Emeritus Faculty, Acad Council, Dermatology
Biology of the keratinocyte in inherited blistering diseases.
1. Studies include cytokine production and production of cytokine receptor antagonists (IL-1Ra)
2. Keratinocytes produce metalloproteinases in response to cytokines. These responses in keratinocytes from normal and diseases skin are studied at the protein level by zymography and at the mRNA level by RT PCR.
3. An uncommon recessively inherited blistering disease associated with premature aging of the skin is the subject of linkage studies in two U.S. families and 5 Egyptian families. These linkages studies do no show linkage to either Type I and Type II keratins. Keratinocytes from these subjects show enhanced sensitivity to UV-C.
We report a woman with recessive dystrophic epidermolysis bullosa (RDEB) in whom there was prolonged sepsis and death at age 22 years. Autopsy revealed multiple epidermolytic skin lesions with chronic ulceration, mesangioproliferative glomerulonephritis and multifocal necrotizing leucoencephalopathy (MNL) of the pons. The latter two conditions may have been mediated by sepsis-associated cytokines. Although mesangioproliferative glomerulonephritis has previously been described in association with RDEB, to our knowledge this is the first report of MNL in a patient with RDEB.
View details for DOI 10.1111/j.1365-2133.2004.06267.x
View details for Web of Science ID 000225628700021
View details for PubMedID 15606525
Calciphylaxis is a rare phenomenon of cutaneous necrosis that typically occurs in association with renal failure and has a poor prognosis. We report 5 new cases of calciphylaxis that illustrate the important clinical and histopathologic features of the disease. All patients had end-stage renal failure at the time that purpuric plaques and nodules were noted; these subsequently progressed to necrotic ulcers with eschars. All skin biopsy specimens showed varying degrees of calcification of the medial layer of blood vessel walls in the dermis and subcutaneous fat. Neither the product of serum calcium and phosphorus concentrations nor parathyroid hormone levels correlated temporally with the clinical observations in every case, emphasizing the importance of clinical-histopathologic correlation. Although certain features of calciphylaxis in humans resemble the animal model originally proposed, there are also some crucial differences. We review the pathogenesis, epidemiology, clinical and histopathologic features, and treatment of this disease.
View details for PubMedID 10365930
Epidermolysis bullosa (EB) is a group of heritable diseases that manifest as blistering and erosions of the skin and mucous membranes. In the dystrophic forms of EB (DEB), the diagnostic hallmark is abnormalities in the anchoring fibrils, attachment structures beneath the cutaneous basement membrane zone. The major component of anchoring fibrils is type VII collagen, and DEB has been linked to the type VII collagen gene (COL7A1) at 3p21, with no evidence for locus heterogeneity. Due to life-threatening complications and significant long-term morbidity associated with the severe, mutilating form of recessive dystrophic EB (RDEB), there has been a demand for prenatal diagnosis from families with affected offspring.Intragenic polymorphisms in COL7A1 and flanking microsatellite markers on chromosome 3p21, as well as detection of pathogenetic mutations in families, were used to perform PCR-based prenatal diagnosis from DNA obtained by chorionic villus sampling at 10-15 weeks or amniocentesis at 12-15 weeks gestation in 10 families at risk for recurrence of RDEB.In nine cases, the fetus was predicted to be normal or a clinically unaffected carrier of a mutation in one allele. These predictions have been validated in nine cases by the birth of a healthy child. In one case, an affected fetus was predicted, and the diagnosis was confirmed by fetal skin biopsy.DNA-based prenatal diagnosis of RDEB offers an early, expedient method of testing which will largely replace the previously available invasive fetal skin biopsy at 18-20 weeks gestation.
View details for Web of Science ID A1996TZ45600008
View details for PubMedID 8900535
This study investigated whether gonadal steroids modulate the expression of the cytokine Interleukin-1 receptor antagonist in monocytes. Human male peripheral monocytes were isolated and cultured in serum free media with serially diluted concentrations of estradiol and progesterone. mRNA expressions with increasing steroid concentrations were compared by reverse transcription-polymerase chain reaction for intracellular and secretory interleukin-1 receptor antagonist specific primers and glyceraldehyde 3-phosphate dehydrogenase primers. Monocyte expression of secretory Interleukin-1 receptor antagonist mRNA was significantly elevated in the presence of normal physiological levels of estradiol (10(-11) M) and progesterone (10(-8) M), while expression was suppressed by higher concentrations of steroids. Intracellular receptor antagonist was also detected. This study is the first to describe the dose related response of cytokine interleukin-1 receptor antagonist to gonadal steroids.
View details for Web of Science ID A1995QQ91400040
View details for PubMedID 7726847