Role of 'platelet-type' 12-lipoxygenase in skin carcinogenesis.

Murine and human skin express an abundance of lipoxygenase isoforms whose functions are not understood. Substantial data have implicated a role for the 'platelet-type' 12-lipoxygenase (P-12LO) metabolite, 12(S)-hydroxy-eicosatetraenoic acid (12-HETE), in a variety of tumor functions. Using P-12LO deficient mice, we sought to examine the role of the P-12LO pathway in tumor initiation and progression. Two distinct genetic strains of P-12LO deficient and wild-type mice, B6/129 Sv and SENCAR, were evaluated in two-stage carcinogenesis experiments. Carcinoma incidence was significantly reduced in the P-12LO deficient mice of the B6/129 Sv background but not the SENCAR-backcrossed mice. In contrast, papilloma incidence was reduced on the SENCAR background but not in the B6/129 Sv strain mice. A separate experiment employing a complete carcinogenesis protocol failed to find any difference in papilloma or carcinoma incidence. Overall, these data suggest that the P-12LO pathway may contribute to tumor incidence and progression in two-stage, but not complete, carcinogenesis, depending on the genetic background.

Basal transepidermal water loss is increased in platelet-type 12-lipoxygenase deficient mice.

The roles of fatty acids in the skin have been under investigation since early reports of the phenotypic abnormalities of mice fed a diet deficient in essential fatty acids. Little is known about the functional significance of fatty acid metabolism by lipoxygenases in epidermis. Here, we have examined the role of platelet-type 12-lipoxygenase which converts arachidonic acid to the oxygenated metabolite 12-hydroperoxyeicosatetraenoic acid, in the skin using platelet-type 12-lipoxygenase-deficient mice generated by gene targeting. Platelet-type 12-lipoxygenase in wild-type mice was localized to the stratum granulosum by immunohistochemical analysis. Platelet-type 12-lipoxygenase-deficient mice lacked immunodetectable platelet-type 12-lipoxygenase in platelets and epidermis, appeared grossly normal, and exhibited an increase in basal transepidermal water loss without alteration in basal mitotic activity. Water loss and mitotic activity in mice with an acetone-disrupted membrane barrier were normal. No defect in ultrastructural properties or content of major fatty acids in dorsal skin or ear inflammation response was apparent in platelet-type 12-lipoxygenase-deficient mice. These results indicate that the platelet-type 12-lipoxygenase pathway in mice is partly responsible for normal permeability barrier function but the mechanism awaits further elucidation.

Differential expression of alpha- and beta-thyroid hormone receptor genes in the developing rat brain under hypothyroidism.

One of the most alarming observations of iodine deficiency disorders (IDD) is neurological cretinism which is caused due to lack of T3 during the crucial stages of brain development. We have developed an iodine-deficient rat model to study the pattern of T3 receptor genes expression in the brain during postnatal development under iodine deficiency. We observed increased expression of c-erbA-alpha 2 and -beta 1 T3 receptor transcripts while c-erbA-alpha 1 remains unchanged in the brain of the iodine-deficient neonates compared with their euthyroid counterparts. Up-regulation of the beta 1 form in the developing brain under iodine deficiency is suggestive of an adaptive process coming into play to protect it from the damages that are inflicted due to hypothyroidism. Though the significance of the increased alpha 2 form in the iodine-deficient rat brain has not yet been ascertained, it can be conjectured that it acts as a homeostatic control over 'functional receptor' (namely beta 1) under developmental hypothyroidism.

Relationship of advance directives to physician-patient communication.

BACKGROUND: Although advance medical directives, such as living wills and durable powers of attorney for health care, are by themselves imperfect instruments for expressing patients' treatment preferences, a possible benefit of these documents is that they will enhance patient-physician communication, especially when end-of-life treatment decisions have to be made. METHOD: Structured interviews were completed for 115 seriously ill cancer patients and 22 of their physicians. The questions dealt with various aspects of advance directives, including communications between the two parties regarding general and specific treatment wishes. Responses were compared in 37 physician-patient pairs for patients who had executed advance directives and in 31 physician-patient pairs for patients who had not executed advance directives. RESULTS: Physicians were frequently unaware of their patients' advance directives. Although patients with advance directives were marginally more likely than patients without advance directives to report discussions about end-of-life treatment decisions, only 34 (30%) out of the total of 115 patients claimed that they had any discussion of treatment decisions with their physicians. Such discussions tended to be about general life attitudes and feelings rather than specific treatments, such as use of artificial nutrition or ventilation. CONCLUSION: Despite public enthusiasm for the use of advance directives and great efforts to promote them, we found little evidence that these documents are associated with enhanced communication between patients and physicians about end-of-life treatment decisions.