bromochloroacetic-acid and Cardiomyopathies

Abnormalities of skin pigmentation are known to be associated sometimes with cardiovascular diseases. Such cases have been reported first in 1954 (14), then in 1962 (16) and 1966 (11), leading to the individualization of the leopard syndrome. In 1973 Rees et al. (21) described a lentiginosis, cardiac myxoma association, and this in turn resulted, in 1985, in a new syndrome (4) supported by several similar findings. We report here a new case with this association.

Topics: Adult; Cardiomyopathies; Epidermis; Heart Atria; Humans; Keratins; Lentigo; Male; Melanocytes; Myxoma; Syndrome

Epidermolysis bullosa simplex (EBS) with cardiomyopathy (EBS-KLHL24) is an EBS subtype caused by dominantly inherited, gain-of-function mutations in the gene encoding for the ubiquitin-ligase KLHL24, which addresses specific proteins to proteasomal degradation. EBS-KLHL24 patients are born with extensive denuded skin areas and skin fragility. Whilst skin fragility rapidly ameliorates, atrophy and scarring develop over time, accompanied by life-threatening cardiomyopathy. To date, pathogenetic mechanisms underlying such a unique disease phenotype are not fully characterized. The basal keratin 14 (K14) has been indicated as a KLHL24 substrate in keratinocytes. However, EBS-KLHL24 pathobiology cannot be determined by the mutation-enhanced disruption of K14 alone, as K14 is similarly expressed in foetal and postnatal epidermis and its protein levels are preserved both in vivo and in vitro disease models. In this study, we focused on foetal keratins as additional KLHL24 substrates. We showed that K7, K8, K17 and K18 protein levels are markedly reduced via proteasome degradation in normal foetal keratinocytes transduced with the mutant KLHL24 protein (ΔN28-KLHL24) as compared to control cells expressing the wild-type form. In addition, heat stress led to keratin network defects and decreased resilience in ΔN28-KLHL24 cells. The KLHL24-mediated degradation of foetal keratins could contribute to congenital skin defects in EBS-KLHL24. Furthermore, we observed that primary keratinocytes from EBS-KLHL24 patients undergo accelerated clonal conversion with reduced colony forming efficiency (CFE) and early replicative senescence. Finally, our findings pointed out a reduced CFE in ΔN28-KLHL24-transduced foetal keratinocytes as compared to controls, suggesting that mutant KLHL24 contributes to patients' keratinocyte clonogenicity impairment.

Topics: Cardiomyopathies; Epidermolysis Bullosa Simplex; Female; Humans; Keratinocytes; Keratins; Mutation; Pregnancy; Proteasome Endopeptidase Complex; Repressor Proteins; Skin Abnormalities

Topics: Animals; Cardiomyopathies; Cell Line, Tumor; Desmin; Desmoplakins; Epidermis; Hair Diseases; HEK293 Cells; Humans; Keratins; Mice; Mice, Knockout; Protein Binding; Protein Domains; Protein Folding; Skin Diseases, Genetic

Squamous cysts and squamous epithelial plaques were observed in a total of seventeen cynomolgus monkeys. Eleven monkeys had squamous cysts, three of them also revealed squamous plaques and six revealed squamous plaques exclusively. At necropsy, cysts were recognized as yellow-white nodules with a smooth surface, that were located superficially along the interventricular septum, on the surface of the left ventricle or the apex of the heart. Microscopically, cysts were lined by a flattened epithelium and filled with keratin. Occasionally the epithelium was multi-layered or replaced by a rim of foreign body-type multinucleated giant cells. All animals with squamous cysts came from Mauritius, while those with squamous plaques came from Mauritius, China and Vietnam. As discussed in man, squamous cysts and plaques in cynomolgus monkeys are considered to represent displaced foregut epithelium, that was sequestered in the dorsal mesocardium prior to closure of the pleuropericardial fold during early embryologic development.

Topics: Animals; Cardiomyopathies; Cysts; Epithelium; Female; Keratins; Macaca fascicularis; Male; Monkey Diseases

Light microscopic, histochemical, immunohistochemical, and ultrastructural methods were used to examine myocardial epithelial masses in the hearts of ten cattle. The tissues consisted of paraffin-embedded or formalin-fixed samples from eight hearts that were being inspected in slaughter houses and from two hearts from calves that died of septicemia. The ages of the cattle ranged from 4 days to 12 years; the breeds were unspecified for all but one Hereford female and the two Holstein calves; and there were three males, four females, and three steers. The masses in these cases were compared with similar appearing lesions found in other animal species. The lesions in the bovine hearts were single to multiple, well circumscribed, found in the left ventricle wall, and composed of squamous to cuboidal epithelial cells that formed tubular, ductular, and acinar structures with lumens that were void or filled with amorphous protein globules. Electron microscopic examination revealed epithelial cells that had sparse apical microvilli, tight apical intercellular junctions, perinuclear bundles of filaments, and rare cilia. Almost half of the bovine epithelial masses (4/9) had occasional diastase-resistant periodic acid-Schiff-positive granules in their cytoplasm, and few had hyaluronidase-resistant alcian blue-positive granules (2/9) or colloidal iron-positive granules (1/9). All myocardial masses had abundant collagen surrounding the tubular and acinar structures, and 2/9 had elastin fibers as well. None of the myocardial masses had Churukian-Schenk or Fontana Masson's silver staining granules in epithelial cells. Immunohistochemically, all bovine myocardial tumors stained positively for cytokeratin (8/8), and occasional masses stained positively for vimentin (3/8) or carcinoembryonic antigen (3/8). None of the masses stained positively for desmin. The myocardial epithelial tumors most likely represent endodermal rests of tissue misplaced during organogenesis.

Topics: Animals; Carcinoembryonic Antigen; Cardiomyopathies; Cattle; Cattle Diseases; Epithelium; Female; Keratins; Male; Microscopy, Electron