Concomitant endoscopic radiofrequency ablation and laparoscopic reflux operative results in more effective and efficient treatment of Barrett esophagus

BACKGROUND: Barrett esophagus (BE) caused by gastroesophageal reflux disease can lead to esophageal cancer. The success of endoscopic treatments with BE eradication depends on esophageal anatomy and post-treatment acid exposure. STUDY DESIGN: Between January 2008 and December 2009, 10 patients were selected for combination treatment of BE using laparoscopic anti-reflux surgery and endoscopic radiofrequency ablation. Retrospective review of preoperative, procedural, and postoperative data was performed. RESULTS: Seven study patients had a pathologic diagnosis of nondysplastic BE and 3 patients had a diagnosis of low-grade dysplasia. Average length of BE lesions was 6.4 ± 4.8 cm. Procedure time averaged 154.4 ± 46.4 minutes. At the time of surgery, the mean number of ablations performed was 4.39 ± 1.99. Six patients were noted to have major hiatal hernias requiring reduction. Five patients (80%) had 100% resolution of their BE at their first postoperative endoscopy. The remaining 3 patients had a ≥50% resolution and underwent subsequent endoscopic ablation. Symptomatic results revealed that 4 patients had substantial dysphagia to solids and other symptoms were minimal. Two patients were noted to have complications related to the ablative treatments. One stricture and 1 perforation were observed. CONCLUSIONS: Endoscopic radiofrequency ablation of BE at the time of laparoscopic fundoplication is feasible and can effectively treat BE lesions. A single combined treatment can result in fewer overall procedures performed to obtain BE eradication

Validation of Plasmodium falciparum dUTPase as the target of 5'-tritylated deoxyuridine analogues with anti-malarial activity

BACKGROUND: Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5'-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported. METHODS: To investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein. RESULTS:Different attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3' replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5'-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol. CONCLUSION: These results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages

Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways

., a mouse malaria parasite. and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery