Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Characterizing Suicide in Toronto: An Observational Study and Cluster Analysis

Objective:

To determine whether people who have died from suicide in a large epidemiologic sample form clusters based on demographic, clinical, and psychosocial factors.

Method:

We conducted a coroner’s chart review for 2886 people who died in Toronto, Ontario, from 1998 to 2010, and whose death was ruled as suicide by the Office of the Chief Coroner of Ontario. A cluster analysis using known suicide risk factors was performed to determine whether suicide deaths separate into distinct groups. Clusters were compared according to person- and suicide-specific factors.

Results:

Five clusters emerged. Cluster 1 had the highest proportion of females and nonviolent methods, and all had depression and a past suicide attempt. Cluster 2 had the highest proportion of people with a recent stressor and violent suicide methods, and all were married. Cluster 3 had mostly males between the ages of 20 and 64, and all had either experienced recent stressors, suffered from mental illness, or had a history of substance abuse. Cluster 4 had the youngest people and the highest proportion of deaths by jumping from height, few were married, and nearly one-half had bipolar disorder or schizophrenia. Cluster 5 had all unmarried people with no prior suicide attempts, and were the least likely to have an identified mental illness and most likely to leave a suicide note.

Conclusions:

People who die from suicide assort into different patterns of demographic, clinical, and death-specific characteristics. Identifying and studying subgroups of suicides may advance our understanding of the heterogeneous nature of suicide and help to inform development of more targeted suicide prevention strategies.     

巨噬细胞迁移抑制因子通过CC趋化因子配体2诱导巨噬细胞聚集

巨噬细胞迁移抑制因子最初是由于能抑制体外巨噬细胞随机迁移而被发现,现在它作为一种重要的调节因子参与一系列炎症性疾病过程.我们最近发现,巨噬细胞迁移抑制因子的缺失使一些由炎症介质诱发的白细胞-内皮细胞相互作用减弱,提示巨噬细胞迁移抑制因子在炎症反应中起作用的机制之一是促进白细胞聚集.……     

Piecemeal degranulation of mast cells in the inflammatory eyelid lesions of interleukin-4 transgenic mice. Evidence of mast cell histamine release in vivo by diamine oxidase-gold enzyme-affinity ultrastructural cytochemistry

We used light and electron microscopy to analyze the eyelid inflammation that develops in transgenic mice that overexpress interleukin-4 (IL-4; Tepper et al, Cell 62:457, 1990). Analysis of alkaline Giemsa-stained plastic sections examined by light microscopy (Dvorak et al, J Exp Med 132:558, 1970), as well as by routine transmission electron microscopy, indicated that the mast cells in the inflammatory eyelid lesions were undergoing piecemeal degranulation, a form of secretion in which the cells' cytoplasmic granules exhibit characteristic morphologic changes that are thought to be associated with the prolonged, vesicle-mediated release of the granules' constituents. Moreover, by using a newly reported enzyme affinity-gold method, which stains histamine based on binding to diamine oxidase-gold (Dvorak et al, J Histochem Cytochem 41:787, 1993), we show that these activated mast cells had released much of their histamine content. The eyelid lesions also exhibited increased numbers of mast cells; interstitial fibrosis, particularly around cutaneous nerves and blood vessels; activated fibroblasts; focal axonal damage; venules with endothelial cells containing numerous vesiculo-vacuolar organelles; and infiltrates of neutrophils and eosinophils. Our findings illustrate that overexpression of the IL-4 gene in vivo can result in eyelid lesions associated with piecemeal degranulation of mast cells, as well as tissue fibrosis and a variety of other pathologic changes. These results also represent the first direct morphologic evidence for histamine secretion by mast cells in vivo.     

The role of statins in the prevention of contrast induced nephropathy: a meta-analysis of 8 randomized trials

Contrast induced nephropathy (CIN) is a common complication of coronary angiography/angioplasty. Prevention is the key to reduce the incidence of CIN and it begins with appropriate pre-procedural management. Statins have been shown to possess pleiotropic effects (anti-oxidant, anti-inflammatory and anti-thrombotic properties) and their effects on CIN were assessed in several studies with conflicting results. Aim of this meta-analysis is to evaluate the efficacy of short-term statins for the prevention of CIN in patients undergoing coronary angiography/percutaneous interventions. We performed formal searches of PubMed, EMBASE, Cochrane central register of controlled trials and major international scientific session abstracts from January 1990 to January 2014 of trials which compares short-term statins versus Placebo for the prevention of CIN in patients undergoing coronary angiography/angioplasty. Data regarding study design, statin dose, inclusion/exclusion criteria, number of patients, and clinical outcome was extracted by 2 investigators. Eight trials were included, with a total of 4734 patients. CIN occurred in 79/2,358 patients (3.3 %) treated with statins versus 153/2,376 patients (6.4 %) of the placebo group [OR 95 % CI 0.50 (0.38–0.66), p < 0.00001; p _het = 0.39]. Benefits were both observed with high-dose short-term statins [OR 95 % CI 0.44 (0.30–0.65), p < 0.0001; p _het = 0.16] and low-dose statins, [OR 95 % CI 0.58 (0.39–0.88), p = 0.010; p _het = 0.90]. By meta-regression analysis, no significant relationship was observed between benefits from statin therapy and patient’s risk profile (p = 0.26), LDL cholesterol (p = 0.4), contrast volume (p = 0.94) or diabetes rate (p = 0.38). This meta-analysis showed that among patients undergoing coronary angiography/percutaneous intervention the use of short-term statins reduces the incidence of CIN, and therefore is highly recommended even in patients with low LDL-cholesterol levels.     

Switching from high-dose clopidogrel to prasugrel in ACS patients undergoing PCI: a single-center experience

Prasugrel has been shown to be superior to clopidogrel in the setting of ACS patients undergoing coronary angioplasty. However, few data have been reported so far on those patients who switch from clopidogrel to prasugrel after coronary angioplasty. Aim of the current study was to evaluate the safety of prasugrel loading dose administration in ACS patients undergoing PCI and preatreated with high-dose clopidogrel. From May 2010 to December 2011 150 ACS patients undergoing coronary angioplasty and pretreated with high-dose clopidogrel, were switched to prasugrel loading dose soon after the procedure. They were matched (ratio 1:2) according to sex and age with a group of 300 ACS patients undergoing angioplasty and treated with high-dose clopidogrel only from May 2010 to December 2011. All demographic clinical and angiographic were collected. Primary endpoint was the rate of major bleeding complications (according to ACUITY trial definition) at 30-day follow-up. Secondary endpoints were: TIMI major and minor bleeding, definite stent thrombosis, major adverse cardiac events (MACE) and Net adverse cardiac events (NACE) at 30-day follow-up. The two groups of patients showed similar baseline demographic, and clinical characteristics. Most of the patients had unstable angina or non-ST segment elevation myocardial infarction. Almost (about 95 %) all patients underwent radial approach. No difference was observed in major bleeding complications according to both ACUITY (2.0 vs 2.0 %) and TIMI Major (0.7 vs 1.3 %) definition. No difference between the two groups was observed in terms of in-stent thrombosis, MACE and NACE at 30-day follow-up. Our observational study showed that switching to prasugrel with loading dose soon after angioplasty among ACS patients who were pretreated with clopidogrel seems to be well tolerated without overt evidence of heightened major bleeding. Future large randomized trials are certainly needed to confirm these findings.