Increased Incidence of Pseudotumor Cerebri Syndrome Among Users of Tetracycline Antibiotics.

BACKGROUND: To determine whether the use of a tetracycline-class antibiotic is associated with an increased risk of developing pseudotumor cerebri syndrome (PTCS). METHODS: We identified patients in the University of Utah Health system who were prescribed a tetracycline-class antibiotic and determined what percentage of those individuals were subsequently diagnosed with PTCS secondary to tetracycline use. We compared this calculation to the number of patients with PTCS unrelated to tetracycline use. RESULTS: Between 2007 and 2014, a total of 960 patients in the University system between the ages of 12 and 50 were prescribed a tetracycline antibiotic. Among those, 45 were diagnosed with tetracycline-induced PTCS. We estimate the incidence of tetracycline-induced PTCS to be 63.9 per 100,000 person-years. By comparison, the incidence of idiopathic intracranial hypertension (IIH) is estimated to be less than one per 100,000 person-years (Calculated Risk Ratio = 178). CONCLUSIONS: Although a causative link between tetracycline use and pseudotumor cerebri has yet to be firmly established, our study suggests that the incidence of pseudotumor cerebri among tetracycline users is significantly higher than the incidence of IIH in the general population.

An Estimation of the Risk of Pseudotumor Cerebri among Users of the Levonorgestrel Intrauterine Device.

Because of a previous association of pseudotumor cerebri (PTC) with levonorgestrel, we wished to evaluate the use of levonorgestrel-eluting intrauterine devices ("levonorgestrel intrauterine systems", LNG-IUS) in our University of Utah and Rigshospitalet PTC patients. In our retrospective series, PTC prevalence was approximately 0.18% and 0.15% in the LNG-IUS population versus 0.02% and 0.04% in the non-LNG-IUS population (Utah and Rigshospitalet, respectively), with no significant differences in PTC signs and symptoms among the two groups. Our investigation suggests that women with an LNG-IUS may have increased risk of developing PTC but does not suggest an LNG-IUS can cause PTC.

Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration.

To assess whether Tie2-mediated vascular stabilization ameliorates neovascular age-related macular degeneration (AMD), we investigated the impact of adeno-associated virus-mediated gene therapy with cartilage oligomeric matrix protein angiopoietin-1 (AAV2.COMP-Ang1) on choroidal neovascularization (CNV), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF) in a mouse model of the disease. We treated mice with subretinal injections of AAV2.COMP-Ang1 or control (AAV2.AcGFP, AAV2.LacZ, and phosphate-buffered saline). Subretinal AAV2 localization and plasmid protein expression was verified in the retinal pigment epithelium (RPE)/choroid of mice treated with all AAV2 constructs. Laser-assisted simulation of neovascular AMD was performed and followed by quantification of HIF, VEGF, and CNV in each experimental group. We found that AAV2.COMP-Ang1 was associated with a significant reduction in VEGF levels (29-33%, p < 0.01) and CNV volume (60-70%, p < 0.01), without a concomitant decrease in HIF1-α, compared to all controls. We concluded that a) AAV2 is a viable vector for delivering COMP-Ang1 to subretinal tissues, b) subretinal COMP-Ang1 holds promise as a prospective treatment for neovascular AMD, and c) although VEGF suppression in the RPE/choroid may be one mechanism by which AAV2.COMP-Ang1 reduces CNV, this therapeutic effect may be hypoxia-independent. Taken together, these findings suggest that AAV2.COMP-Ang1 has potential to serve as an alternative or complementary option to anti-VEGF agents for the long-term amelioration of neovascular AMD.

Multiple mechanisms in Pd(II)-catalyzed S(N)2' reactions of allylic alcohols.

Density functional calculations and experiments were used to examine mechanisms of Pd(II) catalyzed intramolecular cyclization and dehydration in acyclic and bicyclic monoallylic diols, a formal S(N)2' reaction. In contrast to the previously proposed syn-oxypalladation mechanism for acyclic monoallylic diols, calculations and experiments strongly suggest that hydrogen bonding templates a hydroxyl group and Pd addition across the alkene and provides a low energy pathway via anti-addition (anti-oxypalladation) followed by intramolecular proton transfer and anti-elimination of water. This anti-addition, anti-elimination pathway also provides a simple rationale for the observed stereospecificity. For bicyclic monoallylic diol compounds, Pd(II) is capable of promoting either anti- or syn-addition. In addition, palladium chloride ligands can mediate proton transfer to promote dehydration when direct intramolecular proton transfer between diol groups is impossible.

The importance of hydrogen bonding to stereoselectivity and catalyst turnover in gold-catalyzed cyclization of monoallylic diols.

Density functional calculations and experiment were used to examine the mechanism, reactivity, and origin of chirality transfer in monophosphine Au-catalyzed monoallylic diol cyclization reactions. The lowest energy pathway for cyclization involves a two-step sequence that begins with intramolecular C-O bond formation by anti-addition of the non-allylic hydroxyl group to the Au-coordinated alkene followed by concerted hydrogen transfer/anti-elimination to liberate water. Concerted S(N)2'-type transition states were found to be significantly higher in energy. The two-step cyclization pathway is extremely facile due to hydrogen bonding between diol groups that induces nucleophilic attack on the alkene and then proton transfer between diol groups after C-O bond formation. Importantly, intramolecular proton transfer and elimination provides an extremely efficient avenue for catalyst regeneration from the Au-C σ-bond intermediate, in contrast to other Au-catalyzed cyclization reactions where this intermediate severely restricts catalyst turnover. The origin of chirality transfer and the ensuing alkene stereochemistry is also the result of strong hydrogen-bonding interactions between diol groups. In the C-O bond-forming step, requisite hydrogen bonding biases the tethered nucleophilic moiety to adopt a chair-like conformation with substituents in either axial or equatorial positions, dictating the stereochemical outcome of the reaction. Since this hydrogen bonding is maintained throughout the course of the reaction, establishment of the resultant olefin geometry is also attributed to this templating effect. These computational conclusions are supported by experimental evidence employing bicyclic systems to probe the facial selectivity.