K. Wade Foster

Epidemiologic surveillance of cutaneous fungal infection in the United States from 1999 to 2002

BACKGROUND Cutaneous fungal infections are common in the United States, and causative organisms include dermatophytes, yeasts, and nondermatophyte molds. These organisms are in constant competition for their particular environmental niche, often resulting in the emergence of one or more predominant pathogens and displacement of other less competitive species. Changes in the incidence of fungal pathogens can be followed from laboratory culture results of infected cutaneous tissues over time. These data can be used to ascertain past and present trends in incidence, predict increases in antifungal resistance and the adequacy of our current pharmacologic repertoire, and provide insight into future developments. OBJECTIVE This study identifies epidemiologic trends and the predominant organisms causing superficial fungal infections in the United States. METHODS A total of 15,381 specimens were collected from clinically suspected tinea corporis, tinea cruris, tinea capitis, tinea faciei, tinea pedis, tinea manuum, and finger and toe onychomycosis from 1999 through 2002. Specimens were submitted to the Center for Medical Mycology in Cleveland, Ohio, for fungal culture and identification, and the incidence of each species was calculated. RESULTS Dermatophytes remain the most commonly isolated fungal organisms except from clinically suspected finger onychomycosis, in which case Candida species comprise >70% of isolates. Trichophyton rubrum remains the most prevalent fungal pathogen, and increased incidence of this species was observed in finger and toe onychomycosis, tinea corporis and tinea cruris, tinea manuum, and tinea pedis. As the causal agent of tinea capitis, T tonsurans continues to increase in incidence, achieving near exclusionary proportions in the United States. CONCLUSION Consideration of the current epidemiologic trends in the incidence of cutaneous fungal pathogens is of key importance to investigational efforts, diagnosis, and treatment.

Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia

KLF4/GKLF normally functions in differentiating epithelial cells, but also acts as a transforming oncogene in vitro. To examine the role of this zinc finger protein in skin, we expressed the wild-type human allele from inducible and constitutive promoters. When induced in basal keratinocytes, KLF4 rapidly abolished the distinctive properties of basal and parabasal epithelial cells. KLF4 caused a transitory apoptotic response and the skin progressed through phases of hyperplasia and dysplasia. By 6 weeks, lesions exhibited nuclear KLF4 and other morphologic and molecular similarities to squamous cell carcinoma in situ. p53 determined the patch size sufficient to establish lesions, as induction in a mosaic pattern produced skin lesions only when p53 was deficient. Compared with p53 wild-type animals, p53 hemizygous animals had early onset of lesions and a pronounced fibrovascular response that included outgrowth of subcutaneous sarcoma. A KLF4-estrogen receptor fusion protein showed tamoxifen-dependent nuclear localization and conditional transformation in vitro. The results suggest that KLF4 can function in the nucleus to induce squamous epithelial dysplasia, and indicate roles for p53 and epithelial–mesenchymal signaling in these early neoplastic lesions.

KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia.

KLF4 is induced upon growth-arrest in vitro and during epithelial maturation in vivo, and is essential for proper cell fate specification of post-mitotic cells. In spite of a normal role in post-mitotic cells, expression is upregulated and constitutive in certain tumor types. KLF4 functions as an oncogene in vitro, and enforced expression in basal cells of mouse skin rapidly induces lesions similar to hyperplasia, dysplasia and squamous cell carcinoma (SCC). Here we used conditional expression to characterize early steps in KLF4-mediated tumor initiation. In contrast to SCC-like lesions that result when using a conditional, keratin 14 promoter-dependent strategy, lower conditional expression achieved using a MMTV promoter induced only epidermal cycling within morphologically normal skin, a process we termed occult cell turnover. Surprisingly, KLF4-induced hyperplastic lesions showed increased transgene-derived mRNA and protein in maturing, PCNA-negative cells, a property of endogenous KLF4. In contrast, hyperplastic lesions induced by GLI1, a control, showed uniform transgene expression. In KLF4-induced dysplasia and SCC the complementarity of KLF4 and PCNA was replaced by concordance of the two proteins. These studies show that KLF4 transcripts are normally suppressed in cycling cells in a promoter-independent fashion, consistent with a post-transcriptional control, and reveal loss of this control in the transition from hyperplasia to dysplasia. Like the mouse tumors, human cutaneous SCCs and adjacent dysplasias frequently showed maturation-independence of KLF4, with co-expression of KLF4 and PCNA. A smaller subset of human SCCs showed complementarity of KLF4 and PCNA, similar to hyperplastic mouse skin. The results identify parallels between a mouse model and human primary tumors, and show that successive increases of KLF4 in the nuclei of basal keratinocytes leads to occult cell turnover followed by hyperplasia, dysplasia, and invasive SCC.

Radiofrequency Ablation of Facial Nerve Branches Controlling Glabellar Frowning

BACKGROUND Hyperdynamic activity of the corrugator supercilii and procerus muscles causes glabellar furrows. Recently, a novel radiofrequency device has become available that can effectively ablate the efferent nerves controlling corrugator and procerus contraction, producing clinical results that are similar to those of botulinum toxin. OBJECTIVE To assess the efficacy, longevity of effect, and side effects of the radiofrequency ablation device in the treatment of hyperdynamic glabellar furrows. MATERIALS AND METHODS Four probe entry points were used to access branches of the temporal and angular nerves. Seven and two ablations, respectively, were delivered to each temporal branch and angular nerve. RESULTS Twenty‐nine patients underwent bilateral radiofrequency ablation of temporal branches of the facial nerve and the angular nerves. Abrogation of glabellar furrowing was achieved in 90% of patients. No major adverse events were observed. All patients developed mild to moderate swelling, and nine patients (31%) developed purpura in the treated areas. Sixty‐nine percent of patients had effects that lasted 4 months or longer, 41% had effects that lasted 6 months or longer, and 10% had effects lasting longer than 12 months. CONCLUSION Radiofrequency ablation of efferent branches of the temporal and angular nerves effectively eliminates corrugator and procerus contraction and concomitant glabellar furrowing.

Chapter 2:Inflammation after Solar Radiation

Sunlight is composed of a continuous spectrum of electromagnetic radiation that is divided into three main regions according to wavelength: ultraviolet (UV), visible, and infrared [1]. UV radiation comprises the wavelengths from 200 to 400 nm, the span of wavelengths just shorter than those of visib...