Neural pathways between sexually dimorphic forebrain regions develop under the influence of sex steroid hormones during the perinatal period, but how these hormones specify precise sexspecific patterns of connectivity is unknown. A heterochronic coculture system was used to demonstrate that sex steroid hormones direct development of a sexually dimorphic limbichypothalamic neural pathway through a target-dependent mechanism. Explants of the principal nucleus of the bed nuclei of the stria terminalis (BSTp) extend neurites toward explants of the anteroventral periventricular nucleus (AVPV) derived from male but not female rats. Coculture of BSTp explants from male rats with AVPV explants derived from females treated in vivo with testosterone for 9 d resulted in a high density of neurites extending from the BSTp to the AVPV explant, as was the case when the BSTp explants were derived from females and the AVPV explants were derived from males or androgen-treated females. These in vitro findings suggest that during the postnatal period testosterone induces a target-derived, diffusible chemotropic activity that results in a sexually dimorphic pattern of connectivity. Key words: sexual differentiation; axonal guidance; anteroventral periventricular nucleus; bed nucleus of the stria terminalis; coculture; preoptic regionForebrain neural pathways that control reproduction are different in male and female mammals and show considerable plasticity throughout life. Despite the adaptive significance of developmental processes that promote reproduction, little is known about the underlying mechanisms controlling development of the sexually dimorphic forebrain circuits mediating gonadotropin secretion and copulatory behavior. It is well established that the high levels of testosterone present in neonatal males exert a powerful influence on neuronal survival and development of connectivity (Raisman and Field, 1971;Arai, 1981;Arnold and Gorski, 1984;Arnold and Jordan, 1988;Simerly, 1999;Toran-Allerand et al., 1999). However, because there is a great deal of interconnectivity between sexually dimorphic nuclei that express high levels of sex steroid receptors during development, it is difficult to identify the sites of action for testosterone in determining sex-specific patterns of forebrain neural circuitry. Thus, it is unknown whether testosterone acts directly on projection neurons in sexually dimorphic nuclei to promote extension of growth cones and branching of axons or directs development of dimorphic patterns of connectivity by inducing expression of target-derived factors that preferentially guide axons to their targets.To more clearly define the mechanisms that govern development of sexually dimorphic pathways, we focused our attention on a sexually dimorphic, limbic-hypothalamic pathway in the rodent forebrain that has several unique features. The projection from the principal nucleus of the bed nuclei of the stria terminalis (BSTp) to the anteroventral periventricular nucleus of the preoptic region (AVPV) is the most rob...

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The activities of four newly synthesized benzoxazinorifamycin derivatives, either alone or in combination with ofloxacin, against strains of Mycobacterium leprae were determined by assessing their effects on two biochemical parameters of metabolic activity which served as surrogate markers for growth in vitro. KRM-1648 and KRM-2312 were the most active agents tested against both a rifampicin-susceptible isolate (MICs of 0.05 and 0.1 mg/L respectively) and a rifampicin-resistant isolate (MICs of 0.2 and 0.3 mg/L respectively); both compounds were more active than either rifampicin or rifabutin. The activities of the two other derivatives, KRM-1657 and KRM-1668, against a rifampicin- susceptible strain (MICs of 0.3 mg/L) were similar to that of rifampicin, while the MIC of each of these agents for the rifampicin-resistant strain was 1.0mg/L. In common with rifabutin, both of the more active derivatives demonstrated synergy with ofloxacin against the rifampicin-susceptible isolates. The results of this study suggest that these compounds, in combination with ofloxacin as part of multidrug regimens, warrant further evaluation as treatment for patients with leprosy.

The efficacy of three fluorinated quinolones, clinafloxacin (PD 127391), sparfloxacin (PD 131501) and PD 131628, either alone or in combination with rifampicin/rifabutin, against Mycobacterium leprae was evaluated in vitro using two biochemical parameters to measure the metabolic activity of the organism. Clinafloxacin was found to be most effective with an MIC of 0.75 mg/L, followed by sparfloxacin (MIC 1.5 mg/L) and PD131628 (MIC 3.0 mg/L). When combined with rifampicin each of the three quinolones were additive to the activity. However, when combined with rifabutin, both clinafloxacin and sparfloxacin demonstrated pronounced synergic activity. Incorporation of clinafloxacin and rifabutin in a multi-drug therapy regimen is suggested.