Progressive Dysphagia Post Laryngeal Mask Airway Intubation

The laryngeal mask airway (LMA) is an important addition to the anaesthetic equipments; however its use may involve some important complications. We report an unusual and potentially serious complication arising from the use of this equipment. A 58 year old man underwent cataract surgery under general anaesthesia with a laryngeal mask airway. He woke up complaining of sore-throat which progressed to dysphagia and odynophagia over the next three days. The patient was found to have necrotic tissue and defects on the posterior pharyngeal wall which was managed conservatively. Key words: Laryngeal Mask Airway, Complications Dysphagi

Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery

In this study, dissolving microneedles (MNs) were used to enhance ocular drug delivery of macromolecules. MNs were fabricated using polyvinylpyrrolidone (PVP) polymer of various molecular weights (MWs) containing three model molecules of increasing MW, namely fluorescein sodium and fluorescein isothiocyanate–dextrans (with MW of 70 k and 150 k Da). Arrays (3 × 3) of PVP MNs with conical shape measuring about 800 μm in height with a 300 μm base diameter, containing the model drugs, were fabricated and characterized for their fracture forces, insertion forces (in the sclera and cornea), depth of penetration (using OCT and confocal imaging), dissolution time and in vitro permeation. The average drug content of the MNs (only in MN shafts) ranged from 0.96 to 9.91 μg, and the average moisture content was below 11 %. High MW PVP produced MNs that can withstand higher forces with minimal reduction in needle height. PVP MNs showed rapid dissolution that ranged from 10 to 180 s, which was dependent upon PVP’s MW. In vitro studies showed significant enhancement of macromolecule permeation when MNs were used, across both the corneal and scleral tissues, in comparison to topically applied aqueous solutions. Confocal images showed that the macromolecules formed depots within the tissues, which led to sustained permeation. However, use of MNs did not significantly benefit the permeation of small molecules; nevertheless, MN application has the potential for drug retention within the selected ocular tissues unlike topical application for small molecules. The material used in the fabrication of the MNs was found to be biocompatible with retinal cells (i.e. ARPE-19). Overall, this study reported the design and fabrication of minimally invasive rapidly dissolving polymeric MN arrays which were able to deliver high MW molecules to the eye via the intrastromal or intrascleral route. Thus, dissolving MNs have potential applications in enhancing ocular delivery of both small and macromolecules

Creation of a novel peptide with enhanced nuclear localization in prostate and pancreatic cancer cell lines

<p>Abstract</p> <p>Background</p> <p>For improved uptake of oligonucleotide-based therapy, the oligonucleotides often are coupled to peptides that facilitate entry into cells. To this end, novel cell-penetrating peptides (CPPs) were designed for mediating intracellular uptake of oligonucleotide-based therapeutics. The novel peptides were based on taking advantage of the nuclear localization properties of transcription factors in combination with a peptide that would bind putatively to cell surfaces. It was observed that adding a glutamate peptide to the N-terminus of the nuclear localization signal (NLS) of the Oct6 transcription factor resulted in a novel CPP with better uptake and better nuclear colocalization than any other peptide tested.</p> <p>Results</p> <p>Uptake of the novel peptide Glu-Oct6 by cancer cell lines was rapid (in less than 1 hr, more than 60% of DU-145 cells were positive for FITC), complete (by 4 hr, 99% of cells were positive for FITC), concentration-dependent, temperature-dependent, and inhibited by sodium azide (NaN₃). Substitution of Phe, Tyr, or Asn moieties for the glutamate portion of the novel peptide resulted in abrogation of novel CPP uptake; however none of the substituted peptides inhibited uptake of the novel CPP when coincubated with cells. Live-cell imaging and analysis by imaging flow cytometry revealed that the novel CPP accumulated in nuclei. Finally, the novel CPP was coupled to a carboxyfluorescein-labeled synthetic oligonucleotide, to see if the peptide could ferry a therapeutic payload into cells.</p> <p>Conclusions</p> <p>These studies document the creation of a novel CPP consisting of a glutamate peptide coupled to the N-terminus of the Oct6 NLS; the novel CPP exhibited nuclear colocalization as well as uptake by prostate and pancreatic cancer cell lines.</p

Dissolving microneedles for DNA vaccination: Improving functionality via polymer characterisation and RALA complexation

DNA vaccination holds the potential to treat or prevent nearly any immunogenic disease, including cancer. To date, these vaccines have demonstrated limited immunogenicity in vivo due to the absence of a suitable delivery system which can protect DNA from degradation and improve transfection efficiencies in vivo. Recently, microneedles have been described as a novel physical delivery technology to enhance DNA vaccine immunogenicity. Of these devices, dissolvable microneedles promise a safe, pain-free delivery system which may simultaneously improve DNA stability within a solid matrix and increase DNA delivery compared to solid arrays. However, to date little work has directly compared the suitability of different dissolvable matrices for formulation of DNA-loaded microneedles. Therefore, the current study examined the ability of 4 polymers to formulate mechanically robust, functional DNA loaded dissolvable microneedles. Additionally, complexation of DNA to a cationic delivery peptide, RALA, prior to incorporation into the dissolvable matrix was explored as a means to improve transfection efficacies following release from the polymer matrix. Our data demonstrates that DNA is degraded following incorporation into PVP, but not PVA matrices. The complexation of DNA to RALA prior to incorporation into polymers resulted in higher recovery from dissolvable matrices, and increased transfection efficiencies in vitro. Additionally, RALA/DNA nanoparticles released from dissolvable PVA matrices demonstrated up to 10-fold higher transfection efficiencies than the corresponding complexes released from PVP matrices, indicating that PVA is a superior polymer for this microneedle application

DNA vaccination for cervical cancer: Strategic optimisation of RALA mediated gene delivery from a biodegradable microneedle system.

Dissolvable microneedles can be employed to deliver DNA to antigen presenting cells within the skin. However, this technology faces two main challenges: the poor transfection efficacy of pDNA following release from the microneedle matrix, and the limited loading capacity of the micron-scale devices. Two-tier delivery systems combining microneedle platforms and DNA delivery vectors have increased efficacy but the challenge of increasing the loading capacity remains. This study utilised lyophilisation to increase the loading of RALA/pDNA nanoparticles within dissolvable PVA microneedles. As a result, delivery was significantly enhanced in vivo into an appropriate range for DNA vaccination (∼50 μg per array). Furthermore, modifying the manufacturing process was not detrimental to the microneedle mechanical properties or cargo functionality. It was demonstrated that arrays retained mechanical and functional stability over short term storage, and were able to elicit gene expression in vitro and in vivo. Finally, treatment with this novel formulation significantly retarded the growth of established tumours, and proved superior to standard intramuscular injection in a preclinical model of cervical cancer

STEM nanoanalysis of Au/Pt/Ti-Si3N4 interfacial defects and reactions during local stress of SiGe HBTs

A new insight on the behavior of metal contact-insulating interfaces in SiGe heterojunction bipolar transistor is given by high-performance aberration-corrected scanning transmission electron microscopy (STEM) analysis tools equipped with sub-nanometric probe size. It is demonstrated that the presence of initial defects introduced during technological processes play a major role in the acceleration of degradation mechanisms of the structure during stress. A combination of energy-filtered transmission electron microscopy analysis with high angle annular dark field STEM and energy dispersive spectroscopy provides strong evidence that migration of Au-Pt from the metal contacts to Ti/Si3N4 interface is one of the precursors to species interdiffusion and reactions. High current densities and related local heating effects induce the evolution of the pure Ti initial layer into mixture layer composed of Ti, O, and N. Local contamination of Ti layers by fluorine atoms is also pointed out, as well as rupture of TiN thin barrier layer

Time-dependent increase in ribosome processivity

We created a novel tripartite reporter RNA to separately and simultaneously examine ribosome translation rates at the 5′- and 3′-ends of a large open reading frame (ORF) in vitro in HeLa cell lysates. The construct contained Renilla luciferase (RLuc), β-galactosidase and firefly luciferase (FLuc) ORFs linked in frame and separated by a viral peptide sequence that causes cotranslational scission of emerging peptide chains. The length of the ORF contributed to low ribosome processivity, a low number of initiating ribosomes completing translation of the entire ORF. We observed a time-dependent increase in FLuc production rate that was dependent on a poly(A) tail and poly(A)-binding protein, but was independent of eIF4F function. Stimulation of FLuc production occurred earlier on shorter RNA templates. Cleavage of eIF4G at times after ribosome loading on templates occurred did not cause immediate cessation of 5′-RLuc translation; rather, a delay was observed that shortened when shorter templates were translated. Electron microscopic analysis of polysome structures in translation lysates revealed a time-dependent increase in ribosome packing and contact that correlated with increased processivity on the FLuc ORF. The results suggest that ORF transit combined with PABP function contribute to interactions between ribosomes that increase or sustain processivity on long ORFs

Using Weighted Goal Programming Model for Planning Regional Sustainable Development to Optimal Workforce Allocation:An Application for Provinces of Iran

Due to the urbanization and economic growth, planning of regional sustainable development has become one of the major challenges in the world. The key indicators such as gross domestic product (GDP), electricity and energy consumption and greenhouse gas emission (GHG) are considered in sustainable development planning. This paper determines number of required workforce in diferent sectors of each province in Iran considering targets/goals for sustainable development indicators in the 2030 macroeconomic and regional planning. First, the relative goals are designed for GDP, electricity, energy and GHG emission and then, two weighted goal programming models are applied to allocate the optimal workforce among four sectors: agriculture, industry, services and transportation. The frst model minimizes recruitment of new workforce and allows current workforce exchange among the four sectors in each province in order to achieve the goals, while the second model indicates equitable distribution of new workforce recruitment in diferent sectors within each province. In both models, the workforce changes have been investigated based on achieving the desirable growth rates of GDP, GHG, electricity and energy consumption as planned by the government. Based on the results of this paper, policy makers can manage workforce and the government can make optimized decisions to macroeconomic and regional planning