The Utility of Peripherally Restricted Kappa-Opioid Receptor Agonists for Inhibiting Below-Level Pain After Spinal Cord Injury in Mice.

Pain after spinal cord injury (SCI) can be difficult to treat. Drugs that target the opioid receptor (OR) outside the central nervous system (CNS) have gained increasing interest in pain control owing to their low risk of central side effects. Asimadoline and ICI-204448 are believed to be peripherally restricted KOR agonists withlimited access to the CNS. This study examined whether they can attenuate pain hypersensitivity in mice subjected to a contusive T10 SCI. Subcutaneous (s.c.) injection of asimadoline (5, 20 mg/kg) and ICI-204448 (1, 10 mg/kg) inhibited heat hypersensitivity at both doses, but only attenuated mechanical hypersensitivity at the high dose. However, the high-dose asimadoline adversely affected animals' exploratory performance in SCI mice and caused aversion, suggesting CNS drug penetration. In contrast, high-dose ICI-204448 did not impair exploration and remained effective in reducing both mechanical and heat hypersensitivities after SCI. Accordingly, we chose to examine the potential peripheral neuronal mechanism for ICI-204448-induced pain inhibition by conducting in vivo calcium imaging of dorsal root ganglion (DRG) in Pirt-GCaMP6s+/- mice. High-dose ICI-204448 (10 mg/kg, s.c.) attenuated the increased fluorescence intensity of lumbar DRG neurons activated by a noxious pinch (400 g) stimulation in SCI mice. In conclusion, systemic administration of ICI-204448 achieved SCI pain inhibition at doses that did not induce notable side effects and attenuated DRG neuronal excitability which may partly contribute to its pain inhibition. These findings suggest that peripherally restricted KOR agonists may be useful for treating SCI pain, but the therapeutic window must be carefully examined.

Effects of SLCO1B1 on elimination and toxicities of high-dose methotrexate in pediatric acute lymphoblastic leukemia.

Aim: To evaluate the association between SLCO1B1 polymorphisms and elimination/toxicities of high-dose methotrexate (MTX). Methods: SLCO1B1 rs11045879 and rs4149056 polymorphisms were retrospectively genotyped in 301 children with newly diagnosed acute lymphoblastic leukemia. MTX concentration, doses of leucovorin rescue and toxicities were recorded. Results: SLCO1B1 rs11045879C carriers (CC + CT) had higher plasma MTX levels at 96 hr, and longer MTX elimination time. The number of leucovorin rescue doses in rs4149056C carriers (CC + CT) was more than those in TT ones. Moreover, SLCO1B1 polymorphisms were associated with HDMTX toxicities including thrombocytopenia, renal toxicity and anal mucositis, but not associated with MTX level at other time points or delayed elimination. Conclusions: Our data demonstrate that genotyping of SLCO1B1 might be useful to optimize MTX therapy.

Efficacy and Safety of Ginkgo Leaf Extract and Dipyridamole Injection for Ischemic Stroke: A Systematic Review and Meta Analysis.

Objective: Ginkgo leaf extract and dipyridamole injection (GDI), a kind of Chinese medicine preparation, has been considered as a promising supplementary treatment for ischemic stroke. The aim of this study was to systematically evaluate the clinical efficacy and safety of GDI mediated therapy for ischemic stroke. Methods: PubMed, Cochrane Library, Medline, Embase, Web of Science, Wanfang database, Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI) and Chinese Biological Medicine Database (CBM), were searched systematically for clinical trials of conventional treatments combined with GDI for ischemic stroke. The reported outcomes including overall response, hemorrheology and blood lipid indexes, and adverse events were systematically investigated. Results: Data from thirty-nine trials including 3,182 ischemic stroke patients were involved. The results indicated that, compared with conventional treatments alone, the combination of conventional treatments with GDI obviously improved the overall response (odds ratio [OR] = 4.14, 95% confidence interval [CI] = 3.26-5.25, P < 0.00001), neurological status (National Institutes of Health Stroke Scale, OR = -3.13, 95% CI = -3.98 to -2.28, P < 0.00001) and activity of daily living (Barthel Index score, OR = 14.10, 95% CI = 9.51-18.68, P < 0.00001) of patients. Moreover, the hemorheology and blood lipids indexes of ischemic stroke patients were also significantly ameliorated after the combined therapy (P < 0.01). The frequency of adverse events did not differ significantly between the two groups (P > 0.05). Conclusion: Evidence from the meta-analysis suggested that the combination of conventional treatments and GDI is safe and more effective in treating ischemic stroke than conventional treatments alone. Therefore, GDI mediated therapy could be recommended as an adjuvant treatment for ischemic stroke.

Modeling of land use and reservoir effects on nonpoint source pollution in a highly agricultural basin.

Nonpoint source (NPS) pollution is tightly linked to land use activities that determine the sources and magnitudes of pollutant loadings to stream water. The pollutant loads may also be alleviated within reservoirs because of the physical interception resulting from changed hydrological regimes and other biochemical processes. It is important but challenging to assess the NPS pollution processes with human effects due to the measurement limitations. The objective of this study is to evaluate the effects of human activities such as land uses and reservoir operation on the hydrological and NPS pollution processes in a highly agricultural area-the Iowa River Basin-using the Soil and Water Assessment Tool (SWAT). The evaluation of model performance at multiple sites reveals that SWAT can consistently simulate the daily streamflow, and monthly/annual sediment and nutrient loads (nitrate nitrogen and mineral phosphorus) in the basin. We also used the calibrated model to estimate the trap efficiencies of sediment (∼78%) and nutrients (∼30%) in the Coralville Reservoir within the basin. These non-negligible effects emphasize the significance of incorporating the sediment and nutrient removal mechanisms into watershed system studies. The spatial quantification of the critical NPS pollution loads can help identify hot-spot areas that are likely locations for the best management practices.