Background: Two alleles of the mammalian Ras protein acyltransferase are associated with X-linked intellectual disabilities. Results: Mutations of zDHHC9 isolated from XLID patients result in defects to steady state autopalmitoylation levels. Conclusion: Although the zDHHC9 mutations produce similar phenotypes, they are guided by distinct mechanisms. Significance: Elucidation of the catalytic mechanism of PATs is a critical step in designing pharmacological interventions.

Abstract. Local injection of hormones into the tibial epiphyseal growth plate offers a possible model to answer whether sex steroids can affect bone growth directly. To answer this question, we injected different doses of testosterone enanthate (4, 40, 120 and 400 μg/100 g of rat weight) once into the tibial epiphyseal growth plate of castrated 35-day-old male rats. The contralateral tibia was injected with sesame oil and served as control. All animals were sacrificed at age 42 days. Tibias were removed for measurement of epiphyseal growth plate width and blood was collected for measurement of serum IGF-I and testosterone. The lower doses of testosterone enanthate (4, 40 and 120 μg/100 g) did not produce any significant change in epiphyseal growth plate width. Testosterone at the largest dose tested (400 μg/100 g) increased epiphyseal growth plate width by about 15% compared to control (p < 0.01). At this dose, serum testosterone was not increased, suggesting that the effect on epiphyseal growth plate width was not due to higher systemic testosterone concentrations. No differences in IGF-I levels were observed among the groups. We conclude that direct administration of testosterone enanthate at a dose of 400 μg/100 g into the rat tibial epiphyseal growth plate can increase epiphyseal growth plate width.

At least 30-35% of men with erectile dysfunction (ED) fail to respond to treatment with phosphodiesterase type 5 (PDE-5) inhibitors. Testosterone (T) has effects not only on sexual desire, but also on the anatomical and physiological substrate of erection. This study analysed the effects of T administration to men unsuccessfully treated for ED with PDE-5 inhibitors only. Twenty-nine men aged 36-75 years (mean 59 years) with ED were studied. They suffered from ED for a mean of 2.7 years and had subnormal plasma T levels (total T <3.5 ng ml(-1) ). They received parenteral testosterone undecanoate for 102 weeks. Changes of the domains of the International Index of Erectile Function (IIEF) were assessed. After 6 weeks of T treatment, the sexual desire domain of IIEF had improved (from 4.1 ± 1.4 to 7.2 ± 1.7) and erectile function as measured by IIEF started to improve, reaching a plateau after 30 weeks (from 9.1 ± 2.1 to 26.5 ± 2.3). Features of the metabolic syndrome also improved. There were no adverse effects of T administration. Addition of T to treatment of hypogonadal men unsuccessfully treated with PDE-5 inhibitors only, appeared useful and acceptably safe.

Advancements in treatment for the rare genetic disorder known as Alagille Syndrome (ALGS) have been regrettably slow. The large variety of mutations to the JAG1 and NOTCH2 genes which lead to ALGS pose a unique challenge for developing targeted treatments. Due to the central role of the Notch signaling pathway in several cancers, traditional treatment modalities which compensate for the loss in activity caused by mutation are rightly excluded. Unfortunately, current treatment plans for ALGS focus on relieving symptoms of the disorder and do not address the underlying causes of disease. Here we review several of the current and potential key technologies and strategies which may yield a significant leap in developing targeted therapies for this disorder.