A Pantetheinase-Resistant Pantothenamide with Potent,On-Target,and Selective Antiplasmodial Activity

Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC₅₀], ∼20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of α-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC₅₀, 52 ± 6 nM), target specificity, and low toxicity.     

Reduced methylation of the thromboxane synthase gene is correlated with its increased vascular expression in preeclampsia

Preeclampsia is characterized by increased thromboxane and decreased prostacyclin levels, which predate symptoms, and can explain some of the clinical manifestations of preeclampsia, including hypertension and thrombosis. In this study, we examined DNA methylation of the promoter region of the thromboxane synthase gene (TBXAS1) and the expression of thromboxane synthase in systemic blood vessels of normal pregnant and preeclamptic women. Thromboxane synthase is responsible for the synthesis of thromboxane A(2), a potent vasoconstrictor and activator of platelets. We also examined the effect of experimentally induced DNA hypomethylation on the expression of thromboxane synthase in a neutrophil-like cell line (HL-60 cells) and in cultured vascular smooth muscle and endothelial cells. We found that DNA methylation of the TBXAS1 promoter was decreased and thromboxane synthase expression was increased in omental arteries of preeclamptic women as compared with normal pregnant women. Increased thromboxane synthase expression was observed in vascular smooth muscles cells, endothelial cells, and infiltrating neutrophils. Experimentally induced DNA hypomethylation only increased expression of thromboxane synthase in the neutrophil-like cell line, whereas tumor necrosis factor-α, a neutrophil product, increased its expression in cultured vascular smooth muscle cells. Our study suggests that epigenetic mechanisms and release of tumor necrosis factor-α by infiltrating neutrophils could contribute to the increased expression of thromboxane synthase in maternal systemic blood vessels, contributing to the hypertension and coagulation abnormalities associated with preeclampsia.     

A-trains for intraoperative monitoring in patients with recurrent vestibular schwannoma

Background

Second surgery of recurrent vestibular schwannoma (VS) after previous surgery, stereotactic radiosurgery (SR) or fractionated radiotherapy (FR) carries an increased risk for deterioration of facial nerve function, e.g., due to adhesions, underlining the need for intraoperative monitoring. Facial “A-train” EMG activity (“traintime”) correlates with the degree of postoperative facial palsy. Studies investigating A-trains in VS patients with previous surgery, SR or FR are missing. We therefore investigated the value of A-train monitoring in patients undergoing second surgery for VS.

Method

Intraoperative EMG data from patients who underwent second surgery for VS after previous surgery, SR and/or FR at our institution between 2006 and 2012 were retrospectively analyzed. Ten patients were selected (5 male): Seven had previous SR/RT and MS, three previous surgery only. Traintime values and distribution was compared to published thresholds and to 77 patients who underwent first surgery for VS during the same time period.

Results

A-trains were recorded early after opening of the dura, before facial nerve preparation. Mean traintime was 46.9 s (18.51 s – 80.82 s) in patients with previous SR/RT. In patients with previous MS only, traintime was 0.06 s, 0.99 s and 22.46 s. Compared to the literature, traintime was higher than expected in six patients (four with previous SR/RT, two without), respectively seven compared to the 77 patients with first surgery (5 SR/RT). Seven patients with previous SR/RT and none with previous surgery showed diffuse A-train distributions without significant percentages in single channels, compared to 60 of 77 patients with first surgery (p?<?0.02).

Conclusions

Especially SR/RT, but also previous surgery seems to induce changes in the facial nerve leading to hyperexcitability and exceedingly high traintime values. Based on these findings, A-train monitoring in this specific patient group should be interpreted with caution.