T. Passeron

Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophilin/Slac2-a and actin association

Melanosomes are melanin‐containing organelles that belong to a recently individualized group of lysosome‐related organelles. Recently, numerous reports have dissected the molecular mechanisms that control melanosome transport, but nothing was known about the possible regulation of melanosome distribution by exogenous physiological stimulus. In the present report, we demonstrate that a physiological melanocyte‐differentiating agent such as α‐melanocyte‐stimulating hormone, through the stimulation of the cAMP pathway, induces a rapid centrifugal transport of melanosomes, leading to their accumulation at the dendrite tips of melanocytes. Interestingly, the small GTP binding proteins of the p21Rho family and one of their effectors, p160 Rho‐associated kinase, but not PKA, play a key role in redistribution of melanosomes at the extremities of the dendrites. Further, we have investigated, at the molecular level, the effect of cAMP on the different proteins involved in the control of melanosome transport. We demonstrate that cAMP stimulates the expression of Rab27a and rapidly increases the interaction of the melanophilin/Slac2‐a with actin. Thus, we propose that the stimulation of the interaction between melanophilin/Slac2‐a and actin would allow the rapid accumulation of melanosomes in the actin‐rich region of the dendrite extremities.

Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance

We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.

Inhibition of Melanogenesis by the Antidiabetic Metformin

Several reports have demonstrated the inhibitory effect of metformin, a widely used drug in the treatment of type 2 diabetes, on the proliferation of many cancers including melanoma. Recently, it has been shown that metformin is able to modulate the cAMP level in the liver. As cAMP has a crucial role in melanin synthesis and skin pigmentation, we investigated the effect of metformin on melanogenesis both in vitro and in vivo. We showed that metformin led to reduced melanin content in melanoma cells and in normal human melanocytes by decreasing cAMP accumulation and cAMP-responsive element-binding protein phosphorylation. This inhibitory effect is correlated with decreased expression of master genes of melanogenesis, microphthalmia-associated transcription factor, tyrosinase, dopachrome tautomerase, and tyrosinase-related protein 1. Furthermore, we demonstrated that the antimelanogenic effect of metformin is independent of the AMPK pathway. Interestingly, topical application of metformin induced tail whitening in mice. Finally, we confirmed the antimelanogenic effect of metformin on reconstituted human epidermis and on human skin biopsies. These data emphasize the depigmenting effect of metformin and suggest a clinical strategy for using metformin in the topical treatment of hyperpigmentation disorders.

Thalidomide‐induced amenorrhoea: two cases

Sir, Topical 5-aminolaevulinic acid (5-ALA) photodynamic therapy (PDT) has become an effective treatment option in dermatology. We report a 70-year-old man who presented with extensive erythematous patches on his abdomen and infiltrated plaques on his arms and neck. These were preceded by extensive figurate and annular erythema on his trunk and limbs for 10 years. He had a history of congestive cardiac failure, atrial fibrillation and chronic obstructive airway disease. Mycosis fungoides (MF) was confirmed histopathologically and he cleared with a course of oral 8-methoxypsoralen (8-MOP) plus ultraviolet A (PUVA). During the next year his MF progressed in extent and he also developed a solitary tumour (1 ́5 1 ́5 cm) on his left posterior thigh. The extensive patch and plaque MF cleared with a further course of oral 8-MOP PUVA, but the nodule remained and became ulcerated and painful over the next 3 months. Biopsy of this tumour showed an ulcerated epidermis with replacement of the subcutaneous tissue by a dense infiltrate of malignant CD31 T cells (Fig. 1a). There was no lymphadenopathy or organomegaly. Blood investigations were normal. Computed tomographic scans of the thorax and abdomen were negative. The tumour was treated with 5-ALA PDT: 5-ALA 20% in a cream base (Aladerm, Crawford Pharmaceuticals, Milton Keynes, U.K.) was applied, under polythene occlusion, to the tumour. Four hours later, excess 5-ALA was wiped off and fluorescence was graded as satisfactory using Woods light. He received 20 J cm at 20 mW cm using a Waldmann PDT lamp (MSR 1200; 580±740 nm). Irradiance was measured using a calibrated handheld meter (International Light 1400A and Selo33/F/W/QND52 detector with spectral shaping and neutral density filters calibrated by D.Taylor, Gloucester, U.K.). He graded pain during treatment as 8/10 but experienced no other adverse effects. The lesion cleared after five consecutive treatments over 12 weeks. Repeat biopsy showed a lymphohistocytic infiltrate but complete clearing of the original infiltrate of malignant T cells (Fig. 1b). During his course of PDT his generalized patch and plaque MF relapsed. The tumour site has remained clear on clinical examination 1 years later. He has required two courses of PUVA therapy for generalized patch and plaque MF during this period. Topical 5-ALA PDT has been proven to be effective for superficial cutaneous cancers, but there are few reports of its use in treating MF. Shanler et al. treated patch/ plaque-stage cutaneous T-cell lymphoma and showed that protoporphyrin IX accumulated within lymphocytic infiltrates; early therapeutic results were promising. Boehncke et al. using an argon laser at 630 nm showed inhibition of proliferation of malignant transformed T cells in vitro and in vivo. Wolf et al. have demonstrated the efficacy of PDT (20% 5-ALA) using a broad-spectrum source (40 J cm at 44 mW cm) in two patients with MF who cleared after four and five PDT treatments, respectively. However, Amman and Hunziker reported a poor response for an infiltrated plaque of MF to just one PDT treatment using an identical regimen. This suggests that multiple treatments are required to obtain a complete histological response. We have demonstrated the benefits of low light dose, low dose rate topical 5-ALA PDT for nodular MF, but a formal study is needed to confirm our findings.

Erythema gyratum repens, not always a bad omen for patients.

improvement in angioketatoma with ERT, leading to the first demonstration of a-agalsidase efficiency in such dermatological lesions. Mr D., was diagnosed with FD in February 2004 after an ophthalmologic examination for post-traumatic ocular lesion revealing bilateral cornea verticilata. A toxic origin was rapidly excluded and none activity of a-galactosidase A level in leucocyte confirmed FD. First symptoms occurred in childhood with both acroparaesthesia and chronic abdominal pain with diarrhoea. Clinical examination revealed hypohidrosis, hepatomegaly and diffuse scrotal angiokeratomas (Figure 1a). Cardiac echography showed concentric ventricular hypertrophy with decreased ventricular ejection fraction (50%). Renal involvement was limited (creatinine level 70 lmol ⁄ l, proteinuria 1000 mg ⁄ 24 h). Cranial MRI was normal. Results of genomic investigations revealed an a-GAL neomutation (g11047del11 ⁄ Chy). Patient began with agalsidase-b treatment in April 2004, with 1 mg ⁄ kg every 2 weeks. After three infusions, the patient noticed a slight improvement in both hypohydrosis and angiokeratoma lesions. After eight infusions, cardiac function was better and proteinuria declined to 600 mg ⁄ 24 h. After 1-year ERT, dermatological evaluation confirmed the dermatological improvement with diminution of both size and number of scrotal angiokeratoma (Figure 1b), and at the same time, proteinuria decreased to 160 mg ⁄ 24 h. To our knowledge, this is the first case of angiokeratoma improvement with ERT in FD. These dermatological lesions should be regularly monitored in FD to evaluate rapidly and clinically the impact of ERT in vascular lesions of FD.

Kaposi's varicelliform eruption in a patient with pityriasis rubra pilaris (pityriasis rubra pilaris herpeticum)

Editor Kaposi’s varicelliform eruption (KVE) is a distinct cutaneous eruption that arises over a pre-existing dermatosis, and is caused by Herpes simplex virus (HSV) type 1 or type 2 and rarely by Coxsackie A16 virus or vaccine virus. The most common predisposing condition for KVE is atopic dermatitis, but KVE is also described in association with papulosquamous or acantholytic dermatosis. Here, we describe the case of a patient with KVE occurring during the treatment of a pityriasis rubra pilaris (PRP). A 62-year-old woman presented to the dermatology unit with a generalized erythematous scaly descending eruption that has been evolving for 15 days. Medical history was otherwise unremarkable. Physical examination revealed an intense scaly scalp involvement with generalized erythroderma with sparing islands and waxy palmoplantar keratodermia. This clinical appearance and histological inputs (Fig. 1) confirmed the diagnosis of erythrodermic PRP, and the patient was started on UVB-TL01 therapy and 25 mg of acitretin (Soriatane ) per day. After 10 days of treatment, the patient developed a painful, febrile and acute facial eruption with monomorphic, umbilicated and grouped vesiculopustular lesions of the face and upper trunk (Fig. 2). Local sampling using direct immunofluorescence revealed the presence of HSV1, and viroculture confirmed HSV1 infection. A treatment with 3 g of oral valaciclovir (Zelitrex ) per day for 10 days induced complete clinical remission. Kaposi’s varicelliform eruption is traditionally described as an acute and generalized syndrome with an important alteration of clinical status and high fever. KVE usually affects patients suffering from atopic dermatitis, but can develop over several other dermatosis: acantholytic dermatosis (pemphigus, Darier’s disease, Hailey–Hailey, etc.), ichtyosis, mycosis fungoides, acute severe burn injuries and rosacea. Psoriasis and PRP share strikingly similar features so that clinical and histological differential diagnosis of both these entities is difficult to perform. KVE rarely occurs in patients with psoriasis and, to our knowledge, an association of cutaneous HSV widespread infection with PRP has only been described once. Although phototherapy is among treatment options for PRP, it has been reported to aggravate PRP, which may have promoted the infection. Moreover, in our reported case, narrow-band UVB therapy diminished

Localized depigmentation on genital melanosis: a clue for the understanding of vitiligo

dence rate ratio of all age groups analysed. It would appear from the limited data presented that there may be evidence of comorbid disease, associated with metabolic syndrome, detected at an early age in young people with psoriasis. Clearly more work needs to be done in this area. In the interim this provides an opportunity to reinforce healthy lifestyle choices in children in general but particularly those with psoriasis and raises the question of whether we should be monitoring for associated features of metabolic syndrome in this age group.