Kenneth H. Neldner

Selenium compounds have disparate abilities to impose oxidative stress and induce apoptosis.

The cancer chemopreventive effect of selenium cannot be fully accounted for by the role of selenium as a component of the antioxidant enzyme glutathione peroxidase, which suggests that chemoprevention occurs by another mechanism. Several studies have shown that thiol oxidation and free radical generation occur as a consequence of selenium catalysis and toxicity. In the present study, we evaluated three different selenium compounds; selenite, selenocystamine, and selenomethionine to determine the relative importance of the prooxidative effects of these compounds with regard to their ability to induce apoptosis. The experimental results suggest that, in addition to supporting an increased activity of glutathione peroxidase, an antioxidant function that the three selenium compounds did with equal efficacy, catalytic selenite, and selenocystamine generated 8-hydroxydeoxyguanosine DNA adducts, induced apoptosis and were found to be cytotoxic in mouse keratinocytes. The noncatalytic selenomethionine was not cytotoxic, did not generate 8-hydroxydeoxyguanosine adducts and did not induce cellular apoptosis at any of the selenium concentrations studied. In keratinocytes, apoptosis may be initiated by superoxide (O2*-) and oxidative free radicals that are generated by selenite and selenocystamine, but not by selenomethionine.

Classification of pseudoxanthoma elasticum: Report of a consensus conference

Pseudoxanthoma elasticum (PXE) is inherited through both autosomal recessive and autosomal dominant pathways. The seminal pathophysiologic event is an aberrant calcification of elastic fibers in the skin, retina, and cardiovascular systems. Characteristicclinical pathologic events occurin eachof these areasas thedisorderprogresses throughout the lifetime of an affected person. The disorder is also characterized by marked clinical heterogeneity. In 1975, PopeI postulated, on the basis of a Britishstudyof 120patients,the existenceoftwodistinct autosomaldominantand twodistinctautosomal recessive phenotypes. Autosomal dominant inheritance was found in approximately 50% of the patients. Sincethen,Neldner.i onthe basisofa 20-year study of 100 patients in the United States, has reported that 90% of his patients appear to have an autosomal recessive inheritance pattern and that it was impossible to separate the group into subtypes based on the phenotype. In brief, with time all patients tend to merge into a single classic phenotype involving the skin, eyes, and cardiovascular system, but with considerable variation in expression of the disorder. The description ofpatients withocularandhistopathologicmanifestations of PXE in the absence of

Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum

Abstract. We recently published the precise chromosomal localization on chromosome 16p13.1 of the genetic defect underlying pseudoxanthoma elasticum (PXE), an inherited disorder characterized by progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Here we report the identification of mutations in the gene encoding the transmembrane transporter protein, ABC-C6 (also known as MRP-6), one of the four genes located in the region of linkage, as cause of the disease. Sequence analysis in four independent consanguineous families from Switzerland, Mexico, and South Africa and in one non-consanguineous family from the United States demonstrated several different mis-sense mutations to cosegregate with the disease phenotype. These findings are consistent with the conclusion that PXE is a recessive disorder that displays allelic heterogeneity, which may explain the considerable phenotypic variance characteristic of the disorder.

The effects of chronic sunscreen use on the histologic changes of dermatoheliosis

BACKGROUND Sunscreen application to the skin of hairless mice is effective in reversing the histologic changes associated with photoaging (solar elastosis, epidermal thickening, collagen depletion, glycosaminoglycan deposition). These reparative processes have not been studied in human beings. OBJECTIVE The aim of this study was to evaluate histologically the effects of daily application of a UVA/UVB sunscreen versus placebo. METHODS We examined 46 patients who were given either sunscreen or vehicle and asked to apply it daily for 24 months. Punch biopsy specimens were obtained from preauricular skin at 0, 12, and 24 months. Each specimen was examined for epidermal thickening and organization and dermal inflammatory infiltrate by light microscopy. Computer-generated analysis of tissue sections was used to evaluate solar elastosis. RESULTS A significant difference in solar elastosis was found between the treatment groups; however, the other features remained largely unchanged. CONCLUSION The dermal changes of photoaging may be affected differently than epidermal changes when UV radiation exposure is diminished. UVA and UVB may contribute diversely to these cutaneous changes. Computer-generated evaluation of dermatoheliosis may be more accurate than visual inspection.

Contact immunotherapy of resistant warts

Contact immunotherapy has been proved effective in the treatment of resistant warts. This report chronicles our experience with a new contact immunotherapy agent, diphenylcyclopropenone. We have achieved a cure rate of 62% in 45 patients with resistant warts of all types who came to our general dermatology clinic. Cure rates may be lower in patients who have experienced multiple treatment failures. The majority of cures were obtained within 3 to 4 months. Although it appears somewhat less effective than published reports of dinitrochlorobenzene contact immunotherapy, diphenylcyclopropenone contact immunotherapy is an effective treatment for resistant warts and avoids any potential problems from mutagenicity.

A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene : implications for mutation analysis in pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is an inherited disorder of the elastic tissue with characteristic progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Recently mutations in the ABCC6 gene, encoding a transmembrane transporter protein, were identified as cause of the disease. Surprisingly, sequence and RFLP analysis for exon 9 with primers corresponding to flanking intronic sequence in diseased and haplotype negative members from all of our families and in a control population revealed either a homozygous or heterozygous state for the Q378X (1132C→T) nonsense mutation in all individuals. With the publication of the genomic structure of the PXE locus we had identified the starting point of a large genomic segmental duplication within the locus in the cytogenetic interval defined by the Cy19 and Cy185 somatic cell hybrid breakpoints on chromosome 16p13.1. By means of somatic cell hybrid mapping we located this starting point telomeric to exon 10 of ABCC6. The duplication, however, does not include exon 10, but exons 1–9. These findings suggest that one or several copies of an ABCC6 pseudogene (ψABCC6) lie within this large segmental duplication. At least one copy contains exons 1–9 and maps to the chromosomal interval defined by the Cy163 and Cy11 breakpoints. Either this copy and/or an additional copy of ψABCC6 within Cy19-Cy183 carries the Q378X mutation that masks the correct identification of this nonsense mutation as being causative in pseudoxanthoma elasticum. Long-range PCR of exon 9 starting from sequence outside the genomic replication circumvents interference from the ψABCC6 DNA sequences and demonstrates that the Q378X mutation in the ABCC6 gene is associated with PXE in some families. These findings lead us to propose that gene conversion mechanisms from ψABCC6 to ABCC6 play a functional role in mutations causing PXE.

Malignant Melanoma Presenting As Nasal Obstruction

Mucosal melanomas arising in the nasal cavity are rare tumors comprising less than 1 percent of all melanomas. Often, the common clinical symptom is nasal obstruction. Grossly, they may or may not be pigmented and frequently attain large sizes. Histologic diagnosis of these tumors may be difficult, requiring immunohistochemical or electron microscopic confirmation. Aggressive surgical management is the treatment of choice in clinical stage I disease. Subsequent surveillance for recurrence is mandatory. Markers such as 5-S-cysteinyldopa may prove useful in staging, prognosticating, and postoperative surveillance for early recurrence, but their exact role has yet to be delineated. Ultimate prognosis is poor.