Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

Seasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP). Plasmodium falciparum single nucleotide polymorphisms (SNPs) in P. falciparum crt (pfcrt), pfmdr1, pfdhfr, and pfdhps are associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs in P. falciparum isolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment in P. falciparum PCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen for pfcrt 76T (68.5% to 83.0%, P = 0.04), pfdhfr 59R (54.8% to 83.3%, P = 0.0002), and pfdhfr 108N (55.0% to 87.2%, P = 0.0001), with trends toward selection of pfmdr1 86Y, pfdhfr 51I, and pfdhps 437G. After SMC with DP, only borderline selection of wild-type pfmdr1 D1246 (mutant; 7.7% to 0%, P = 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00941785","term_id":"NCT00941785"}}NCT00941785.)     

Contribution of Inertial Cavitation in the Enhancement of In Vitro Transscleral Drug Delivery

In ocular drug delivery, the sclera is a promising pathway for administering drugs to both the anterior and posterior segments of the eye. Due to the low permeability of the sclera, however, efficient drug delivery is challenging. In this study, pulsed ultrasound (US) was investigated as a potential method for enhancing drug delivery to the eye through the sclera. The permeability of rabbit scleral tissue to a model drug compound, sodium fluorescein, was measured after US-irradiation at 1.1 MHz using time-averaged acoustic powers of 0.5–5.4 W (6.8–12.8 MPa peak negative pressure), with a fixed duty cycle of 2.5% for two different pulse repetition frequencies of 100 and 1000 Hz. Acoustic cavitation activity was measured during exposures using a passive cavitation detector and was used to quantify the level of bubble activity. A correlation between the amount of cavitation activity and the enhancement of scleral permeability was demonstrated with a significant enhancement in permeability of US exposed samples compared to controls. Transmission electron microscopy showed no evidence of significant alteration in viability of tissue exposed to US exposures. A pulsed US protocol designed to maximum cavitation activity may therefore be a viable method for enhancing drug delivery to the eye.     

A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood–brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: “symptomatic salvaged tissue” (SST) and “asymptomatic infarcted tissue” (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia–reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.     

Effect of high-intensity interval training on the profile of muscle deoxygenation heterogeneity during incremental exercise

This study examines the effect of high-intensity interval training (HIT) on the spatial distribution of muscle deoxygenation during incremental exercise. Young untrained male adults (n = 11) performed an incremental bicycle exercise before and after a running HIT of 6 weeks. Muscle deoxygenation (HHb) and blood volume (Hb_tot) were monitored continuously by near-infrared spectroscopy at eight sites in the vastus lateralis. The rise in HHb during incremental exercise was significantly higher after training, in comparison with before training (P = 0.020), whereas the rise in Hb_tot was not affected by training. The standard deviation of HHb and the relative dispersion of HHb at the eight sites were not significantly different irrespective of the intensity of exercise between pre- and post-training. After training, the standard deviation of HHb was greater at 60, 70, and 80 % of $ \dot{V}{\text{O}}_{ 2} { \max } $ than at rest. Finally, training significantly increased the standard deviation of Hb_tot (P = 0.036). These results indicate that HIT changes the muscle deoxygenation profile during incremental exercise, suggesting an improvement in the O₂ extraction with training. HIT did not reduce the spatial heterogeneity of muscle deoxygenation and blood volume during incremental exercise. This indicates that the intra-muscular distribution of the VO₂/O₂ delivery ratio was not improved by 6 weeks HIT.