Percutaneous Absorption Of Dexamethasone Estimated By A Plasma Radioimmunoassay

Percutaneous absorption of dexamethasone and its effect on the pituitary adrenal axis were measured in vivo in normal human subjects after application to skin. Specific plasma dexamethasone and cortisol radioimmunoassays were used. Following application of 1% dexamethasone on 500cm2 of normal skin, the plasma dexamethasone concentration was maximal at 2 hr, and the average absorption was 0.25% over 8hr; significant cortisol suppression occurred at 2, 4, and 8hr. This technique: (1) provides an accurate assessment of the in vivo absorption of dexamethasone applied to human skin, (2) avoids exposure of the subjects to radioactive steroids, (3) permits estimation of the quantity of unmetabolized steroids absorbed, and (4) serves as a possible model for the development of similar assays for other topical steroids

Mice Doubly-Deficient in Lysosomal Hexosaminidase A and Neuraminidase 4 Show Epileptic Crises and Rapid Neuronal Loss

Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts GM2 to GM3 ganglioside. Hexa−/− mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise GM2 ganglioside via a lysosomal sialidase into glycolipid GA2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4−/−;Hexa−/−) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa−/− or Neu4−/− siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating GM2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa−/− mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa−/− mice

Increased Levels of Nuclear Androgen Receptors in Hyperplastic Prostate of Aging Men

Several publications indicate the dihydrotestosterone content of hyperplastic prostatic tissue from man and dog is increased. There is limited information concerning an abnormality in the androgen receptor content in this disorder. In men, we determined the androgen receptor concentration in cytosol, nuclei, the nuclear matrix, and nuclease solubilized salt extract fractions from benign prostatic hyperplasia (BPH) and normal prostate. Nine BPH cases (age 61 ± 7, mean ± SD) and seven controls (age 29 ± 10.6) were compared. Prostates were obtained during autopsy performed within 12 h after death and frozen at -70°C until analysis. Four grams of tissue were homogenized and centrifuged for separation of nuclei and cytosol. Androgen receptors were estimated with an improved assay procedure. The androgen receptor content per mg of DNA in whole nuclei and in the salt extract fraction (P \u3c 0.01 and \u3c0.05 respectively) was higher in BPH cases than in controls. Cytosol did not show a significant difference. For both groups, receptors were undetectable in the nuclear matrix. We speculate that increased androgen receptor bound to chromatin of hyperplastic tissue may be causally related to the development of BPH in aging man