Origin of threshold behaviour in psoriatic skin

The mechanisms that lead to the psoriatic morphology are not fully elucidated. Several lines of evidence suggest that the positive feedback between keratinocytes and immunocytes plays a key role in the development of the lesions. On the other hand, little information is available on the negative regulatory controls that maintain a new homoeostasis level in psoriatic skin. We suggest here that the interplay of these two contrary feedbacks is likely to entail a hysteresis effect and that psoriasis is likely to be interpreted as a critical phenomenon characterized by a catastrophic shift of the skin from a normal to a hyperplastic state.     

A potential suppressor of TGF-beta delays catagen progression in hair follicles

TGF-beta plays important roles in the induction of catagen during the hair cycle. We examined whether TGF-beta2 could activate a caspase in human hair follicles. Using active caspase-9 and -3 specific antibodies, we found that TGF-beta2 activated these caspases in two regions, the lower part of the hair bulb and the outer layer of the outer root sheath. In addition, we searched for a plant extract that can effectively suppress TGF-beta action. We found that an extract of Hydrangea macrophylla reduced synthesis of a TGDbeta-inducible protein. We confirmed that the extract has a potential to promote hair elongation in the organ culture system. Furthermore, it delayed in vivo progression of catagen in a mouse model. Our results suggest that the induction of catagen by TGF-beta is mediated via activation of caspases and that a suppressor of TGF-beta could be effective in preventing male pattern baldness.     

The prevention of disability for people affected by leprosy: whose attitude needs to change?

This paper reflects on the current emphases in the domain of prevention of disability (POD). A review of literature is presented and issues relating to the challenges that affect POD, in the changing scenario of services for leprosy-affected people are considered. A notable conclusion is that the preservation of peripheral nerve function is primarily dependent on early detection; due to challenges that may compromise that essential service, it is suggested that a sharper focus needs to be given to interventions that prevent secondary disabilities. The paradox of pragmatic and simple interventions is that they are difficult to implement. The main issue is that there is a requirement for a commitment to a fundamental change in the relationship between health providers (at all levels) and recipients.     

Current concepts and review of efalizumab in the treatment of psoriasis

Efalizumab is a recombinant humanized monoclonal IgG1 antibody that targets CD11a, a cell surface protein that plays a key role in the T-cell-mediated steps leading to the pathogenesis of psoriasis. The efficacy and safety of efalizumab have been studied extensively in patients with moderate to severe chronic plaque psoriasis. Clinical trial data developed in several large phase 3 studies have demonstrated that efalizumab rapidly improves both physician- and patient-assessed measures of clinical efficacy, and that the observed changes are sustainable over extended periods of continuous treatment, with a favorable safety profile. Efalizumab represents a new therapeutic option for the long-term management of moderate to severe chronic plaque psoriasis.     

Characterization of pigmented fungi by melanin staining

A case is reported of deep cutaneous mycosis in an immunosuppressed patient who, after heart transplantation, developed a solitary blue-black skin nodule that was excised. No cultures were taken. The nodule, in the dermis, was a granuloma with microabscesses containing a few pale yellowish-brown fungal spores that were found after much searching in hematoxylin- and eosin-stained sections. Stains for melanin showed numerous spores and septate branching hyphae that also stained with P.A.S. Melanin staining indicated that the fungi were dematiaceous and that the lesion was a phaeomycotic cyst. Staining of stock cultures of fungi for melanin showed good correlation between the amount of pigment in cell walls of fungi and the accentuation of staining when a melanin stain was incorporated.     

Complement in hidradenitis suppurativa

This is a study on the pathogenesis (causes) of hidradenitis suppurativa (HS). HS is a common skin disorder that affects almost 1% of people in Europe. It manifests with boils in areas of the skin rich in sweat glands like the axilla (arm pits), the breast, the groins and the buttocks. These boils progressively enlarge and rupture with the production of pus and blood. Stress usually proceeds this process. This study was undertaken at the University Hospital of Athens in Greece. The authors measured the concentrations of C5a and C5b‐9 in the plasma (blood) of patients with HS. The rationale for their study was that C5a causes the influx of neutrophils and the formation of pus. It was found that C5a and C5b‐9 are largely elevated in HS and that this is associated with HS severity, so higher levels of C5a and C5b‐9 are linked with worse HS symptoms. Interestingly, the authors describe that C5a stimulates the over‐activation of monocytes, which are cells causing inflammation. Based on this finding, the authors suggest that over‐production of C5a is a newly discovered pathway for the pathogenesis of HS. The authors also show how the drug IFX‐1, that selectively blocks C5a function, decreases the activation of monocytes and may become a promising new medicine for the treatment of HS.     

A phenotype combining hidradenitis suppurativa with Dowling–Degos disease caused by a founder mutation in PSENEN

Dowling‐Degos disease is rare genetic disorder that starts to appear during puberty, featuring abnormal skin colouring (pigmentation) most commonly in the folds of the skin, known as flexural areas. Familial hidradenitis suppurativa is also a rare genetic disorder that features recurrent boils in flexural areas. It usually starts to appear around puberty. Sometimes the two disorders co‐exist in the same person. Defects in the same gene, called PSENEN, were recently found in patients who have both hidradenitis suppurativa and Dowling‐Degos. The product of PSENEN is a protein that is a part of a complex named NOTCH that plays an important role in the development of the skin and other organs. Here we report 4 Jewish Ashkenazi families who presented with clinical features characteristic of both disorders. All patients were found to carry the same gene defect in PSENEN, a defect that was never shown before. We checked the area around the gene and found it to be the same in all patients. This means that all patients got the mutation from a common ancestor. In the next step of our research project we wanted to show that defect in PSENEN actually influences NOTCH. We used cells from a patient and compared it to cells from a healthy person. We showed that there is less PSENEN in the cells of the patients, and when we insert a special element inside the cells that makes them glow when NOTCH is active, patient cells glow less than cells from healthy people. In conclusion, in this present study we showed a new genetic defect in PSENEN that can cause two diseases at once: Dowling‐Degos disease and hidradenitis suppurativa. We also show that NOTCH is important in both of these diseases.     

Melanoma mimicking seborrheic keratosis: an error of perception precluding correct dermoscopic diagnosis

Seborrheic keratosis is a common skin lesion that can usually be recognized either clinically or dermoscopically. However, melanomas mimicking seborrheic keratoses, as well as melanomas arising in association with seborrheic keratoses, have been described. We report the case of a patient with a lesion that initially revealed "classic" dermoscopic features of a seborrheic keratosis. However, during follow-up, changes in color developed within the center of the lesion that led the clinician to the correct diagnosis of melanoma. Upon retrospective evaluation of the baseline image of the lesion; the clinician was now able to "see" that which his brain could not appreciate on initial examination and to realize that the lesion had subtle features suspect for melanoma. This case represents a diagnostic pitfall due to errors in perception. Dermatologists should be cognizant of "errors in perception"; we suggest that a final dermoscopic judgment of a seborrheic keratosis be rendered by combining the gestalt diagnosis of the overall pattern, with deliberate dermoscopic analysis of all quadrants of the lesion.     

The morbidity of psoriatic disease

There is a considerable area of intersection between the negative consequences of psoriatic skin inflammation and the negative consequences of psoriatic joint inflammation. However, available evidence indicates that PsA also has a unique set of possible undesirable outcomes, such as severe disability and increased mortality, that are particularly serious. In light of this evidence, it has become increasingly clear that PsA is not the relatively mild condition it was once believed to be, but rather a disease that can have a dramatic negative impact on affected patients.     

Is Antibiotic Resistance in Cutaneous Propionibacteria Clinically Relevant?

It is well recognized that some patients with acne do not respond adequately to antibiotic therapy. It is important to distinguish antibiotic recalcitrant acne which we would suggest represents acne that shows a diminished response to treatment irrespective of the cause as opposed to 'antibiotic-resistant acne' which is acne that is less responsive to treatment as a direct consequence of skin colonization with resistant propionibacteria. Here we show that antibiotic-resistant acne is not just a theoretical possibility but a real phenomenon that could have important consequences for patients and prescribers. The relationship between skin colonization by antibiotic-resistant propionibacteria and treatment outcomes is a complex one that is explained at the follicular level by physiological differences affecting local drug concentrations. A systematic review of the literature on antibiotic-resistant propionibacteria revealed methodological shortcomings in studies of their prevalence and a paucity of evidence on their clinical significance. Despite the elucidation of resistance mechanisms in cutaneous propionibacteria, our continuing inability to distinguish between strains of Propionibacterium acnes means that we still do not fully understand how resistance spreads, although person-to-person transfer is most likely. Finally, we present a decision tree for acne management in an era of prudent antimicrobial prescribing that provides an alternative to existing treatment algorithms by placing topical retinoids and not antibiotics at the cornerstone of acne management.     

Genetic counseling

In spite of all that has been discussed, there are no hard data documenting what influences a couple's decision to have more children after the birth of a child with a genetic disorder. It is likely that recurrence risk does not play a major role. The difference between a 25 per cent and a 50 per cent recurrence risk with each pregnancy probably does not have a great deal of personal significance. However, the burden of a disease is something to which every couple can relate. They know how the disease has affected the living situation of their family, and that is very meaningful. Because genetic counseling services are not standardized and the prediction of the outcome of these services is so difficult to quantify, third parties have not been very agreeable to pay for genetic counseling. I think it is important, however, to realize that the standardization of procedures may be less important than the emotional support given to a couple during the difficult time after they have been informed that their child has a genetic disease.     

DeoxyArbutin: a novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency

Modulation of melanogenesis in the melanocytes can be achieved using chemicals that share structural homologies with the substrate tyrosine and as thus competitively inhibit the catalytic function of tyrosinase. We have developed a new tyrosinase inhibitor, deoxyArbutin (dA), based on this premise. DeoxyArbutin demonstrates effective inhibition of mushroom tyrosinase in vitro with a Ki that is 10-fold lower that hydroquinone (HQ) and 350-fold lower than arbutin. In a hairless, pigmented guinea pig model, dA demonstrated rapid and sustained skin lightening that was completely reversible within 8 weeks after halt in topical application. In contrast, HQ induced a short but unsustained skin lightening effect whereas kojic acid and arbutin exhibit no skin lightening effect. Results from a panel of safety tests supported the overall establishment of dA as an actionable molecule. In a human clinical trial, topical treatment of dA for 12 weeks resulted in a significant or slight reduction in overall skin lightness and improvement of solar lentigines in a population of light skin or dark skin individuals, respectively. These data demonstrate that dA has potential tyrosinase inhibitory activity that can result in skin lightening and may be used to ameliorate hyperpigmentary lesions.     

Thalidomide and thrombosis

BACKGROUND: Teratogenicity and neuropathy are the well known serious side effects induced by thalidomide. We describe 5 cases of thrombotic events occurring within a brief delay after the onset of thalidomide in a manner that suggests that thalidomide could have acted as a precipiting or as a starting factor in these events. OBSERVATIONS: Five patients including 4 patients with lupus erythematosus (1 discoid lupus, 1 subacute lupus and 2 systemic lupus erythematosus) and one patient with a severe atopic dermatitis, all without previous history of vascular events, developed an arterial thrombosis (2 cases) or a venous thrombosis (3 cases), severe in 4 cases, few days or weeks after the onset of thalidomide treatment (50 to 100 mg daily). DISCUSSION: All the patients had risk factors of thrombosis: the presence of antiphospholipids and/or anticardiolipin antibodies in lupus erythematosus patients and a trauma in the atopic case. However the absence of a previous story of thrombosis, its rapid occurrence after the onset of thalidomide and its severity are intriguing. In addition, recent studies demonstrate that thalidomide has various effects that would act, among other things, on angiogenesis. Thus, we think that a doubt exists on a negative effect of thalidomide in thrombosis risk factors patients and that this hypothesis has to be confirmed.     

PLANTAR MALIGNANT MELANOMA

A case of a 51 year old man with a plantar malignant melanoma is reported. The tumor had clinical and histologic features of lentigo maligna melanoma, but its biologic activity was that of a more potently malignant tumor. Electron microscopic observation reveales features similar to that of lentigo maligna melanoma, but not inconsistent with that of superficial spreading melanoma. A consideration of our case and of previous reports suggests that there is a relationship between the biologic potency and the site of involvement of lentigo maligna melanoma and that such lesions on relatively non-pigmented areas such as the palms, soles, mucous membranes, and nail beds should be treated as having a highly malignant potential.     

Vitronectin: effects on keratinocyte motility and inhibition of collagen-induced motility.

Epibolin, a plasma protein, was initially purified on the basis of its ability to enhance spreading of keratinocytes. It is now known that epibolin is identical to serum spreading factor, S protein, and vitronectin, and the current name for the protein is vitronectin. Studies of vitronectin on cultured keratinocytes showed that it caused spreading and epiboly but not cellular adhesion to the substratum. In studies with other types of cells, vitronectin increased migration of several types of cells in a Boyden chamber. Because some agents that enhance spreading and adhesion, such as collagen and fibronectin, also increase motility, we tested whether vitronectin increased motility of keratinocytes. By photographing and quantitating motility of keratinocytes plated on a bed of colloidal gold particles, we determined that vitronectin increased local movement of keratinocytes in a concentration-dependent fashion, resulting in clearing of gold particles in a circular pattern around the cells, but did not cause the production of tracks found in cultures plated on collagen or fibronectin. The small increases in clearing of the gold particles that occurred in the presence of vitronectin were abolished by antibody to vitronectin. Furthermore, the marked increase in motility produced by type I collagen was significantly reduced when the keratinocytes were treated with vitronectin. Antibody to vitronectin also abrogated the vitronectin-induced reduction in collagen-stimulated motility, confirming that this action was specific for vitronectin. Serum, which contains vitronectin, stimulated motility in a fashion identical to purified vitronectin, but serum lacking vitronectin was inactive. These studies show that vitronectin causes a localized increase in movement associated with spreading resulting in a halo around individual cells, that vitronectin does not enhance directional motility of keratinocytes in this assay but in contrast antagonizes such motility produced by collagen, and that vitronectin is the factor in serum responsible for this effect. The findings with vitronectin and collagen show that these agents stimulate different types of motility. The roles in wound healing of agents stimulating different types of motility are unclear and require further study.     

Gadd45a activation protects melanoma cells from ultraviolet B-induced apoptosis

Epidemiological and biological studies indicate that solar UVB radiation is involved in cutaneous malignant melanoma etiology. Indeed, melanocytes are very frequently exposed to solar UV radiation, which induces cell damage and may promote cell transformation. We previously showed that melanocytes and melanoma cells exposed to UVB radiation activates a p53-independent pathway involving Gadd45a and, more recently, that Gadd45a plays a critical role in UVB-induced G2 cell cycle arrest of melanoma cells. In this study, we demonstrate that the inhibition of UV-induced Gadd45a overexpression by RNA interference results in a dramatic increase of cell death. We identify this cell death as apoptosis, with activation of Caspase-3 and a decrease in Bcl-x(L) expression. Furthermore, we show that inhibition of UV-induced Gadd45a overexpression also leads to increased sensitivity of melanoma cells to therapeutic agents such as DTIC and Cisplatin. We conclude that UVB-induced Gadd45a overexpression protects melanoma cells from apoptosis, both by causing a G2 cell cycle arrest and by inhibiting the mitochondrial apoptotic pathway. These observations suggest that Gadd45a inactivation could be a useful way to sensitize melanoma cells to chemotherapy. JID journal club article: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub     

Úlceras dolorosas múltiples en la pierna resistentes al tratamiento asociadas a lesiones dermatomiositis-like en las articulaciones interfalángicas de las manos: hidroxiurea como agente causal

The onset of a dermatomyositis-like rash and persistent skin ulcers during long-term treatment with hydroxyurea is a very rare event that has not been fully described in the literature.The fact that these lesions have a typical clinical presentation and course, and that complete resolution can only be achieved by immediate withdrawal of the drug, means that dermatologists should be aware of this condition in order to avoid a delay in diagnosis.We present the case of a 76-year-old woman who developed a dermatomyositis-like eruption associated with chronic ulcers on the lower limbs during long-term treatment with hydroxyurea.