Background: Previous research has demonstrated genetic and environmental influences on abuse of individual substances, but there is less known about how these factors may influence the co-occurrence of abuse of different illicit drugs.

Our objective is to assess treatment efficacy, safety and pattern of response and recurrence in patients with recurrent high-grade glioma treated with bevacizumab and irinotecan. We reviewed retrospectively 51 patients with recurrent high-grade glioma treated with this combination at the Henry Ford Hermelin Brain Tumor Center from 11/15/2005 to 04/01/2008. The 6-month progression-free survival (PFS) for anaplastic gliomas (AGs) was 78.6 and 63.7% for glioblastoma. The median PFS was 13.4 months for AG and 7.6 months for those with glioblastoma. The overall survival rate (OS) at 6 months was 85.7% for AG and 78.0% for glioblastoma. The 12-month OS was 77.9% for AG and 42.6% for glioblastoma. The median OS time for AGs was not reached and was 11.5 months for those with glioblastoma. Thirty-six out of 51 (70.59%) patients demonstrated partial (32/51) or complete (4/51) radiographic response to treatment and 8/51 (15.69%) remained stable. Of the 38 who demonstrated progression on post-gadolinium studies, 23 showed distant progression with or without local recurrence. Seven patients showed progression on FLAIR without concordant findings on post-Gd sequences. Six patients (11.76%) discontinued treatment due to a treatment-emergent adverse event, including one with end-stage renal failure and another with gastric perforation. No symptomatic intracranial hemorrhages were reported. Patients with recurrent high-grade glioma treated with bevacizumab plus irinotecan demonstrate an excellent radiographic response rate and improved clinical outcome when compared to historical data. The high rate of distant tumor progression suggests that tumors may adapt to inhibition of angiogenesis by increased infiltration and vascular co-option.

Retinal pigment epithelium-specific protein 65 kDa (RPE65) is a protein responsible for isomerization of all-trans-retinaldehyde to its photoactive 11-cis-retinaldehyde and is essential for the visual cycle. RPE65 mutations can cause severe, early onset retinal diseases such as Leber congenital amaurosis (LCA). A naturally occurring rodent model of LCA with a recessive nonsense Rpe65 mutation, the rd12 mouse, displays a profoundly diminished rod electroretinogram (ERG), an absence of 11-cis-retinaldehyde and rhodopsin, an overaccumulation of retinyl esters in retinal pigmented epithelial (RPE) cells, and photoreceptor degeneration. rd12 mice were injected subretinally at postnatal day 14 with rAAV5-CBA-hRPE65 vector. RPE65 expression was found over large areas of RPE soon after treatment. This led to improved rhodopsin levels with ERG signals restored to near normal. Retinyl ester levels were maintained at near normal, and fundus and retinal morphology remained normal. All parameters of restored retinal health remained stable for at least 7 months. The Morris water maze behavioral test was modified to test rod function under very dim light; rd12 mice treated in one eye performed similar to normally sighted C57BL/6J mice, while untreated rd12 mice performed very poorly, demonstrating that gene therapy can restore normal vision-dependent behavior in a congenitally blind animal.

The virulence plasmids of Salmonella typhimurium and other invasive Salmonella serovars have long been associated with the ability of these bacteria to cause systemic infection beyond the intestines in orally inoculated animals. Genetic analysis of virulence genes on the high-molecular-weight plasmids has revealed that no more than five genes spanning a 6.2-kb region are sufficient to replace the entire plasmid for conferring virulence. However, the exact virulence function(s) encoded by these genes has not been elucidated. In this report, we measured the possible effect of the virulence plasmid on the growth rate of S. typhimurium in mice by two complementary procedures. The first procedure used segregation of a temperature-sensitive plasmid in vivo to provide a measure of bacterial divisions and the number of recovered marker plasmid-containing salmonellae as a measure of killing. In the second procedure, aroA deletions were transduced into virulence plasmidcontaining and plasmid-cured S. typhimurium. Since AroA-salmonellae are inhibited for growth in vivo, if the virulence plasmid affected only growth rate, no difference in the recoveries of the paired AroA-strains would be seen. Virulence plasmid-containing S. typhimurium segregated the marker plasmid more rapidly than did the virulence plasmid-cured strain, and AroA-derivatives of both strains were recovered equally from mice. Therefore, the S. typhimurium virulence plasmid increased growth rate but had no detectable effect on killing or bacterial movement into deep tissues. To examine whether the plasmid accomplished this function by