The transition metals nickel (Ni), chromium (Cr) and cobalt (Co) are common causes of allergic contact dermatitis (ACD). Given the high frequency with which these allergens can be associated with hand eczema in those responsible for domestic work, it has been suggested that contamination of household consumer products with these metals may be of relevance to the causation/chronicity of hand dermatitis. Dose-response studies using 48 h occlusive patch test conditions in sensitized individuals show that !90% of sensitized patients fail to react below 1 p.p.m., even on irritated skin. Assessment under more realistic exposure conditions has shown that in the presence of irritants and/ or following repeated exposures, such individuals rarely react to levels below 10 p.p.m. On the basis of this information, it was recommended a decade ago that household (and other consumer) products should not contain more than 5 p.p.m. of each of Ni, Cr or Co and that, for an even greater degree of protection, the ultimate target level should be 1 p.p.m. The data generated since the original recommendations were made serve to reinforce the validity of these recommendations. Indeed, it is our view that typically the level of each of these transition metals should not normally exceed 1 p.p.m. Then, where consumer products meet this guideline fully, modern quantitative risk assessment shows clearly that elicitation of ACD is highly improbable, and the chance of the induction of sensitization is even lower. Some 10 years ago, the possibility that traces of the allergenic transition metals, nickel (Ni), chromium (Cr) and cobalt (Co), present as contaminants in household products might give rise to allergic contact dermatitis (ACD) was raised (1, 2) and then extensively reviewed (3). At that time, it was concluded that the risk of the induction of sensitization was negligible and the risk of elicitation in presensitized individuals was acceptably low, as long as the level of contamination was kept to very low levels: 'It is recommended that, for consumer products, current good practice which ensures Ni, Co and Cr contamination is less than 5 p.p.m. of each metal is an acceptable standard. To minimize the risk for very sensitive individuals (4), and when and where standardized analytical techniques permit, it is recommended that the ultimate target should be not more than 1 p.p.m. of each metal in consumer products.'Since that publication, several new pieces of information have become available. Firstly, an interlaboratory study in Italy of housewives' eczema showed no relationship of this disease to transition metal allergy (5, 6). In addition, new dose-response data which aid our understanding of elicitation thresholds in sensitized individuals have been published and have further information on the levels of product contamination with additional commentary on the possibility that trace levels of Ni, Cr and Co might play a role in ACD (and in particular in the chronicity of some hand eczemas) has been presented. Finally, now there are sop...

To record the profile of toxic effects of polyethylene glycol-coated liposomal doxorubicin hydrochloride (Doxil) to the skin, and to evaluate whether the long circulation pattern and enhanced accumulation of liposomes in specific skin sites will result in any unique presentations.Design: Patients were accrued in the frame of doserange-finding studies that examine the toxic effects and antitumor activity of Doxil therapy in metastatic breast and prostate cancers. All patients receiving Doxil were instructed to report any skin eruption or discomfort. Skin examination was performed on a regular basis at every cycle of Doxil therapy and after specific complaints.Setting: Outpatient day care unit of the oncology institute of a secondary-referral medical center.Patients: Sixty patients (45 women and 15 men). Main Outcome Measures:A basic severity scale of I through IV was adopted for toxic effects to the skin, based on National Cancer Institute common toxicity criteria. Results:The following 4 patterns of skin eruptions were encountered: hand-foot syndrome (n=24), diffuse follicular rash (n=6), intertrigolike eruption (n=5), and new formation of melanotic macules (n=3). Another major toxic effect of Doxil was stomatitis, which was found to be the dose-limiting factor for the maximal single dose. Alopecia and extravasation injuries did not occur. Conclusions:The profile of toxic effects of Doxil to the skin reflects its unique pharmacokinetics and tissue distribution. These skin reactions vary significantly from those associated with doxorubicin in non-liposomeencapsulated form.

The controls of human keratin expression in situ remain to be fully elucidated. Here, we have investigated the effects of the neurohormone prolactin (PRL) on keratin expression in a physiologically and clinically relevant test system: organ-cultured normal human hair follicles (HFs). Not only do HFs express a wide range of keratins, but they are also a source and target of PRL. Microarray analysis revealed that PRL differentially regulated a defined subset of keratins and keratin-associated proteins. Quantitative immunohistomorphometry and quantitative PCR confirmed that PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. PRL also up-regulated K15 promoter activity and K15 protein expression in situ, whereas it inhibited K6 and K31 expression. These regulatory effects were reversed by a pure competitive PRL receptor antagonist. Antagonist alone also modulated keratin expression, suggesting that "tonic stimulation" by endogenous PRL is required for normal expression levels of selected keratins. Therefore, our study identifies PRL as a major, clinically relevant, novel neuroendocrine regulator of both human keratin expression and human epithelial stem cell biology in situ.

Maggot therapy is a relatively rapid and effective treatment, particularly in large necrotic wounds requiring debridement and resistant to conventional treatment and conservative surgical intervention.

In order to obtain a comprehensive picture of the molecular events regulating cutaneous photodamage of intact human epidermis, suction blister roofs obtained after a single dose of in vivo ultraviolet (UV)B exposure were used for microarray profiling. We found a changed expression of 619 genes. Half of the UVB-regulated genes had returned to pre-exposure baseline levels at 72 h, underscoring the transient character of the molecular cutaneous UVB response. Of special interest was our finding that several of the central p53 target genes remained unaffected following UVB exposure in spite of p53 protein accumulation. We next compared the in vivo expression profiles of epidermal sheets to that of cultured human epidermal keratinocytes exposed to UVB in vitro. We found 1931 genes that differed in their expression profiles between the two groups. The expression profile in intact epidemis was geared mainly towards DNA repair, whereas cultured keratinocytes responded predominantly by activating genes associated with cell-cycle arrest and apoptosis. These differences in expression profiles might reflect differences between mature differentiating keratinocytes in the suprabasal epidermal layers versus exponentially proliferating keratinocytes in cell culture. Our findings show that extreme care should be taken when extrapolating from findings based on keratinocyte cultures to changes in intact epidermis.

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Monilethrix is a structural defect of the hair shaft usually inherited in an autosomal dominant fashion and caused by mutations in the hHb1, hHb3, and hHb6 keratin genes. Autosomal recessive inheritance in this disease has been sporadically reported. We encountered 12 Jewish families from Iraq, Iran, and Morocco with microscopic findings of monilethrix, but with no evidence of vertical transmission. Since no mutations were found in these three hair keratin genes, we examined nine chromosomal regions containing gene clusters encoding skin and hair genes. On chromosome 18q, a common haplotype in the homozygous state was found among all seven Iraqi patients, but not in 20 controls (P<0.0001). Sequencing of the main candidate gene from this region revealed four different mutations in desmoglein 4 (DSG4). Mutations in DSG4 have been previously reported in localized autosomal recessive hypotrichosis, a disorder that shares the clinical features of monilethrix but lacks the characteristic microscopic appearance of the hair shaft. Our findings have important implications for genetic counseling to monilethrix patients and families, and suggest that DSG4-associated hair disorders may be more common than previously thought.

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