Porphyrin Cross-Linkers for Generating Soluble Molecularly Imprinted Polymers from Polyethyleneimine

Molecular recognition is vital to many biochemical processes and is at the heart of promising bio-medically related technologies. Molecular imprinting has a long-standing history as a successful method for mimicking the molecular recognition phenomena exhibited by nature, whereby artificial receptors are prepared for a given target molecule based on synthetic polymers. The molecularly imprinted polymer (MIP) contains a three dimensional network with a memorized cavity specific to the shape and functionality of the templated target molecule. The utility of traditional MIPs has been limited due to an inherent lack of solubility. We have worked toward developing a system that allows for the preparation of soluble MIPs targeting quadruplex DNA, specifically the human telomeric repeat (TTAGGG)4. To do so we have synthesized a series of meso-substituted, water soluble, tetracationic pyridinium porphyrins which we have successfully coupled to polyethyleneimine (PEI), forming a condensation polyamide. We have demonstrated that one of these porphyrins can be used as an efficient polymer cross-linker, which provides a unique quadruplex DNA binding site in the polymer network. Unfortunately, the high cationic charge density found on PEI has been found to elicit potential dilemmas in the utility of this method. Attempts have been made to reduce this charge by increasing the cross-linking agent and partially acetylating the PEI. While the network structure of this soluble cross-linked polymer still requires optimization, it has shown promise and demonstrates the opportunities for new soluble molecularly imprinted polymer designs that include quadruplex binding sites

4D Printing of origami structures for minimally invasive surgeries using functional scaffold

Origami structures have attracted attention in biomedical applications due to their ability to develop surgical tools that can be expanded from a minimal volume to a larger and functional device. On the other hand, four-dimensional (4D) printing is an emerging technology, which involves 3D printing of smart materials that can respond to external stimuli such as heat. This short communication introduces the proof of concept of merging origami and 4D printing technologies to develop minimally invasive delivery of functional biomedical scaffolds with high shape recovery. The shape-memory effect (SME) of the PLA filament and the origami designs were also assessed in terms of deformability and recovery rate. The results showed that herringbone tessellation origami structure combined with internal natural cancellous bone core satisfies the design requirement of foldable scaffolds. The substantial and consistent SME of the 4D printed herringbone tessellation origami, which exhibited 96% recovery compared to 61% for PLA filament, was the most significant discovery of this paper. The experiments demonstrated how the use of 4D printing in situ with origami structures could achieve reliable and repeatable results, therefore conclusively proving how 4D printing of origami structures can be applied to biomedical scaffolds

Role of ankle-brachial pressure index as a predictor of coronary artery disease severity in diabetic and non-diabetic patients

PurposeThe aim of the study was to estimate the role of ankle-brachial pressure index (ABI) in predicting severity of coronary artery disease (CAD) in patients with or without diabetes mellitus.MethodsThis study included 120 patients with CAD proved by coronary angiography and ABI was measured for all of them. They were divided into 4 groups; Group (A): Non-diabetic patients without peripheral arterial disease (PAD) (ABI < or =0.9) , Group (B):diabetic patients without PAD (ABI < or =0.9), Group (C):Non-diabetic patients with PAD (ABI>0.9) and Group (D):diabetic patients with PAD (ABI>0.9).ResultsHypertension was more prevalent in group (D) (p value>0.05). Group (C) had the highest mean age and the highest percentage of smokers, after normalization of the effects of the risk factors mean Gensini score, mean number of affected coronary vessels, mean number of coronary artery lesions and the percentage of coronary artery chronic total occlusions (CTO) were significantly higher in groups (C & D) (p>0.001) (Table 1).ConclusionABI had a significant relationship with the degree of CAD severity. Therefore ABI seems to be a reliable independent prognostic marker of CAD severity in patients with or without diabetes mellitus

Fabrication and characterization of oxygen-generating polylactic acid/calcium peroxide composite filaments for bone scaffolds

The latest advancements in bone scaffold technology have introduced novel biomaterials that have the ability to generate oxygen when implanted, improving cell viability and tissue maturation. In this paper, we present a new oxygen-generating polylactic acid (PLA)/calcium peroxide (CPO) composite filament that can be used in 3D printing scaffolds. The composite material was prepared using a wet solution mixing method, followed by drying and hot melting extrusion. The concentration of calcium peroxide in the composite varied from 0% to 9%. The prepared filaments were characterized in terms of the presence of calcium peroxide, the generated oxygen release, porosity, and antibacterial activities. Data obtained from scanning electron microscopy and X-ray diffraction showed that the calcium peroxide remained stable in the composite. The maximum calcium and oxygen release was observed in filaments with a 6% calcium peroxide content. In addition, bacterial inhibition was achieved in samples with a calcium peroxide content of 6% or higher. These results indicate that an optimized PLA filament with a 6% calcium peroxide content holds great promise for improving bone generation through bone cell oxygenation and resistance to bacterial infections

Preparation and characterisation of amino acids based trimethoprim salts

Trimethoprim (TMP) is a dihydrofolate reductase (DHFR) inhibitor which prevents the conversion of dihydrofolic acid into tetrahydrofolic acid, resulting in the depletion of the latter and leading to bacterial death. Oral bioavailability of TMP is hindered by both its low solubility and low permeability. This study aims to prepare novel salts of TMP using anionic amino acids; aspartic and glutamic acid as counter ions in order to improve solubility and dissolution. TMP salts were prepared by lyophilisation and characterized using FT-IR spectroscopy, proton nuclear magnetic resonance (1HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). Both the amino acids formed salts with TMP in a 1:1 molar ratio and showed a 280 fold improvement in solubility. Investigation of the microbiological activity of the prepared salts against TMP sensitive Escherichia coli showed that the new salts not only retained antibacterial activity but also exhibited higher zone of inhibition which was attributed to improved physicochemical characters such as higher solubility and dissolution. The results are an important finding that could potentially impact on faster onset of antibacterial activity and reduced therapeutic dose when administered to patients. Studies are underway investigating the effect of ion-pairing TMP with amino acids on the permeability profile of the drug

A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2±0.05N/mm2 to 2.85±0.36N/mm2 upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets' disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets

Understanding the compaction behaviour of low-substituted HPC : macro, micro, and nano-metric evaluations

The fast development in materials science has resulted in the emergence of new pharmaceutical materials with superior physical and mechanical properties. Low-substituted hydroxypropyl cellulose is an ether derivative of cellulose and is praised for its multi-functionality as a binder, disintegrant, film coating agent and as a suitable material for medical dressings. Nevertheless, very little is known about the compaction behaviour of this polymer. The aim of the current study was to evaluate the compaction and disintegration behaviour of four grades of L-HPC namely; LH32, LH21, LH11, and LHB1. The macrometric properties of the four powders were studied and the compaction behaviour was evaluated using the out-of-die method. LH11 and LH22 showed poor flow properties as the powders were dominated by fibrous particles with high aspect ratios, which reduced the powder flow. LH32 showed a weak compressibility profile and demonstrated a large elastic region, making it harder for this polymer to deform plastically. These findings are supported by AFM which revealed the high roughness of LH32 powder (100.09 ± 18.84 nm), resulting in small area of contact, but promoting mechanical interlocking. On the contrary, LH21 and LH11 powders had smooth surfaces which enabled larger contact area and higher adhesion forces of 21.01 ± 11.35 nN and 9.50 ± 5.78 nN, respectively. This promoted bond formation during compression as LH21 and LH11 powders had low strength yield

Chemical shark repellent: Myth or fact? The effect of a shark necromone on shark feeding behaviour

a b s t r a c t Since 1942, the search for an effective chemical shark repellent has been ongoing research concern in the United States. A long-standing anecdote that sharks avoid areas containing decomposing shark tissue has initiated new interest in identifying trace chemical alarm signals produced during decomposition (necromones). A commercially-sourced shark necromone produced from putrefied shark tissue was evaluated over a five-year period in South Bimini, Bahamas. Competitively-feeding populations of Caribbean reef sharks (Carcharhinus perezi) and blacknose sharks (Carcharhinus acronotus) were exposed to necromones using pressurized aerosol canisters at the surface. Shark density estimations were made at the initial, 1 min and 5 min intervals after preliminary exposure along with continuous exposure of feeding stimulus. In both species, an unambiguous halt in feeding behavior was observed within 1 min after exposure of the necromone. For aerosol delivery, a 150 mL dose of the necromone from a single aerosol canister is able to halt all feeding activity in a combined population of C. perezi and C. acronotus. Shark necromones induced a spectacular alarm response in interacting sharks resulting in a temporary evacuation of an area containing feeding stimuli. Additionally, sharks were not deterred by alternative treatment presentations of 10% weight percent (w/w) aqueous urea, 10% w/w oleic acid in ethanol, or water buffered to pH 8.5. Habituation to the necromone was not observed for repeated tests at the same location. In all experiments, the presence of a shark necromone did not produce a similar aversion response for teleosts as observed in C. perezi or C. acronotus; however, anecdotal observations demonstrate that teleosts increased their feeding rate in the presence of the necromone. Experimental controls using denatured ethanol or water confirmed that feeding sharks were not deterred by bubbles, sound, or the solvents used to extract the necromones. Comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry indicates that the necromone is a complex solution rich in amino acids and putrefaction products. Experiments demonstrate that the key chemical component responsible for the alarm response is within these amino acids and/or putrefaction products, but further experimentation is needed to more accurately identify the active ingredient. Shark necromones hold particular promise for use in shark bycatch reduction and conservation. The existence of a putative chemical shark repellent has been confirmed

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London