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MEDNIK syndrome-acronym for mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia-is caused by AP1S1 gene mutations, encoding σ1A, the small subunit of the adaptor protein 1 complex, which plays a crucial role in clathrin coat assembly and mediates trafficking between trans-Golgi network, endosomes and the plasma membrane. MEDNIK syndrome was first reported in a few French-Canadian families sharing common ancestors, presenting a complex neurocutaneous phenotype, but its pathogenesis is not completely understood. A Sephardic-Jewish patient, carrying a new AP1S1 homozygous mutation, showed severe perturbations of copper metabolism with hypocupremia, hypoceruloplasminemia and liver copper accumulation, along with intrahepatic cholestasis. Zinc acetate treatment strikingly improved clinical conditions, as well as liver copper and bile-acid overload. We evaluated copper-related metabolites and liver function retrospectively in the original French-Canadian patient series. Intracellular copper metabolism and subcellular localization and function of copper pump ATP7A were investigated in patient fibroblasts. Copper metabolism perturbation and hepatopathy were confirmed in all patients. Studies in mutant fibroblasts showed abnormal copper incorporation and retention, reduced expression of copper-dependent enzymes cytochrome-c-oxidase and Cu/Zn superoxide dismutase, and aberrant intracellular trafficking of Menkes protein ATP7A, which normalized after rescue experiments expressing wild-type AP1S1 gene. We solved the pathogenetic mechanism of MEDNIK syndrome, demonstrating that AP1S1 regulates intracellular copper machinery mediated by copper-pump proteins. This multisystem disease is characterized by a unique picture, combining clinical and biochemical signs of both Menkes and Wilson's diseases, in which liver copper overload is treatable by zinc acetate therapy, and can now be listed as a copper metabolism defect in humans. Our results may also contribute to understand the mechanism(s) of intracellular trafficking of copper pumps.

Background: Acne vulgaris is an extremely common skin disorder that can be treated effectively with drugs that are currently available. Poor compliance, however, is a major factor in the high failure rates seen in acne treatment. Compliance might be enhanced by considering patient preferences for acne medications. Conjoint analysis is well suited for the study of patient preferences in healthcare, but is novel to the field of dermatology., Objectives: The study aimed to determine and compare patient preferences for four topical antibiotics used for 1 week, once or twice daily, to treat acne vulgaris., Methods: A randomised, phase IV, single-centre, cross-over study was performed using conjoint analysis and a traditional patient questionnaire. Over 4 weeks, the patients used each of four topical antibiotics for 1 week: erythromycin/zinc solution, clindamycin phosphate lotion, benzoyl peroxide (BP)/erythromycin gel (each applied twice daily) and clindamycin phosphate gel (applied once daily). The conjoint analysis examined five different attributes of acne medications: form, storage, product life once opened, method of application and regimen (each with two or three possible options). From 108 possible permutations of the five attributes, 16 hypothetical medications were selected at random and described on printed cards. Pre- and post-treatment, the patients ranked the cards in order of preference and rated each hypothetical product based on their likelihood to use it. For each patient, product 'utilities' were then calculated by multiple regression. The patients also completed a patient acceptability questionnaire, by which they rated the product acceptability after 1 week of treatment with each of the four topical antibiotics. The patients later ranked the medications in order of preference after using all four treatments. Adverse events were recorded in diary cards to assess tolerability., Results: Of 67 patients recruited, 64 used all four medications and completed the study. The conjoint analysis found that a gel formulation, room temperature storage, product life of up to 18 months once opened, application with fingers and once-daily regimen were the options ranked first for the five product attributes. According to the ranking order (out of 108) for the combination of attributes representing the four study medications, clindamycin phosphate gel had the highest rankings (6 and 1 pre- and post-treatment, respectively) and BP/erythromycin gel had the lowest rankings (93 and 70 pre- and post-treatment). The rankings of clindamycin phosphate lotion and erythromycin/zinc solution worsened from pre- to post-treatment, indicating a shift in patient preference after they experienced products 'in-use' during the study. Based on the questionnaire, clindamycin phosphate gel was liked best by the highest proportion of patients (33%). In terms of overall satisfaction, the order of preference was: (i) clindamycin phosphate gel, (ii) clindamycin phosphate lotion, (iii) BP/erythromycin gel and (iv) erythromycin/zinc solution. Adverse events related to medication occurred most frequently with erythromycin/zinc solution and BP/erythromycin gel. Clindamycin phosphate gel was the only product not associated with any episodes resulting in a change of medication or dose., Conclusions: Conjoint analysis provided a convenient, reliable tool for assessing patient preferences for topical antibiotics used to treat acne. The patients clearly preferred a gel formulation that could be applied with the fingers once daily and stored at room temperature for as long as 18 months. One product (clindamycin phosphate gel) combined all five of the preferred attributes, a preference confirmed by the simulated product rankings. These findings of the conjoint analysis are consistent with the safety profiles and the results of the traditional questionnaire.

Two clinical trials were conducted, one involving 273 subjects with experimental rhinovirus colds and the other involving 281 subjects with natural colds. Symptomatic volunteers were randomized to receive oral lozenges containing zinc gluconate (13.3 mg), zinc acetate (5 or 11.5 mg), or placebo. The median duration of illness in zinc gluconate recipients was 2.5 days, contrasted with 3.5 days in the placebo recipients (P=.035), in the experimental colds study. Zinc gluconate had no effect on symptom severity and zinc acetate had no effect on either duration or severity. Neither formulation had an effect on the duration or severity of natural cold symptoms. Evaluation of blinding, taste, and adverse events revealed no significant differences among the 4 treatment arms. Zinc compounds appear to have little utility for common-cold treatment.