Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation.

Essentials Vessel stenosis due to large thrombus formation increases local shear 1-2 orders of magnitude. High shear at stenotic sites was exploited to trigger eptifibatide release from nanocapsules. Local delivery of eptifibatide prevented vessel occlusion without increased tail bleeding times. Local nanocapsule delivery of eptifibatide may be safer than systemic antiplatelet therapies. SUMMARY: Background Myocardial infarction and stroke remain the leading causes of mortality and morbidity. The major limitation of current antiplatelet therapy is that the effective concentrations are limited because of bleeding complications. Targeted delivery of antiplatelet drug to sites of thrombosis would overcome these limitations. Objectives Here, we have exploited a key biomechanical feature specific to thrombosis, i.e. significantly increased blood shear stress resulting from a reduction in the lumen of the vessel, to achieve site-directed delivery of the clinically used antiplatelet agent eptifibatide by using shear-sensitive phosphatidylcholine (PC)-based nanocapsules. Methods PC-based nanocapsules (2.8 × 1012 ) with high-dose encapsulated eptifibatide were introduced into microfluidic blood perfusion assays and into in vivo models of thrombosis and tail bleeding. Results Shear-triggered nanocapsule delivery of eptifibatide inhibited in vitro thrombus formation selectively under stenotic and high shear flow conditions above a shear rate of 1000 s-1 while leaving thrombus formation under physiologic shear rates unaffected. Thrombosis was effectively prevented in in vivo models of vessel wall damage. Importantly, mice infused with shear-sensitive antiplatelet nanocapsules did not show prolonged bleeding times. Conclusions Targeted delivery of eptifibatide by shear-sensitive nanocapsules offers site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.

An international survey of nutritional practices in low- and middle-income countries: a report from the International Society of Pediatric Oncology (SIOP) PODC Nutrition Working Group.

BACKGROUND/OBJECTIVES: Optimal nutritional status is important in children with cancer, as it can influence clinical outcomes. To improve the nutritional health of children and adolescents receiving treatment for cancer residing in low income and middle-income countries (LMIC), we investigated nutrition practices among these nations' institutions providing treatment for childhood cancer. SUBJECT/METHODS: A cross-sectional survey of nutrition practice was administered to staff members at institutions providing treatment for children with cancer between 2011 and 2012. Countries classified as low income and middle income were divided by geographical region. Final analysis was performed with 96 surveys, which included 27 institutions from Asia, 27 institutions from Latin America and Caribbean, 27 institutions from Africa and 15 institutions from Europe. RESULTS: The study found that 55% of institutions had a dietician available on their service. Access to dieticians, lack of nutrition resources and lack of nutrition education of staff were the main barriers to providing nutrition care in LMIC. Half of the institutions performed nutritional assessment at diagnosis, and the methods used varied widely. Twenty-nine percent of all institutions used complementary and alternate therapies within their clinical practice, and 35% of institutions reported that nutrition education was provided to patients and families. CONCLUSIONS: Priority areas for improving the nutritional management in LMIC include the following: (1) improved nutrition education and assessment tools for doctors and nurses; (2) increased availability of nutrition education resources for families and patients; and (3) identification of the role of complementary and alternative therapies in closing gaps in symptom management in these institutions.

Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis.

BACKGROUND: Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystal-induced interleukin 1 beta (IL1beta) release contributes to inflammation in subcutaneous air pouch and peritoneal models of acute gout and pseudogout. However, consequences of IL1 inhibition have not been explored in more clinically relevant models of crystal-induced arthritis. OBJECTIVE: To develop a novel mouse model of acute gouty ankle arthritis and use it to assess the effects of genetic deletion of IL1 receptor type (IL1R1) and of exogenous mIL1 Trap (a high-affinity blocker of mouse IL1alpha and IL1beta) on pain, synovitis and systemic inflammatory biomarkers. METHODS: MSU crystals were injected into the mouse ankle joint and pain and ankle swelling were measured over 4 days. The effects of IL1 inhibition were determined in this model, and in the comparator models of crystal-induced peritonitis and subcutaneous air pouch inflammation. RESULTS: Both IL1R1-null mice and mice pretreated with mIL1 Trap showed reduced neutrophil influx in MSU and CPPD crystal-induced peritonitis and air pouch models (p<0.05). In the ankle joint model, both IL1R1 knockout mice and pretreatment with mIL1 Trap were associated with significant reductions in MSU crystal-induced elevations in hyperalgesia, inflammation, serum amyloid A and the levels of multiple inflammatory cytokines and chemokines (p<0.05). Additionally, it was found that administration of mIL1 Trap after MSU crystal injection reduced established hyperalgesia and ankle swelling. CONCLUSIONS: IL1 inhibition both prevented and relieved pain and ankle joint inflammation in response to intra-articular MSU crystals in mice. Results suggested that IL1 Trap has the potential to both prevent and treat gouty arthritis.

Effects of creatine supplementation on aerobic power and cardiovascular structure and function.

This project aimed to determine 1) whether creatine (Cr) supplementation affects cardiovascular structure and function and 2) to examine its effect on aerobic power. Eighteen males undertook aerobic testing on a cycle ergometer and echocardiographic assessment of the heart. The experimental group (N = 9) ingested 20g x day(-1) of Cr for seven days followed by l0g x day(-1) for a further 21 days. The control group (N = 9) followed an identical protocol ingesting a placebo for the same period. Assessment was performed pre-, mid- (seven days) and post-testing (28 days). A MANOVA with repeated measures was used to test for group differences before and after supplementation. The Cr group demonstrated a significant increase in body mass for the pre-mid (1.0 +/- 0.6 kg) and the pre-post (1.5 +/- 0.7 kg) testing occasions. Submaximal VO2 decreased significantly from the pre-mid and pre-post testing occasions by between 4.8% to 11.4% with Cr supplementation at workloads of 75 W and 150 W. Other oxygen consumption measures and exercise time to exhaustion, for the Cr group, showed decreasing trends that approached significance. Additionally, there was a significant pre-post decrease in maximum heart rate of 3.7%. There were no changes in any of the echocardiographic or blood pressure measures for either group. The present results suggest short term Cr supplementation has no detectable negative effect on cardiac structure or function. Additionally, Cr ingestion improves submaximal cycling efficiency. These results suggest that the increase in efficiency may be related to peripheral factors such an increase in muscle phosphocreatine, rather than central changes.