and exclusion of infectious and neoplastic disorders. As this is a reactive disorder, management is focused on treating the underlying condition. Unfortunately, psoriasis was difficult to manage in both our patients and they defaulted further treatment. It is important to recognize ESFA as it can be confused with infectious or malignant disorders.

Complete remission of recalcitrant genital warts with a combination approach of surgical debulking and oral isotretinoin in a patient with systemic lupus erythematosus.

Genital warts in immunocompromised patients can be extensive and recalcitrant to treatment. We report a case of recalcitrant genital warts in a female patient with systemic lupus erythematosus (SLE), who achieved complete remission with a combination approach of surgical debulking and oral isotretinoin at an initial dose of 20 mg/day with a gradual taper of dose over 8 months. She had previously been treated with a combination of topical imiquimod cream and regular fortnightly liquid nitrogen. Although there was partial response, there was no complete clearance. Her condition worsened after topical imiquimod cream was stopped because of her pregnancy. She underwent a combination approach of surgical debulking and oral isotretinoin after her delivery and achieved full clearance for more than 2 years duration. Oral isotretinoin, especially in the treatment of recalcitrant genital warts, is a valuable and feasible option when other more conventional treatment methods have failed or are not possible. It can be used alone or in combination with other local or physical treatment methods.

Complementary role of a polymerase chain reaction test in the diagnosis of onychomycosis.

BACKGROUND: The successful treatment of onychomycosis depends on accurate diagnosis. Conventional diagnostic methods, including direct microscopy and fungal culture, are non-specific, insensitive and time-consuming. Recently, PCR has shown promise in improving the diagnosis of onychomycosis. We aimed to evaluate a commercially available PCR kit for the in vitro detection of dermatophytes and specifically Trichophyton rubrum in nail specimens with suspected onychomycosis, and to compare the detection rates of PCR with conventional diagnostic methods. METHODS: Nail specimens were prospectively collected from patients with clinically suspected onychomycosis. All nail specimens were positive on direct microscopic examination. PCR and fungal cultures were administered, and the detection rates of dermatophytes were compared. RESULTS: In all, 107 nail specimens were analysed. The fungal culture was positive in 57 (53%) specimens (38 dermatophytes and 19 non-dermatophytes). PCR was positive in 77 (72%) specimens (63 T. rubrum and 14 pan-dermatophyte). A total of 37 specimens (35%) were positive for both fungal culture and PCR. PCR detected dermatophytes in 39 specimens that were missed by the fungal culture, increasing the diagnosis of dermatophyte-positive specimens by 37%. Five dermatophyte-culture-positive specimens were negative for PCR. CONCLUSIONS: This study demonstrates that PCR increases the sensitivity of detection of dermatophytes in nail specimens. Despite its limitations, the use of PCR can complement direct microscopic examination and fungal cultures to aid clinicians in the diagnosis of suspected dermatophytic onychomycosis.

Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors.

Cancer is a leading cause of death worldwide. Tumor cells exploit various signaling pathways to promote their growth and metastasis. To our knowledge, the role of angiopoietin-like 4 protein (ANGPTL4) in cancer remains undefined. Here, we found that elevated ANGPTL4 expression is widespread in tumors, and its suppression impairs tumor growth associated with enhanced apoptosis. Tumor-derived ANGPTL4 interacts with integrins to stimulate NADPH oxidase-dependent production of O(2)(-). A high ratio of O(2)(-):H(2)O(2) oxidizes/activates Src, triggering the PI3K/PKBα and ERK prosurvival pathways to confer anoikis resistance, thus promoting tumor growth. ANGPTL4 deficiency results in diminished O(2)(-) production and a reduced O(2)(-):H(2)O(2) ratio, creating a cellular environment conducive to apoptosis. ANGPTL4 is an important redox player in cancer and a potential therapeutic target.