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.     

Neuropeptide Y Attenuates Stress‐Induced Bone Loss Through Suppression of Noradrenaline Circuits

Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress‐induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress‐induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6‐week restraint, or cold‐stress protocol, Npy‐null mice exhibit three‐fold greater bone loss compared to wild‐type mice, owing to suppression of osteoblast activity. This stress‐protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin‐releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy‐null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy‐null mice blocks the increase in circulating noradrenaline and the stress‐induced bone loss. Thus, NPY protects against excessive stress‐induced bone loss, through Y2 receptor‐mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research.     

Biomechanical Characteristics of Biplane Multiplanar Tension-Side Fixation for Lapidus Fusion

Although plating on the plantar, tension-side of the metatarsocuneiform joint provides an inherent biomechanical advantage for Lapidus arthrodesis, it has not been widely adopted owing to the morbidity associated with plantar application. To overcome these limitations, a modification to 90-90 locked biplanar plating was developed to provide the biomechanical advantages of multiplanar fixation and tension-side fixation, allowing application through a conventional incision. We tested the hypothesis that biplanar plating with tension-side fixation (low-profile straight dorsal plate and anatomic medial-plantar plate) would demonstrate improved mechanical stability compared with a previously tested 90-90 biplanar construct (small straight plate dorsally and medially) under cyclic loading. Both constructs were tested in static load to failure (3 pairs) and cyclic loading (10 pairs) with plantar cantilever bending using surrogate anatomic bone models. With static ultimate failure, the biplanar plate construct with tension-side fixation failed at a significantly greater failure load than did the straight biplanar plate construct (247.3?±?18.4 N versus 210.9?±?10.4 N; p?=?.04). With cyclic failure testing, the biplanar plate construct with tension-side fixation endured a significantly greater number of cycles (206,738?±?49,103 versus 101,780?±?43,273; p?<?.001) and a significantly greater dynamic failure load (207.5?±?24.3 N versus 162.5?±?20.6 N; p?<?.001) compared with the straight biplanar plate construct. These results have demonstrated that under simulated static and cyclic Lapidus arthrodesis loading, biplanar plating with tension-side fixation provides superior strength compared with the straight biplanar construct. Thus, this construct shows promise for clinical application as a practical approach to tension-side fixation and an early return to weightbearing after Lapidus fusion.     

Multidrug-resistant organisms in patients from Ukraine in the Netherlands,March to August 2022

Since March 2022, there has been an emergence of multidrug-resistant organisms (MDRO) in the Netherlands in patients originating from Ukraine (58 patients, 75 isolates). For about half of these patients, recent hospitalisation in Ukraine was reported. Genomic surveillance revealed that the majority of the MDRO represent globally spread epidemic lineages and that 60% contain New Delhi metallo-β-lactamase (NDM) genes. Professionals should be aware of an increase in such MDRO associated with migration and medical evacuation of people from Ukraine.     

急性冠状动脉综合征置入支架患者使用替罗非班和阿司匹林时泮托拉唑对消化道保护作用的评价

目的:急性冠状动脉综合征(ACS)置入支架患者使用盐酸替罗非班、阿司匹林、氯吡格雷、低分子肝素(四联)时,评价泮托拉唑对消化道的保护作用.方法:选择ACS置入支架治疗的患者266例,随机分入观察组134例,对照组132例,所有患者均服用阿司匹林、氯吡格雷、低分子肝素和盐酸替罗非班.观察组患者静脉注射泮托拉唑40 mg/d 4～5天,之后改为泮托拉唑片剂40 mg/次,2次/天,服用30天.观察两组间30天全因死亡、再次心肌梗死、再次经皮冠状动脉介入治疗(PCI)、再次住院、颅内出血和消化道出血状况.结果:观察组134例患者30天内全因死亡5例、再次心肌梗死4例、再次PCI4例和再次住院8例;对照组132例患者分别为8例、6例、5例和13例,两组相比差异均无统计学意义(P>0.05);两组均无颅内出血发生.观察组消化道大出血0和总消化道出血事件3例,对照组分别为5例和15例,两组比较观察组消化道大出血和总消化道出血事件少于对照组(P<0.05),差异均有统计学意义.结论:ACS置入支架治疗的患者,盐酸替罗非班治疗是安全有效的,未见颅内出血发生.静脉注射和口服泮托拉唑并不增加30天全因死亡、再次心肌梗死、再次PCI和再次住院发生,同时可以减少30天内消化道出血发生率特别是消化道大出血事件的发生,具有良好的消化道保护作用和安全性.