Receptors, cells and circuits involved in pruritus of systemic disorders.

Pruritus is a sensory phenomenon accompanying a broad range of systemic disorders including hematologic and lymphoproliferative disorders, metabolic and endocrine diseases, solid tumours, and infectious diseases. The molecular mechanisms involved in itch sensation remain enigmatic in most of these diseases. However, from studies in patients and animal models a large number of mediators and receptors responsible for scratching behaviour have been identified in recent years. New insights into the interplay between neuronal and non-neuronal cells in the initiation, modulation and sensitization of itch sensation have been acquired. This review highlights the current knowledge of the molecular mechanism involved in pruritus of systemic disorders and summarizes the signalling pathways of biogenic amines, neuropeptides, proteases, eicosanoids, cytokines, opioids, endocannabinoids, neurotrophins, phospholipids and other signalling molecules participating in pruritus.

Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates.

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.

Angioinvasive Fusarium and concomitant Enterococcus infection arising in association with leukemia cutis.

Leukemia cutis represents the cutaneous infiltration of neoplastic leukocytes or their precursors that results in clinically identifiable skin lesions. For patients with myelodysplastic syndrome, developing such a lesion may indicate impending leukemic transition. These patients are also often immunocompromised, putting them at risk for infection by opportunistic fungal pathogens such as Fusarium. We describe an 85-year-old man with myelodysplastic syndrome who presented with a reddish-purple nodule with a surrounding erythematous plaque on his shin. Histopathologic examination revealed a dense diffuse infiltrate of large atypical cells in the reticular dermis, with ulceration and necrosis. Immunohistochemical studies showed positive staining with CD15, CD68 and myeloperoxidase of constituent large cells. Concurrently, there were branching and septate hyphae with occasional macroconidia-like structures throughout the infiltrate. Cultures from this lesion grew Fusarium and Enterococcus, supporting the diagnosis: leukemia cutis with superinfection involving both Fusarium and Enterococcus. To our knowledge, this is a novel report of two separate infections occurring in a lesion of leukemia cutis. This case shows that in patients with a hematologic malignancy and skin lesions, a high index of suspicion for infection is necessary when reviewing both the clinical and histopathological data to avoid overlooking an important occult infectious agent.

Phenotypic categorization of genetic skin diseases reveals new relations between phenotypes, genes and pathways.

MOTIVATION: Systematic analysis of connection between proteins, their cellular function and phenotypic manifestations in disease is a central problem of biological and clinical research. The solution to this problem requires the development of new approaches to link the rapidly growing dataset of gene-disease associations with the many complex and overlapping phenotypes of human disease. RESULTS: We analyze genetic skin disorders and suggest a manually designed set of elementary phenotypes whose combinations define diseases as points in a multidimensional space, providing a basis for phenotypic disease clustering. Placing the known gene-disease associations in the context of this space reveals new patterns that suggest previously unknown functional links between proteins, signaling pathways and disease phenotypes. For example, analysis of telangiectasias (spider vein diseases) reveals a previously unrecognized interplay between the TGF-beta signaling pathway and pentose phosphate pathway. This interaction may mediate glucose-dependent regulation of TGF-beta signaling, providing a clue to the known association between angiopathies and diabetes and implying new gene candidates for mutational analysis and drug targeting.

A gender gap in the dermatology literature? Cross-sectional analysis of manuscript authorship trends in dermatology journals during 3 decades.

BACKGROUND: Despite a dramatic influx of female dermatologists during the last 30 years, women in academic dermatology departments remain relatively clustered in junior faculty positions. Research in other specialties showing a disparity in the academic productivity of women has led to many hypotheses regarding factors that may place them at a competitive disadvantage. It is unknown, however, whether similar differences in academic productivity might also serve as barriers to advancement in dermatology, or whether any productivity gap actually exists in this specialty that experienced a more substantial entry of women. OBJECTIVE: Because publication in peer-reviewed journals is one of the core measures of academic productivity used in the promotion process, we evaluated trends in the prevalence of female authorship in top dermatology journals during the last 3 decades. METHODS: We conducted an observational study of trends in the sex distribution of US authors in 3 prestigious general dermatology journals (in 1976, 1986, 1996, and 2006) and 3 subspecialty dermatology journals (in 2006 only). Journals were chosen based on published impact factors and citation half-lives. RESULTS: During the last 3 decades, the proportion of women authoring manuscripts in the 3 major general dermatology journals increased from 12% to 48% of US-affiliated first authors (P < .001) and from 6.2% to 31% of US-affiliated senior authors (P < .001). Separate analyses by journal and by article type showed similar increases. The prevalence of female authors in subspecialty journals in 2006 was slightly more variable. LIMITATIONS: Although the publications selected for this study capture many of the most respected US journals in dermatology, they may not be representative of all journals in which dermatologists publish. CONCLUSIONS: Female dermatologists are authoring publications in growing numbers that match or exceed their prevalence in the academic and overall workforce. This suggests that other factors (differences in productivity outside of the publishing arena, differences in job descriptions or opportunities, differences in career aspirations, a lack of institutional support or flexibility, or gender bias) may be associated with the ongoing reduced advancement of women to senior academic dermatology ranks relative to their male colleagues, and further research is warranted to explore these possibilities.

Eruptive angiokeratomas on the glans penis.

Angiokeratomas are benign proliferations of dilated thin-walled blood vessels in the upper dermis with overlying epidermal hyperkeratosis. There are several clinical variants of angiokeratomas: 1. Fordyce: smooth reddish-purple papules on scrotum or vulva; 2. Mibelli: hyperkeratotic papules on fingers or toes, solitary, multiple, or circumscriptum (grouped papules usually on an extremity); 4. angiokeratoma corporis diffusum, widespread papules that are a manifestation of one of several inherited lysozomal storage diseases. Herein, we report a rare case of multiple angiokeratomas of Fordyce on the corona of the glans penis.

Congenital atrophic dermatofibrosarcoma protuberans in a 7-month-old boy treated with Mohs micrographic surgery.

Dermatofibrosarcoma protuberans is a rare, malignant, slow-growing, locally invasive tumor of the skin. Although most cases are acquired and diagnosed in adulthood, there have been an increasing number of congenital dermatofibrosarcoma protuberans mimicking benign birthmarks described in the literature. The clinical presentation of this tumor is often one of an indurated exophytic plaque or nodule; however, a rare variant can present as atrophic or sclerotic in nature. We report a case of congenital atrophic dermatofibrosarcoma protuberans of the groin in a 7-month-old boy, successfully treated with Mohs micrographic surgery.

A Web-Based Tool for Patient Triage in Emergency Department Settings: Validation Using the Emergency Severity Index.

BACKGROUND: We evaluated the concordance between triage scores generated by a novel Internet clinical decision support tool, Clinical GPS (cGPS) (Lumiata Inc, San Mateo, CA), and the Emergency Severity Index (ESI), a well-established and clinically validated patient severity scale in use today. Although the ESI and cGPS use different underlying algorithms to calculate patient severity, both utilize a five-point integer scale with level 1 representing the highest severity. OBJECTIVE: The objective of this study was to compare cGPS results with an established gold standard in emergency triage. METHODS: We conducted a blinded trial comparing triage scores from the ESI: A Triage Tool for Emergency Department Care, Version 4, Implementation Handbook to those generated by cGPS from the text of 73 sample case vignettes. A weighted, quadratic kappa statistic was used to assess agreement between cGPS derived severity scores and those published in the ESI handbook for all 73 cases. Weighted kappa concordance was defined a priori as almost perfect (kappa > 0.8), substantial (0.6 < kappa < 0.8), moderate (0.4 < kappa < 0.6), fair (0.2 < kappa< 0.4), or slight (kappa < 0.2). RESULTS: Of the 73 case vignettes, the cGPS severity score matched the ESI handbook score in 95% of cases (69/73 cases), in addition, the weighted, quadratic kappa statistic showed almost perfect agreement (kappa = 0.93, 95% CI 0.854-0.996). In the subanalysis of 41 case vignettes assigned ESI scores of level 1 or 2, the cGPS and ESI severity scores matched in 95% of cases (39/41 cases). CONCLUSIONS: These results indicate that the cGPS is a reliable indicator of triage severity, based on its comparison to a standardized index, the ESI. Future studies are needed to determine whether the cGPS can accurately assess the triage of patients in real clinical environments.

Genetics for the practicing dermatologist.

In the era of robust genome sequencing, a working understanding of genetics has become important for the clinician. For the dermatologist, understanding the flow of genetic information from genotype to phenotype can aid in the delivery of effective patient care. In this article, we will review concepts in genetics and the human genome and how they contribute to clinical dermatology.

Innovative management of pruritus.

Pruritus remains a significant problem facing dermatologists and can be associated with various dermatoses and systemic derangements. At times, one can treat the underlying cutaneous or systemic process to alleviate itch. However, it is frequently challenging to identify the cause of a patient's itch and, in this situation, even more difficult to manage the symptom effectively. In this article, the authors discuss the approach to a patient with generalized pruritus without clinically obvious dermatoses. They also addresses mechanisms and management modalities of itch in common systemic diseases, including cholestasis, uremia, and neuropathic dysfunction.

Phenotypic and genotypic analyses of genetic skin disease through the Online Mendelian Inheritance in Man (OMIM) database.

Despite unprecedented gains in genomic technologies and genotype resolution, there remain tremendous challenges in our ability to capture disease "phenomes." We propose a previously unreported method for deconvolving human disease into elemental features, thereby creating a third space that interacts with both the disease and genotypic spaces. Using cutaneous and noncutaneous clinical findings available through Johns Hopkins University's Online Mendelian Inheritance in Man (OMIM) database, we set out to deconstruct genetic skin disease (GSD) into its various components, to more fully explore the relationship between these features within the complex phenotypic space and to characterize the genotypic space within which these disorders exist. Using OMIM, we defined the current state of GSD as including 560 distinct disorders associated with 501 unique protein-encoding genes. The most common elemental skin features included [corrected] hair/nail phenotypes, while [corrected] the most common systemic features included those associated with developmental, musculoskeletal, and neurological systems. As a proof of principle, we focused on a single skin feature- café-au-lait macules-and partitioned the disease space into hierarchical groupings on the basis of this finding. Finally, functional analyses among GSD loci were mapped back to skin features, providing insights into pigmentary and auditory features. Phenotypic deconvolution provides a framework for analyzing medical disorders and can aid in the organization and elucidation of biological mechanisms related to human disease.

Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step.

Proteasomes mediate the regulated degradation of Insig-1, a membrane protein of the endoplasmic reticulum (ER) that plays a crucial role in lipid metabolism. We showed previously that sterols inhibit this degradation by blocking ubiquitination of Insig-1. Here we show that unsaturated fatty acids stabilize Insig-1 without affecting its ubiquitination. Instead unsaturated fatty acids inhibit extraction of ubiquitinated Insig-1 from membranes, a process known to be mediated by valosin-containing protein and necessary for ER-associated degradation. Valosin-containing protein is recruited to Insig-1 through the action of another protein, Ubxd8. Unsaturated fatty acids block the binding between Ubxd8 and Insig-1, thereby abrogating the membrane extraction of Insig-1. Unsaturated fatty acid-mediated stabilization of Insig-1 enhances the ability of sterols to inhibit proteolytic activation of SREBP-1, which activates transcription of genes involved in fatty acid synthesis. The current study provides a molecular mechanism for regulation of proteasome-mediated ER protein degradation at a postubiquitination step.

Intramembrane aspartic acid in SCAP protein governs cholesterol-induced conformational change.

The polytopic membrane protein SCAP transports sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum (ER) to the Golgi, thereby activating cholesterol synthesis. Cholesterol accumulation in the ER membranes changes SCAP to an alternate conformation in which it binds ER retention proteins called Insigs, thereby terminating cholesterol synthesis. Here, we show that the conserved Asp-428 in the sixth transmembrane helix of SCAP is essential for SCAP's dissociation from Insigs. In transfected hamster cells, mutant SCAP in which Asp-428 is replaced by alanine (D428A) remained in an Insig-binding conformation when cells were depleted of sterols. As a result, mutant SCAP failed to dissociate from Insigs, and it failed to carry SREBPs to the Golgi. These data identify an important functional residue in SCAP, and they provide genetic evidence that the conformation of SCAP dictates the rate of cholesterol synthesis in animal cells.

Membrane topology of human insig-1, a protein regulator of lipid synthesis.

Insig-1 is an intrinsic protein of the endoplasmic reticulum (ER) that regulates the proteolytic processing of membrane-bound sterol regulatory element-binding proteins (SREBPs), transcription factors that activate the synthesis of cholesterol and fatty acids in mammalian cells. When cellular levels of sterols rise, Insig-1 binds to the membranous sterol-sensing domain of SREBP cleavage-activating protein (SCAP), retaining the SCAP/SREBP complex in the ER and preventing it from moving to the Golgi for proteolytic processing. Under conditions of sterol excess, Insig-1 also binds to the ER enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, facilitating its ubiquitination and proteasomal degradation. Here, we use protease protection, glycosylation site mapping, and cysteine derivitization to define the topology of the 277-amino acid human Insig-1. The data indicate that short segments at the N and C termini of Insig-1 face the cytosol. Most of the protein is buried within the membrane, forming six transmembrane segments separated by five short luminal and cytosolic loops that range from approximately 5 to 16 amino acids. The membranous nature of Insig-1 is consistent with its sterol-dependent binding to hydrophobic sterol-sensing domains in SCAP and HMG CoA reductase.

Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism.

Sterol accumulation in membranes blocks the exit of SCAP from the ER, preventing SREBP cleavage and reducing cholesterol synthesis. Sterols act through SCAP's sterol-sensing domain by an obscure mechanism. Here, we show that addition of cholesterol to ER membranes in vitro causes a conformational change in SCAP, detected by the unmasking of closely spaced trypsin cleavage sites. Two mutant forms of SCAP (Y298C and D443N) that are refractory to sterol regulation in vivo are also refractory to sterol-induced conformational change in vitro. 25-hydroxycholesterol, a potent regulator of SCAP in vivo, fails to change SCAP's conformation in vitro, suggesting that oxysterols act in intact cells by translocating cholesterol from plasma membrane to ER. These studies demonstrate an in vitro effect of cholesterol on the sterol regulatory machinery.