Survival after multiple nail gun injuries to the brain,lung, and heart: a case report and a review of the literature

Most nail gun injuries involve the extremities and result from work-related accidents. Injuries to the brain or thorax are relatively rare, and cases with injuries to both regions are even rarer and often lethal. Initial evaluation, resuscitation, and surgical planning can be challenging for emergency physicians and surgeons. We present the details of a man with multiple nail gun injuries to the brain, lung, and heart following a suicide attempt. The patient presented to the emergency department in shock. After immediate resuscitation, emergent sternotomy, and subsequent craniotomy, he was discharged without significant morbidity. According to the literature, this is the only reported case involving multiple nail gun injuries to the brain, lungs, and heart. The mortality rate of multiple nail gun injuries involving the head and chest is approximately 20%. Rapid evaluation, immediate resuscitation, and appropriate imaging and surgery are crucial for increasing survival and achieving a good prognosis. Emergency sternotomy for cardiac injury is the foremost priority, and the timing of craniotomy depends on the patient’s vital sign status and whether brain injury is evident.A preprint of this article is available online: DOI: 10.21203/rs.3.rs-35448/v1.     

Cell-derived nanovesicle-mediated drug delivery to the brain: Principles and strategies for vesicle engineering

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Silk fibroin microparticles as carriers for delivery of human recombinant BMPs. Physical characterization and drug release

Bone morphogenetic proteins (BMPs) are cytokines with strong ability to promote new bone formation. Herein, we report the use of silk fibroin microparticles as carriers for the delivery of BMP‐2, BMP‐9 or BMP‐14. BMP‐containing fibroin microparticles were prepared by a mild methodology using dropwise addition of ethanol, exhibiting mean diameters of 2.7 ± 0.3 µm. Encapsulation efficiencies varied between 67.9 ± 6.1 % and 97.7 ± 2.0 % depending on the type and the amount of BMP loaded. Release kinetics showed that BMP‐2, BMP‐9 and BMP‐14 were released in two phases profile, with a burst release in the first two days followed by a slower release, for a period of 14 days. The release data were best explained by Korsmeyer's model and the Fickian model of drug diffusion. Silk fibroin microparticles can offer a promising approach for the sustained delivery of different BMPs in tissue engineering applications. Copyright © 2010 John Wiley & Sons, Ltd.     

The accuracy of human senses in the detection of neonatal heart rate during standardized simulated resuscitation: Implications for delivery of care,training and technology design

Aim

Auscultation and palpation are recommended methods of determining heart rate (HR) during neonatal resuscitation. We hypothesized that: (a) detection of HR by auscultation or palpation will vary by more than ±15 BPM from actual HR; and (b) the inability to accurately determine HR will be associated with errors in management of the neonate during simulated resuscitation.

Subjects and methods

Using a prospective, randomized, controlled study design, 64 subjects participated in three simulated neonatal resuscitation scenarios. Subjects were randomized to technique used to determine HR (auscultation or palpation) and scenario order. Subjects verbalized their numeric assessment of HR at the onset of the scenario and after any intervention. Accuracy of HR determination and errors in resuscitation were recorded. Errors were classified as errors of omission (lack of appropriate interventions) or errors of commission (inappropriate interventions). Cochran's Q and chi square test were used to compare HR detection by method and across scenarios.

Results

Errors in HR determination occurred in 26–48% of initial assessments and 26–52% of subsequent assessments overall. There were neither statistically significant differences in accuracy between the two techniques of HR assessment (auscultation vs palpation) nor across the three scenarios. Of the 90 errors in resuscitation, 43 (48%) occurred in association with errors in HR determination.

Conclusions

Determination of heart rate via auscultation and palpation by experienced healthcare professionals in a neonatal patient simulator with standardized cues is not reliable. Inaccuracy in HR determination is associated with errors of omission and commission. More reliable methods for HR assessment during neonatal resuscitation are required.     

临床给药差错归因分析及其防范措施的研究

目的通过对给药护理差错进行归因分析,针对性的采取有效防范措施,减少临床护理差错的发生,提高护理质量。方法对2003年1月42008年9月发生的68例临床给药差错进行回顾性分析。结果68例临床给药差错中,床号、姓名查对错误居首位;工作年限在5年之内及15年以上的护士发生差错的概率较高。结论必须重视科学人性化管理和细节管理,改进查对方式,合理安排人力资源,规范护士培训,提高护士个人素质,才能有效预防护理缺陷的发生。     

Expansion of the lymphatic vasculature in cancer and inflammation: New opportunities for in vivo imaging and drug delivery

Over the last 15 years, discovery of key growth factors and specific molecular markers for lymphatic vessels has enabled a new era of molecular research on the lymphatic vascular system. As a result, it has been found that lymphangiogenesis, the expansion of existing lymphatic vessels, plays an important role in tumor progression and in the control of chronic inflammation. At the same time, technical advancements have been made to improve the visualization of the lymphatic system. We have recently developed liposomal and polymer-based formulations of near-infrared lymphatic-specific imaging tracers for the non-invasive quantitative in vivo imaging of lymphatic vessel function. Using these tracers, a near-infrared stereomicroscope system allows imaging of initial and collecting lymphatic vessels with high spatial and temporal resolution in mice. In addition, we have developed a new method, using antibodies to a lymphatic specific marker and positron emission tomography, to sensitively detect lymphatic expansion in lymph nodes as the earliest sign of cancer metastasis. These imaging methods have great potential to provide non-invasive measures to assess the functionality of the lymphatic system and to assess the efficiency of lymphatic drug delivery.     

Overcoming the delivery barrier of oligonucleotide drugs and enhancing nucleoside drug efficiency: The use of nucleolipids

With the rapid development of synthetic technology and biological technology, many nucleic acid-based drugs have entered the clinical trials. However, their inherent disabilities in actively and efficiently penetrating cell membranes still severely restrict their further application. The main drawback of cationic lipids, which have been widely used as nonviral vectors of nucleic acids, is their high cytotoxicity. A series of nucleoside-based or nucleotide-based nucleolipids have been reported in recent years, due to their oligonucleotide delivery capacity and low toxicity in comparison with cationic lipids. Lipophilic prodrugs of nucleoside analogs have extremely similar structures with nucleolipid vectors and are thus helpful for improving the transmembrane ability. This review introduces the progress of nucleolipids and provides new strategies for improving the delivery efficiency of nucleic acid-based drugs, as well as lipophilic prodrugs of nucleosides or nucleotides for antiviral or anticancer therapies.     

Structure and dynamics of liposomes designed for drug delivery: coarse-grained molecular dynamics simulations to reveal the role of lipopolymer incorporation

In this work, coarse-grained molecular dynamics simulations are carried out in NPTH and NVTE statistical ensembles in order to study the structure and dynamics properties of liposomes coated with polyethylene glycol (PEG). The considered liposomes are made by membrane bilayer DPPC with DPPC-PEG incorporated lipopolymers, in an aqueous environment. We have described the two essential PEG conformation regimes, mushroom and brush, and their properties which depend on the grafting density. The effects of grafting density on the structure and dynamics of the membrane were also studied. Our simulations were then discussed by comparing with the available experimental results and by referring to the suitable theoretical models. The results from the NPTH simulations agree with the experimental data of X-ray diffraction and with scale and mean-field theories in terms of thickness of the PEG layer and thickness of the DPPC bilayer membrane. The results from NVTE simulations are found in good agreement with the experimental results from studying the diffusion of the DPPC bilayer membrane and the PEG. The analysis of the mean square displacement revealed that the dynamics of the membranes in the plane show a subdiffusion due to the cage effect and that the grafted PEG dynamics is better described by the Rouse diffusion-mode. Thus, from a macroscopic viewpoint, the incorporation of DPPC-PEG plays an important role in the protection and lubrication of the liposome.

In this work, coarse-grained molecular dynamics simulations are carried out in NPTH and NVTE statistical ensembles in order to study the structure and dynamics properties of liposomes coated with polyethylene glycol (PEG).     

Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: An attractive tool for drug delivery

Polymeric micelles and vesicles have emerged as versatile drug carriers during the past decades. Furthermore, stimuli-responsive systems are developed whose properties change after applying certain external triggers. Therefore, a triggered release of drugs from stimuli-sensitive micelles and vesicles has become an interesting challenge in the pharmaceutical field. Polymeric micelles or vesicles are mainly composed of amphiphilic block copolymers that are held together in water due to strong hydrophobic interactions between the insoluble hydrophobic blocks, thus forming a core–shell or bilayer morphology. Consequently, destabilisation of these assemblies is induced by increasing the polarity of the hydrophobic blocks. Preferably, this process should be the consequence of an external trigger, or take place in a certain time frame or at a specific location. A variety of mechanisms has recently been described to accomplish this transition, which will be reviewed in this paper. These mechanisms include the destabilisation of polymeric micelles and vesicles by temperature, pH, chemical or enzymatic hydrolysis of side chains, oxidation/reduction processes, and light.     

Brain tumor targeting of magnetic nanoparticles for potential drug delivery: Effect of administration route and magnetic field topography

Our previous studies demonstrated feasibility of magnetically-mediated retention of iron oxide nanoparticles in brain tumors after intravascular administration. The purpose of this study was to elucidate strategies for further improvement of this promising approach. In particular, we explored administration of the nanoparticles via a non-occluded carotid artery as a way to increase the passive exposure of tumor vasculature to nanoparticles for subsequent magnetic entrapment. However, aggregation of nanoparticles in the afferent vasculature interfered with tumor targeting. The magnetic setup employed in our experiments was found to generate a relatively uniform magnetic flux density over a broad range, exposing the region of the afferent vasculature to high magnetic force. To overcome this problem, the magnetic setup was modified with a 9-mm diameter cylindrical NdFeB magnet to exhibit steeper magnetic field topography. Six-fold reduction of the magnetic force at the injection site, achieved with this modification, alleviated the aggregation problem under the conditions of intact carotid blood flow. Using this setup, carotid administration was found to present 1.8-fold increase in nanoparticle accumulation in glioma compared to the intravenous route at 350 mT. This increase was found to be in reasonable agreement with the theoretically estimated 1.9-fold advantage of carotid administration, R_d. The developed approach is expected to present an even greater advantage when applied to drug-loaded nanoparticles exhibiting higher values of R_d.     

Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: Lessons learned of the EPR effect and image-guided drug delivery

Paclitaxel (PTX) nanocrystals (200 nm) were produced by crystallization from a solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of a survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48 h by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20 mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for theranostics, in tracking drug distribution and pharmacokinetics.     

A comparison of quantitative computerized and human panel coronary endpoint measures: Implications for the design of angiographic trials

The Monitored Atherosclerosis Regression Study was a double-blind, 2-year, placebo-controlled, randomized, serial angiographic trial which tested reduction of low density lipoprotein-cholesterol with monotherapy using lovastatin on the progression of coronary atherosclerosis. Angiographic outcome was evaluated both by a panel of human readers who visually inspected matched film pairs to arrive at a global change score and by automated computerized vessel edge finding and lesion measurement (quantitative coronary angiography, QCA). In this paper, we model the association between QCA measures of coronary artery lesion change and the panel-based global change score. QCA measures included: per-patient changes in percent diameter stenosis and minimum lumen diameter averaged over all lesions; per-patient changes in average diameter and percent involvement averaged over all segments; the numbers of progressing and regressing lesions and new total occlusions; and the development of any new lesions.We found that when evaluating coronary artery lesion change, panelists evaluate changes in percent diameter stenosis for both low grade (<50% diameter stenosis at baseline) and high grade (≥50% diameter stenosis at baseline) lesions as well as new total occlusions and the number of progressing lesions. Although computerized quantification of the size of a lesion at baseline and as an endpoint may be a more precise measure than that by human panel interpretation, QCA fails to incorporate many other important aspects of coronary angiographic change visualized over the entire coronary artery tree by a panel of human interpreters. Thus, the global change score provides a “multiple endpoint” for coronary angiographic trials which does not suffer from the problems of statistical analysis and interpretation of multiple hypothesis tests which usually accompany true multiple endpoint measures. Choice of either or both endpoints in preparing angiographic trials depends on careful consideration of the desired information as well as the cost of carrying out the endpoint analysis.     

Development and characterization of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies

Dry eye syndrome is a common disorder of the tear film caused by decreased tear production or increased evaporation. The objective of this study was to evaluate the potential effectiveness of Cyclosporine A (CsA) nanoparticles (NPs) for the treatment of inflammation of the eye surface. Topical CsA is currently the only and safe pharmacologic treatment of severe dry eye symptoms. The NPs were prepared using either poly-lactide-co-glycolide (PLGA) or a mixture of PLGA with Eudragit®RL or were coated with Carbopol®. The mean size of CsA loaded NPs was within the range from 148 to 219 nm, except for the Carbopol® coated NPs (393 nm). The drug entrapment efficiency was very high (from 83 to 95%) and production yield was found between 75 and 92% in all preparations. The zeta potential of the Eudragit® RL containing NPs was positive (19-25 mV). The NPs formulations exhibited a biphasic drug release with initial burst followed by a very slow drug release and total cumulative release within 24 h ranged from 75 to 90%. Kinetically, the release profiles of CsA from NPs appeared to fit best with the Weibull model. The viability of L929 cells was decreased by increasing the concentration of the various NPs examined as well as the incubation time. The amount of NPs uptake was related to the polymer type used. The highest degree of cellular uptake (52.2%), tear film concentration of the drug (366.3 ng/g) and AUC_0 → 24 (972.6 ng h/g) value were obtained from PLGA: Eudragit® RL (75:25)-CsA NPs formulations. The change of surface characteristics of NPs represents a useful approach for improvement of ocular retention and drug availability.     

Bufuralol metabolism in human liver: a sensitive probe for the debrisoquine-type polymorphism of drug oxidation

The genetically controlled polymorphism causing decreased metabolism of debrisoquine is closely related to that of the metabolism of bufuralol and numerous other drugs and has important clinical consequences. A sensitive in vitro assay was developed which quantifies the production of 1'-hydroxy-bufuralol (carbinol) from bufuralol in human liver microsomes. Initial formation rates of carbinol suggested Michaelis-Menten kinetics with an apparent KM of 61 and 171 mumol l-1 and Vmax of 3.2 and 5.8 nmol mg-1 microsomal protein h-1 in two human liver samples. The Vmax in microsomes of thirty-two liver samples was 4.2 +/- 1.0 (SD) nmol carbinol mg-1 protein h-1. Metabolism of debrisoquine in vivo, as expressed by the 'metabolic ratio' of debrisoquine over 4-OH debrisoquine correlated (r = -0.65, P less than 0.01; n = 18) with carbinol production rate in microsomes in vitro. Microsomes of one individual identified as poor metabolizer of debrisoquine in vivo showed reduction of carbinol formation to 1.97 nmol mg-1 h-1. Mixing his microsomes with those of an extensive metabolizer resulted in additive formation of carbinol excluding mediation of the defect by a soluble inhibitor. These data support the concept of a primary defect in microsomal oxidation of bufuralol. The described assay offers a sensitive tool to investigate the molecular mechanism of the 'debrisoquine polymorphism'.     

刺激响应型纳米探针的制备及其对卵巢癌细胞的磁共振成像与药物输运研究

目的  构建基于肿瘤微环境下刺激响应型纳米探针介孔二氧化硅@阿霉素@二氧化锰纳米片(mSiO₂@DOX@MnO₂),探索其在卵巢癌细胞的特异性MRI与药物释放性能。方法  以转铁蛋白为稳定剂和靶向分子,通过超声分散法制备MnO₂纳米片,以MnO₂纳米片为门控,通过静电相互作用构建mSiO₂@DOX@MnO₂纳米探针。检测其Zeta电位、微观形貌、药物控释、光学性质及MRI性能。采用细胞增殖/毒性检测试剂盒检测纳米复合物对HO-8910卵巢癌细胞和CHO仓鼠卵巢细胞的细胞毒性。检验其在肿瘤细胞内的药物释放情况及细胞水平的MRI成像效果。结果  mSiO₂@DOX@MnO₂纳米探针在正常生理环境下几乎无MR信号,药物释放率小于10%。在肿瘤微环境高谷胱甘肽（GSH）浓度下产生较强的T1加权信号,其T1弛豫效率r1为5.86 mmol/（L·s）。在pH=5.0的酸性环境中,DOX的释放率在15 h左右开始维持在相对稳定水平,释放率约为33%。相同pH=7.4条件下,GSH高浓度组较低浓度组释放率明显增高,约为55%。当pH=5.0时,GSH浓度为10 mmol/L时,释放率最高,高达80%。mSiO₂@DOX@MnO₂纳米探针在实验浓度内对肿瘤细胞毒性较强,对正常CHO细胞毒性较弱,当mSiO₂@DOX@MnO₂纳米复合物中DOX含量约为100 μg/mL,HO-8910细胞存活率仅为24%,CHO细胞的存活率约为86%。HO-8910细胞、CHO细胞在不同质量浓度mSiO₂@DOX@MnO₂作用下存活率差异均有统计学意义（P < 0.05）。当锰离子浓度为1.12 mmol/L时,HO-8910细胞组的T1驰豫时间为467.60±4.45 ms,CHO细胞组的T1驰豫时间为1681.47±1.88 ms。同一浓度下的纳米探针对HO-8910细胞和CHO细胞MRI的T1弛豫时间两两比较差异均有统计学意义（P < 0.05）。结论  构建的mSiO₂@DOX@MnO₂纳米探针可靶向识别卵巢癌细胞,在肿瘤细胞酸性环境下及高水平GSH刺激响应下实现T1加权成像、药物的精准释放,可实现卵巢癌细胞水平的靶向磁共振成像及治疗。     

Highlights of the Annual Meeting of the Italian Association for Cell Cultures (AICC): new drug delivery strategies and technological platforms for diagnosis and therapy of tumors (Part II)

In recent decades considerable advances have been achieved in the development of new strategies based on the specific delivery of drugs into tumor tissues through the use of bio-materials and nanoparticles. The AICC meeting was divided into different sessions addressing different issues. The first section was about new delivery systems for either drugs or DNA. In detail, the pharmacokinetics and pharmaco-distribution of different carrier systems were explained. Thereafter, the possibility of drug delivery with pegylated liposomes or with nanoparticles or micelles was analyzed. The crossing of the blood–brain barrier by pegylated liposomes in order to deliver antitumor drugs to brain tumor sites was also explored.     

A novel system for expansion and delivery of human keratinocytes for the treatment of severe cutaneous injuries using microcarriers and compressed collagen

Cell therapy with autologous or allogeneic keratinocytes applied as a single‐cell suspension is well established in clinical practice in the treatment of severe burn injuries to augment epithelial barrier restoration. Yet, the application of cell sprays can lead to significant cell loss owing to lack of adhesion of cell suspension to the wound bed. The development of a robust and controllable method of transplanting cells onto the wound bed is yet to be established. The ability to control adhesion and distribution of cells by using a cell carrier embedded in a biodegradable scaffold could significantly improve the treatment of cutaneous wounds with keratinocyte cell therapy. Several microcarrier‐based systems for expanding keratinocytes already exist. A new method for expansion of human keratinocytes in a feeder‐free, defined medium system on microcarriers has been developed. The cells retained their basal, proliferative phenotype after rapid expansion in a clinically relevant time‐frame. The cell‐laden microcarriers were further incorporated into collagen scaffolds fabricated by plastic compression. When cultured in vitro, cells continued to proliferate and migrate along the surface of the collagen scaffold. Using an in vitro wound bed model, cells were observed to form mostly single cell layers and in some areas multiple cell layers within 8 days, while retaining their basal, proliferative phenotype, indicating the suitability of this cell transplantation method to improve epithelial barrier restoration. This advanced cell expansion and delivery method for cutaneous cell therapy provides a flexible tool for use in clinical application. Copyright © 2017 John Wiley & Sons, Ltd.