RESUMEN
Vasomotor thermo-dysregulation (hot flashes) are an often debilitating symptom of menopause. Effective treatment is achieved primarily through activation of the estrogen receptor (ER)α with estrogens but is also associated with increased risk for breast and uterine cancer. In this study, we have tested novel compounds lacking the B ring of 17-hydroxy-ß-estradiol (E2) (A-CD compounds) with differing ratios of ERα:ERß binding affinities for the ability to reduce diurnal/nocturnal tail-skin temperatures (TSTs) in the ovariectomized female rat menopausal hot flash model. Normal mammary tissue expresses the predominantly antiproliferative ERß. Therefore, we hypothesized that a preferential ERß agonist with fractional ERα activity would safely reduce TSTs. The A-CD compound, L17, is a preferential ERß agonist that has a ratio of ERß:ERα binding affinity relative to E2 of 9.3 (where ERß:ERα for E2, 1.0). In the ovariectomized rat, daily administration of low doses (1 mg/kg) of the A-CD compound TD81 (ERα:ERß relative affinity, 15.2) was ineffective in temperature regulation, whereas L17 showed a trend toward TST reduction. Both E2 and the A-CD compound, TD3 (ERß:ERα relative affinity, 5.0), also reduced TSTs but had marked proliferative effects on mammary and uterine tissues. At 2 mg/kg, L17 strongly reduced TSTs even more effectively than E2 but, importantly, had only minimal effect on uterine weight and mammary tissues. Both E2- and L17-treated rats showed similar weight reduction over the treatment period. E2 is rapidly metabolized to highly reactive quinones, and we show that L17 has 2-fold greater metabolic stability than E2. Finally, L17 and E2 similarly mediated induction of c-fos expression in neurons within the rat thermoregulatory hypothalamic median preoptic nucleus. Thus, the A-CD compound, L17, may represent a safe and effective approach to the treatment of menopausal hot flashes.
Asunto(s)
Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Menopausia , Modelos Animales , Sistema Vasomotor/fisiología , Adiposidad/efectos de los fármacos , Animales , Unión Competitiva , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Estradiol/química , Estradiol/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor beta de Estrógeno/agonistas , Estrógenos/química , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Sofocos/metabolismo , Sofocos/fisiopatología , Humanos , Inmunohistoquímica , Ligandos , Glándulas Mamarias Humanas/efectos de los fármacos , Glándulas Mamarias Humanas/crecimiento & desarrollo , Glándulas Mamarias Humanas/metabolismo , Estructura Molecular , Ovariectomía , Área Preóptica/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Útero/efectos de los fármacos , Útero/crecimiento & desarrollo , Útero/metabolismo , Sistema Vasomotor/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
A 21-year-old division I collegiate football player who had a history of several stingers presented with 5 days of persistent left neck and shoulder pain associated with paresthesias and upper extremity weakness. His symptoms began immediately during a game when he was struck on the right side of his helmet, which induced a compression-extension mechanism of injury to his neck. Clinical and electrodiagnostic evaluation was consistent with a left C5 radiculopathy, but magnetic resonance imaging of the cervical spine yielded normal results. The mean subaxial cervical space available for the cord (MSCSAC) index is a novel tool to predict chronic stinger syndrome. It is calculated by subtracting the sagittal diameter of the spinal cord from the disc-level sagittal diameter of the spinal canal at levels C3 through C6 and then averaging these values. A cutoff of < 4.3 mm has been shown to predict a greater-than-13-fold increase in risk of developing chronic stinger syndrome. This patient had a MSCSAC index of 3.2 mm, which correlated with his history of multiple stingers. The MSCSAC index may be a useful tool to help counsel athletes on the risk of developing future stingers, although more extensive research on this measurement tool is indicated.
RESUMEN
We have used map-based approaches to clone a locus containing two genes, Avr1b-1 and Avr1b-2, required for avirulence of the oomycete pathogen Phytophthora sojae (Kaufmann & Gerdemann) on soybean plants carrying resistance gene Rps1b. Avr1b-1 was localized to a single 60-kb bacterial artificial chromosome (BAC) clone by fine-structure genetic mapping. Avr1b-1 was localized within the 60-kb region by identification of an mRNA that is expressed in a race-specific and infection-specific manner and that encodes a small secreted protein. When the Avr1b-1 protein was synthesized in the yeast Pichia pastoris and the secreted protein infiltrated into soybean leaves, it triggered a hypersensitive response specifically in host plants carrying the Rps1b resistance gene. This response eventually spread to the entire inoculated plant. In some isolates of P. sojae virulent on Rps1b-containing cultivars, such as P7081 (race 25) and P7076 (race 19), the Avr1b-1 gene had numerous substitution mutations indicative of strong divergent selection. In other isolates, such as P6497 (race 2) and P9073 (race 25), there were no substitutions in Avr1b-1, but Avr1b-1 mRNA did not accumulate. Genetic complementation experiments with P6497 revealed the presence of a second gene, Avr1b-2, required for the accumulation of Avr1b-1 mRNA. Avr1b-2 was genetically mapped to the same BAC contig as Avr1b-1, using a cross between P7064 (race 7) and P6497. The Avr1k gene, required for avirulence on soybean cultivars containing Rps1k, was mapped to the same interval as Avr1b-1.