Analysis of exposure margins in developmental toxicity studies for detection of human teratogens.

The draft Step 2 ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high-dose in reproductive and developmental toxicity studies. To help determine an appropriate exposure margin for embryofetal developmental toxicity testing, a retrospective analysis was undertaken to determine what threshold would have been sufficient to detect hazards to embryofetal development in rats and rabbits for 18 known and 4 presumed human teratogens. The analysis showed that using a high dose that provided at least a 6-fold exposure margin in the developmental toxicity studies would have been sufficient to detect the teratogenic hazard with relevance for humans for all these therapeutics.

The accuracy of the inferior>superior>nasal>temporal neuroretinal rim area rule for diagnosing glaucomatous optic disc damage.

Purpose: To determine the accuracy with which the optic disc can be diagnosed as normal or glaucomatous according to the ISNT rule, whereby, in the normal eye, the neuroretinal rim area follows the order inferior (I) > superior (S) > nasal (N) > temporal (T).

Design: Prospective, cross-sectional, observational, case series.

Participants: Fifty-one normal individuals and 78 individuals with open-angle glaucoma exhibiting field loss (median mean deviation, -4.

Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome.

Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription.