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Background Toxic epidermal necrolysis (TEN) is a rare, life-threatening condition caused by certain medications. Keratinocytes affected by TEN have been found to undergo apoptosis mediated by Fas-FasL interactions. Treatment with intravenous immunoglobulin (IVIG) has been proposed to inhibit this interaction. Objective To demonstrate the effectiveness of IVIG therapy in reducing mortality in patients with TEN. Design A retrospective analysis of 16 consecutive patients with TEN who were treated with IVIG. The SCORTEN system, a validated predictor of TEN mortality, was used to analyze the data of these patients. Using SCORTEN, we compared the predicted mortality of our patient population with observed mortality. Setting Dermatology inpatient unit at a university-affiliated hospital. Intervention All 16 patients received IVIG treatment daily for 4 days. Fifteen patients received 1 g/kg per day and 1 patient received 0.4 g/kg per day. Main Outcome Measures For each patient, causes of TEN and other medical problems were documented prior to IVIG therapy, as were the 7 independent SCORTEN risk factors. Results One patient died. Based on the SCORTEN system, 5.81 patients were expected to die. These mortality rates were compared using the standardized mortality ratio (SMR) analysis ([Σ observed deaths/Σ expected deaths] × 100) to determine the efficacy of this treatment, which showed that patients with TEN treated with IVIG were 83% less likely to die than those not treated with IVIG (SMR = 0.17; 95% confidence interval, 0.0-0.96). Conclusion Based on comparison of our observed mortality rate with the SCORTEN-predicted mortality rate, treatment with IVIG significantly decreased mortality in patients with TEN.

Five consecutive patients with cryofibrinogenaemia in association with painful leg ulcers and intravascular dermal thrombi were treated with stanozolol, an androgenic steroid with fibrinolytic properties. In all patients treatment was followed by rapid and striking pain relief and healing of the ulcers. Cryofibrinogenaemia was not detected on subsequent laboratory evaluation, and dermal intravascular thrombi had resolved on repeat histological examination.

Objective: To estimate the frequency of recorded screening for skin cancer in primary care settings. Design: Retrospective observational cohort study. Setting: Two academically affiliated Department of Veterans Affairs Medical Centers. Subjects: Two hundred randomly selected patients at least 50 years old and receiving care at outpatient medical clinics. Main Outcome Measure: Frequency of documented skin examinations, in comparison with other tests routinely done as screening, during a 2-year period. Methods: Medical record review to identify how often selected components of the physical examination and specific procedures were documented during ambulatory visits. Results: Among the 200 subjects, the frequency of documented examinations and procedures included fecal occult blood testing in 120 (60%), rectal examination in 128 (64%), and sigmoidoscopy in 93 (47%); prostate examination was performed in 114 (59%) of 193 men. In contrast, skin examination was documented in only 56 (28%) of 200 subjects (P Conclusion: Skin cancer screening is infrequently documented and therefore possibly omitted in the context of primary care visits. Arch Dermatol. 1997;133:1423-1425

Inpatient dermatologic services are diminishing. A recent survey 1 of dermatology residents reports that 17% do not care for hospitalized patients and that less than 1% of residents care for 60 or more hospitalized patients per month. One reason for this decrease is the increasing pressure to contain medical costs. Stringent guidelines have been set up for hospital admission, length of stay, and intensity of care, all encompassed in a specific diagnostic related group that represents a certain sum for a given diagnosis. Despite these firm criteria, few objective tests are used routinely to assess the outcome, effectiveness, or cost of dermatologic hospitalization. One outcome measure is the Psoriasis Area and Severity Index, which is often used to quantify the effectiveness of treatments for psoriasis. 2 In addition, a patient-oriented measure of outcome, the Dermatology Life Quality Index, and other depression and anxiety tests can be used to measure objectively

Background and Design: We determine whether a subset of internists exist who are better at diagnosing skin disease and therefore select themselves to treat the majority of patients with dermatologic disorders. A survey was conducted in which internists reported their self-perception regarding their abilities in dermatology, the amount of dermatology training they had received, and the percentage of patients they encounter with and treat for skin diseases. This was correlated with results from an objective photographic (Kodachrome) examination assessing their diagnostic abilities in dermatology. The setting was university and private practices in Miami, Fla, and New Haven, Conn. The participants were general internists, medical subspecialists, and medical residents. After completing a self-administered questionnaire, each physician then participated in an examination where they were shown 20 color photographs of common skin disorders. We correlate the relationship between the survey variables and the results of the photographic examination. Results: Eighty-four internists diagnosed 50.5% of the diseases correctly. Internists perceive themselves as mediocre in dermatology (2.6, on a scale of 1-5, 5 being the best), which correlated with their poor performance on the photographic evaluation ( P =.04). Internists reported having limited education or training in dermatology (>85% having P =.07). Notably, there was no correlation between internists' ability in dermatology and the percentage of patients they encounter with and treat for skin disease. Conclusions: Internists receive limited training and have resultant poor performance in diagnosing skin disease. Internists are aware of their limited ability in dermatology as demonstrated by their mediocre self-perceived ability. Notably, no correlation was found between internists' abilities in dermatology and the percentage of patients they encounter and treat for skin disease. Therefore, we did not demonstrate a subset of internists, superior at dermatology, who treat the majority of patients with skin disease. This suggests patients with skin disease may be better served by dermatologists. Arch Dermatol. 1996;132:1043-1046

The abrupt development of cyanotic and painful toes, "the blue toe syndrome," has been attributed to a number of medical conditions. We describe a patient in which the workup for this condition failed to elucidate a typical cause. Skin biopsy, serologic findings, and response to treatment led to the diagnosis of secondary syphilis. Our experience indicates that secondary syphilis should be included in the differential diagnosis of patients presenting with the blue toe syndrome. (Arch Intern Med. 1994;154:1029-1031)

† Background.— Skin grafting is commonly used to treat nonhealing wounds. However, how skin grafts help to heal wounds is not entirely known. Why epithelium from grafted skin is able to migrate and cover these wounds, while epithelium at the edge of nonhealing wounds is unable to, is a long unanswered biologic question. Observations.— The recent use of cultured epithelial allografts has rekindled interest in the biology of skin grafts. Replaced, even in chronic wounds, by recipient epithelium, cultured epithelial allografts appear to work by providing a potent stimulus to healing imparted by the graft itself. Based on this, we have reassessed how skin autografts help to heal wounds and hypothesize that, in a similar fashion, autografts may work not only by replacing tissue but also by providing a stimulus for healing. Conclusions.— We suggest that skin grafts may work not only as tissue replacement but as pharmacologic agents that provide a stimulus for healing. We believe that, someday, it may be possible to augment the stimulatory properties of donor skin to speed healing of the recipient wound. ( Arch Dermatol. 1993;129:481-483)

• Living tissues possess direct current surface electropotentials that regulate, at least in part, the healing process. Following tissue damage, a current of injury is generated that is thought to trigger biological repair. In addition, exogenous electrical stimuli have been shown to enhance the healing of wounds in both human subjects and animal models. Intractable ulcers have demonstrated accelerated healing and skin wounds have resurfaced faster and with better tensile properties following exposure to electrical currents. This article examines the bioelectric properties of living systems and reviews the existing literature on electrical stimulation and wound healing. ( Arch Dermatol . 1990;126:222-225)

The hitherto unnoticed, statistically significant tendency of the Dutch demonstrative adjective deze ‘this/these’ to occur closer to sentence-initial position than die ‘that/those’ is shown to be a consequence of the greater mean referential distance (cf. Givon (1983)) associated with NPs containing deze versus those containing die . This contrast is due to (a) the tendency of NPs containing deze to rephrase or reinterpret rather than simply repeat earlier referents, and (b) the independent tendency of NPs containing deze to maintain both kinds of reference — rephrasing and simple repetition — over longer stretches of text than NPs containing die . It is argued that the association of deze with both longer referential distances and reinterpretation of referents and of die with both shorter referential distances and simple repetition reflects the use of the two demonstratives to differentiate major (more important) from minor (less important) entities in discourse. But this is not enough. If the grammarian is to make linguistically significant generalizations, this particular use of the forms — revealing most clearly the demonstratives' ‘imperative-like’ character — cannot be viewed in isolation from their other non -discourse uses, to which it shows tantalizing partial similiarities. It must be taken as symptomatic of a more general difference in meaning between deze and die . Here, however, the grammarian grapples with the classic issue of non-uniqueness (cf. Saussure (1962: 147–154)). As is shown by two separate semantic analyses of the demonstratives, sketched within the respective frameworks of Cognitive Grammar and the Columbia School, one may explain (integrate) the various uses of deze and die in different ways and it is an open question which way will turn out to be most fruitful. The ultimate theoretical significance of the difference in ‘privileges of occurrence’ shown by deze and die is that it underscores both the necessity and the difficulty of delimiting the semantic content of grammatical categories.

Traditional grammars of Modern Standard Dutch teach that zullen is the ‘auxiliary verb of the future tense’. In spite of the dissatisfaction of such linguists as A. W. de Groot and F. G. Droste, the exact meaning of zullen and the precise mechanism by which it can function as a future auxiliary remain to be elucidated. C.I. Ebeling's recent discussion, though containing valuable suggestions, constitutes no final solution. It is proposed here that the use of zullen in Modern Standard Dutch follows from its membership, together with the forms moeten and kunnen, in a system which characterizes occurences as hypothetical rather than real. Because zullen - in contrast to the other elements of the system - does not specify the degree of likelihood of the event in question, it may be interpreted as signaling futurity, inference, command, or the intention of the speaker. The particular messages transmitted with zullen in specific instances are conclusions drawn from the interaction of its own meaning with the particular member of the tense system with it is combined and with observable factors in the extra-linguistic context. Seen in this framework, the textbook functions of zullen, both as a ‘modal auxiliary’ and as a ‘future auxiliary’ illustrate the following principle: the language user will favor that member of a closed system of semantic oppositions whose meaning is least inappropriate to a given message.

The gap junction protein, connexin43 (Cx43), has critical roles in the inflammatory, edematous, and fibrotic processes following dermal injury and during wound healing, and is abnormally upregulated at the epidermal wound margins of venous leg ulcers (VLUs). Targeting Cx43 with ACT1, a peptide mimetic of the carboxyl-terminus of Cx43, accelerates fibroblast migration and proliferation, and wound reepithelialization. In a prospective, multicenter clinical trial conducted in India, adults with chronic VLUs were randomized to treatment with an ACT1 gel formulation plus conventional standard-of-care (SOC) protocols, involving maintaining wound moisture and four-layer compression bandage therapy, or SOC protocols alone. The primary end point was mean percent ulcer reepithelialization from baseline to 12 weeks. A significantly greater reduction in mean percent ulcer area from baseline to 12 weeks was associated with the incorporation of ACT1 therapy (79% (SD 50.4)) as compared with compression bandage therapy alone (36% (SD 179.8); P=0.02). Evaluation of secondary efficacy end points indicated a reduced median time to 50 and 100% ulcer reepithelialization for ACT1-treated ulcers. Incorporation of ACT1 in SOC protocols may represent a well-tolerated, highly effective therapeutic strategy that expedites chronic venous ulcer healing by treating the underlying ulcer pathophysiology through Cx43-mediated pathways.

1 Journal of Investigative Dermatology (2013), Volume 133 © 2013 The Society for Investigative Dermatology QUESTIONS 1. What is your diagnosis? a. Rothmund–Thomson syndrome. b. Hutchinson–Gilford syndrome. c. Werner syndrome. d. Aplasia cutis congenita. e. Anhidrotic ectodermal dysplasia. JID VisualDx Quiz: July 2013 Andrew Styperek1 and Robert S. Kirsner1 Journal of Investigative Dermatology (2013) 133, e6; doi:10.1038/jid.2013.217

1 Journal of Investigative Dermatology (2013), Volume 133 © 2013 The Society for Investigative Dermatology QUESTIONS 1. What is your diagnosis? a. Eosinophilic fasciitis. b. Scleroderma. c. Scleredema. d. Nephrogenic systemic fibrosis. e. Graft-versus-host disease. JID VisualDx Quiz: May 2013 Sadegh Amini1 and Robert S. Kirsner1 Journal of Investigative Dermatology (2013) 133, e4; doi:10.1038/jid.2013.123

For answers, visit our website or scan the adjacent tag. Atopic dermatitis (AD) is a common chronic inflammatory skin disorder with both acute and chronic stages (Akdis et al., 2006). Often referred to as “the itch that scratches,” AD is characterized by severe pruritus, which may substantially impact the quality of life in sufferers. Recently, human protease-activated receptor-2 (PAR-2) was found to mediate itch (Reddy et al., 2010), generating considerable interest in compounds that activate this receptor. Among these compounds is cathepsin S (CTSS), a lysosomal cysteine protease that functions in a variety of ways, including as an elastase in alveolar macrophages. This compound may also play a role in the degradation of antigenic proteins into peptides for presentation on major histocompatibility complex class II molecules. To study the role of CTSS, Kim et al. (2012, this issue) utilized a transgenic mouse that overexpresses human CTSS. The investigators hypothesized that over expression of human CTSS in this model would lead to the AD-like symptoms and signs of itching and scratching and histopathological changes that resemble those in AD. Indeed, the transgenic mice that overexpressed CTSS scratched more, and this increased scratching led to reddening, scaling, and thickening of the skin. PAR-2 expression was also increased as a result of CTSS overexpression, and both CTSS and PAR-2 levels correlated with a thickened epidermis. Although barrier function was not examined, a variety of cytokines, including IL-4, IL-10, tumor necrosis factor-a, IL-2, IFN-g, IL-1b, monocyte chemotactic protein-1, and granulocyte–macrophage colony-stimulating factor, were analyzed. Through the following questions, we examine this paper in greater detail. For brief answers, please refer to the supplementary information online .

Data suggest that vitamin D intake may have chemopreventive efficacy against melanoma, but there have been no published epidemiologic studies examining the association between vitamin D intake and melanoma risk in a large prospective cohort. We examined whether dietary and supplemental vitamin D intake was associated with melanoma risk among 68,611 men and women who were participants of the Vitamins and Lifestyle cohort study. Participants reported dietary vitamin D intake over the past year and 10-year use of multivitamin and individual vitamin D supplements on a baseline questionnaire. After follow-up through 2006, 455 incident melanomas were identified through linkage to the Surveillance, Epidemiology, and End Results cancer registry. Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for vitamin D intake after adjustment for melanoma risk factors. Compared with the lowest quartile, we did not detect a risk reduction of melanoma in the highest quartiles of dietary vitamin D intake (RR = 1.31, CI = 0.94–1.82), 10-year average supplemental vitamin D intake (RR = 1.13, CI = 0.89–1.43), or combined dietary and supplemental intake (1.05, CI = 0.79–1.40). In this large prospective cohort, we did not find an association between vitamin D intake and melanoma risk.

Recessive dystrophic epidermolysis bullosa (RDEB, OMIM ID #226600) is a severe blistering disease that affects quality of life and is associated with increased mortality, often from squamous cell carcinoma (Fine et al., 1999). Mutations in COL7A1, the gene that encodes type VII collagen, lead to blistering with resultant wounds and scarring. Treatment approaches have included tissue-, cell-, and gene-based therapies, including recent efforts at bone marrow ablation and allogeneic stem cell transplantation (Wagner et al., 2010). Because a single gene defect is responsible for the disease manifestations, researchers have focused on the development of gene therapy approaches. Unfortunately, several problems have hampered clinical development of vector-based gene therapy for this disease, including low transfer efficacy and the large size of the COL7A1 cDNA (Goto et al., 2006). In a previous study, a COL7A1 “minigene” that encoded a truncated type VII collagen was developed. This minigene was compatible size-wise with retroviral vectors and reversed the DEB phenotype to normal in transduced keratinocytes (Chen et al., 2000). An alternative to retroviral gene therapy is trans-splicing, an approach that employs the cell spliceosome to recombine an endogenous target pre-mRNA and an exogenously delivered RNA molecule called the pre-transsplicing molecule (PTM). A partial, wild-type coding sequence from the PTM is inserted to replace disease-causing sequences in order to generate a new, reprogrammed wild-type mRNA to correct the disease phenotype (Wally et al., 2008). In this issue, Murauer et al. report on their efforts with trans-splicing techniques to create a potential therapy for RDEB. These investigators introduced a partial, wild-type COL7A1 PTM via retroviral transduction of RDEB keratinocytes and achieved full-length type VII collagen expression. Transduced cells displayed functional correction of the RDEB phenotype, including normal morphology, reduced invasive capacity, normal localization of type VII collagen at the basement membrane, and assembly of collagen into anchoring fibril-like structures. Through the following questions, we examine this paper in greater detail. For brief answers, please refer to the supplementary information online

Epithelia establish a microbial barrier against infection through the production of antimicrobial peptides (AMPs). In this study, we investigated whether catestatin (Cst), a peptide derived from the neuroendocrine protein chromogranin A (CHGA), is a functional AMP and is present in the epidermis. We show that Cst is antimicrobial against relevant skin microbes, including Gram-positive and Gram-negative bacteria, yeast, and fungi. The antimicrobial mechanism of Cst was found to be similar to other AMPs, as it was dependent on bacterial charge and growth conditions, and induced membrane disruption. The potential relevance of Cst against skin pathogens was supported by the observation that CHGA was expressed in keratinocytes. In human skin, CHGA was found to be proteolytically processed into the antimicrobial fragment Cst, thus enabling its AMP function. Furthermore, Cst expression in murine skin increased in response to injury and infection, providing potential for increased protection against infection. These data demonstrate that a neuroendocrine peptide has antimicrobial function against a wide assortment of skin pathogens and is upregulated upon injury, thus demonstrating a direct link between the neuroendocrine and cutaneous immune systems.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe mechanobullous disease characterized at the molecular level by mutations in the COL7A1 gene, leading to reduced type VII collagen and defective anchoring fibrils at the dermal–epidermal junction (DEJ) (Fine et al., 2000). Patients who inherit this condition suffer from recurrent blistering, cutaneous ulcers, severe scarring, and deformities, and they are at high risk for developing life-threatening squamous cell carcinoma (Mallipeddi, 2002). Currently, there is no treatment for RDEB.