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Background: Current options to treat clinical relapse in inflammatory central nervous system (CNS) conditions such as cerebral ischemia-reperfusion injury are limited, and agents that are more effective are required. Disruption of the blood-brain barrier is an early feature of lesion formation that correlates with clinical exacerbation and facilitates the entry of inflammatory medium and inflammatory cells. Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring anti-inflammatory antagonist of the interleukin-1 (IL-1) family. The broad-spectrum anti-inflammatory effects of IL-1RA have been investigated against various forms of neuroinflammation. However, the effect of IL-1RA on blood-brain barrier disruption following ischemia-reperfusion has not been reported.Methods: In this study, we investigated the effects of IL-1RA and a novel protein (IL-1RA-PEP) that was fused to IL-1RA with a cell penetrating peptide, on blood-brain barrier integrity, in male rats subjected to transient middle cerebral artery occlusion.Results: After intravenous administration, IL-1RA-PEP (50 mg/kg) penetrated cerebral tissues more effectively than IL-1RA. Moreover, it preserved blood-brain barrier integrity, attenuated changes in expression and localization of tight junction proteins and matrix metalloproteinases, and enhanced angiogenesis in ischemic brain tissue. Further study suggested that the effects of IL-1RA-PEP on preserving blood-brain barrier integrity might be closely correlated with the p65/NF-κB pathway, as evidenced by the effects of the inhibitor JSH-23.Conclusions: Collectively, our results demonstrated that IL-1RA-PEP could effectively penetrate the brain of rats with middle cerebral artery occlusion and ameliorate blood-brain barrier disruption. This finding might represent its novel therapeutic potential in the treatment of the cerebral ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Dabigatran etexilate may be underutilized in geriatric patients because of inadequate clinical experience in individuals with severe renal impairment and post-marketing reports of bleeding events. Assessing the degree of anticoagulation may improve the risk:benefit ratio for dabigatran. The aim of this prospective study was to identify whether therapeutic drug monitoring of dabigatran anticoagulant activity using a chromogenic anti-factor IIa assay is a viable option for therapy individualization. Methods: Plasma dabigatran concentration was assessed in nine patients with nonvalvular atrial fibrillation aged 75 years or older currently receiving dabigatran etexilate for prevention of stroke, using an anti-factor IIa chromogenic assay and HPLC-MS/MS. Trough concentrations were evaluated on two separate occasions to determine intrapatient variation. Results: Blood was collected at 13.1 ± 2.3 h (mean ± SD) post dose from patients prescribed dabigatran etexilate 150 mg twice daily (5/9 patients) or dabigatran etexilate 75 mg twice daily (4/9 patients). Results from the anti-factor IIa chromogenic assay correlated with dabigatran concentrations as assessed by HPLC-MS/MS (r² = 0.81, n = 16). There was no correlation between dabigatran trough values taken at separate visits (r²= 0.002, n = 7). Furthermore, there was no correlation found between the drug concentrations and patients' renal function determined by both creatinine and cystatin-C based equations. None of the patients enrolled in the study were in the proposed on-therapy trough range during at least one visit. Conclusion: The chromogenic anti-factor IIa assay demonstrated similar performance in quantifying dabigatran plasma trough concentrations to HPLC-MS/MS. Single measurement of dabigatran concentration by either of two methods during routine visits may not be reliable in identifying patients at consistently low or high dabigatran concentrations. [ABSTRACT FROM AUTHOR]

Background: Food allergy is the most common cause of anaphylaxis in children. Intramuscular delivery of epinephrine auto-injectors (EAI) is the standard of care for the treatment of anaphylaxis. We examined if children and adolescents at risk of anaphylaxis weighing 15-30 kg and >30 kg would receive epinephrine into the intramuscular space with the currently available EAI in North America and Europe. Methods: The distance from skin to muscle (STMD) and skin to bone (STBD) on the mid third anterolateral area of the right thigh was measured by ultrasound applying either high pressure (max) or slight pressure (min) in 102 children weighing 15-30 kg (group 1) and 100 children and adolescents, weighing more than 30 kg (group 2). Results: Using a high pressure EAI (HPEAI), Epipen Jr® and Auvi-Q®/Allerject® 0.15 mg, 11/102 (11%) children in group 1 and 38/102 (38%) using another HPEAI, Jext®, had a STMDmax that showed a risk of intraosseous injection. There was a 1% risk of subcutaneous injection with these devices. There was no risk of intraosseous injection using a low pressure EAI (LPEAI), Emerade®. In group 2, the risk of intraosseous injection using a HPEAI was 3% and no risk using a LPEAI. However, the risk of subcutaneous injection using HPEAI was 9% and using LPEAI was 2%. Conclusion: There is a risk of intraosseous injection using HPEAI (Epipen®/Epipen Jr®, Auvi-Q®/Allerject® and especially Jext®) in children at risk of anaphylaxis. There was also a risk of subcutaneous injection using the currently available HPEAI in children and adolescents. [ABSTRACT FROM AUTHOR]

Background: Inflammatory response markers have been proposed to predict the clinical outcomes in various cancers. The aim of this study was to explore the influence of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) on the prognosis of osteosarcoma., Methods: Three hundred fifty-nine patients who underwent curative surgery for osteosarcoma were enrolled from 2005 to 2010. NLR and PLR were calculated from peripheral blood cell counts taken at pre-treatment. Optimal cutoff values of NLR and PLR were determined on the basis of receiver operating characteristic curve analysis. A predictive model was established to predict the clinical outcome for overall survival, and the predictive accuracy of this model was determined by concordance index (c-index)., Results: Our results showed that advanced stage and metastasis at diagnosis were significantly associated with the high NLR and PLR groups. NLR was an independent prognostic indicator for overall survival (HR = 1.80, 95% CI = 1.35-2.41, P < 0.001) and progression-free survival (HR = 1.65, 95% CI = 1.26-2.15, P < 0.001), except for PLR. The nomogram could perform well in the prediction of overall survival in patients with osteosarcoma (c-index 0.829)., Conclusions: Our results suggest that both NLR and PLR can reflect clinical prognosis. NLR is more predictive of overall survival and progression-free survival than PLR.

Background: Evidence from clinical studies support the fact that abnormal cholesterol metabolism in the brain leads to progressive cognitive dysfunction. The low-density lipoprotein receptor (LDLR) is well-known for its role in regulating cholesterol metabolism. Whether LDLR involved in this impaired cognition and the potential mechanisms that underlie this impairment are unknown., Methods: Twelve-month-old Ldlr-/- mice (n = 10) and wild-type littermates C57BL/6 J (n = 14) were subjected to the Morris water maze test. At 1 week after completion of the behavioural testing, all of the animals were sacrificed for analysis of synaptic and apoptotic markers., Results: The plasma cholesterol concentration of Ldlr-/- mice was increased moderately when compared with C57BL/6 J mice (P < 0.05). Behavioural testing revealed that Ldlr-/- mice displayed impaired spatial memory, and moreover, the expression levels of synaptophysin and the number of synaptophysin-immunoreactive presynaptic boutons in the hippocampal CA1 and dentate gyrus were decreased (all P < 0.05). Ultrastructural changes in the dentate gyrus were observed using transmission electron microscopy. Furthermore, apoptosis in the hippocampus of Ldlr-/- mice was revealed based on elevation, at both the mRNA and protein levels, of the ratio of Bax/Bcl-2 expression (all P < 0.05)and an increase in activated-caspase3 protein level (P < 0.05)., Conclusion: LDLR deficiency contributes to impaired spatial cognition. This most likely occurs via negative effects that promote apoptosis and synaptic deficits in the hippocampus.

Background: The gut of phloem feeding insects is critical for nutrition uptake and xenobiotics degradation. However, partly due to its tiny size, genomic information for the gut of phloem feeding insects is limited., Results: In this study, the gut transcriptomes of two species of invasive whiteflies in the Bemisia tabaci complex, Middle East Asia Minor 1 (MEAM1) and Mediterranean (MED), were analyzed using the Illumina sequencing. A total of 12,879 MEAM1 transcripts and 11,246 MED transcripts were annotated with a significant Blastx hit. In addition, 7,000 and 5,771 gut specific genes were respectively identified for MEAM1 and MED. Functional analyses on these gut specific genes demonstrated the important roles of gut in metabolism of insecticides and secondary plant chemicals. To reveal the molecular difference between guts of MEAM1 and MED, a comparison between gut transcriptomes of the two species was conducted and 3,910 pairs of orthologous genes were identified. Based on the ratio of nonsynonymous and synonymous substitutions, 15 genes were found evolving under positive selection. Many of those genes are predicted to be involved in metabolism and insecticide resistance. Furthermore, many genes related to detoxification were expressed at an elevated level in the gut of MED compared to MEAM1, which might be responsible for the MED's higher resistance to insecticides and environmental stresses., Conclusion: The sequencing of MED and MEAM1 gut transcriptomes and extensive comparisons of MEAM1 and MED gut transcripts provide substantial sequence information for revealing the role of gut in whiteflies.