Antibacterial Effect of Human Mesenchymal Stem Cells is Mediated in Part from Secretion of the Antimicrobial Peptide LL-37

Recent in vivo studies indicate that mesenchymal stem cells (MSCs) may have beneficial effects in the treatment of sepsis induced by bacterial infection. Administration of MSCs in these studies improved survival and enhanced bacterial clearance. The primary objective of this study was to test the hypothesis that human MSCs possessed intrinsic antimicrobial properties. We studied the effect of human MSCs derived from bone marrow on the bacterial growth of Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. MSCs as well as their conditioned medium (CM) demonstrated marked inhibition of bacterial growth in comparison with control medium or normal human lung fibroblasts (NHLF). Analysis of expression of major antimicrobial peptides indicated that one of the factors responsible for the antimicrobial activity of MSC CM against Gram-negative bacteria was the human cathelicidin antimicrobial peptide, hCAP-18/LL-37. Both m-RNA and protein expression data showed that the expression of LL-37 in MSCs increased after bacterial challenge. Using an in vivo mouse model of E. coli pneumonia, intratracheal administration of MSCs reduced bacterial growth (in colony-forming unit) in the lung homogenates and in the bronchoalveolar lavage (BAL) fluid, and administration of MSCs simultaneously with a neutralizing antibody to LL-37 resulted in a decrease in bacterial clearance. In addition, the BAL itself from MSC-treated mice had a greater antimicrobial activity in comparison with the BAL of phosphate buffered saline (PBS)-treated mice. Human bone marrow-derived MSCs possess direct antimicrobial activity, which is mediated in part by the secretion of human cathelicidin hCAP-18/ LL-37.

TEENAGERS AND ILLICIT DRUG-USE - EXPANDING THE USER VS NONUSER DICHOTOMY

The present study examines proximal and distal factors associated with the use and non-use of illegal substances within a sample of 860 teenagers in North Wales. Arguing that there is predictive utility in expanding the traditional 'users vs non-users' design dichotomy, four groups are identified-resistant and vulnerable non-users and experimental and repeated users. 'Person' variables (life satisfaction, deviance, hopelessness and drug-related attributions) appeared to primarily differentiate the vulnerable group from their resistant counterparts and identify this, as yet non-using group, with user samples. It is suggested that these variables might represent 'risk' factors for illicit substance use and that the group design employed suggests they precede, rather than follow as a consequence of, illicit drug use. Like their resistant counterparts however, the vulnerable group are differentiated from user samples on some lifestyle and context indices. It is argued that these represent 'protective' influences in an otherwise at-risk group of non-users. Variables associated with an escalation of illicit drug use are discussed in considering the differences between the experimental and repeated user groups. Apart from the more proximal factor of drug-related attributions, 'person' variables appeared less involved here. Repeated users did however, tend to use a greater number of drugs, have a greater proportion of friends who also used illegal substances and significantly fewer had a Welsh cultural identity.

Non-steroidal anti-inflammatory drug and aspirin use and the risk of head and neck cancer

Background: Evidence for non-steroidal anti-inflammatory drugs (NSAIDs) preventing head and neck cancer (HNC) is inconclusive; however, there is some suggestion that aspirin may exert a protective effect.

Methods: Using data from the United States National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined the association between aspirin and ibuprofen use and HNC.

Results: Regular aspirin use was associated with a significant 22% reduction in HNC risk. No association was observed with regular ibuprofen use.

Conclusion: Aspirin may have potential as a chemopreventive agent for HNC, but further investigation is warranted.

Physical characterisation and component release of poly(vinyl alcohol)-tetrahydroxyborate hydrogels and their applicability as potential topical drug delivery systems

Poly(vinyl alcohol)-tetrahydroxyborate (PVA-THB) hydrogels are dilatant formulations with potential for topical wound management. To support this contention, the physical properties, rheological behaviour and component release of candidate formulations were investigated. Oscillatory rheometry and texture profile analysis were used at room temperature and 37 °C. Results showed that it was possible to control the rheological and textural properties by altering component concentration and modifying the type of PVA polymer used. Hydrogels made using PVA grades with higher degrees of hydrolysis displayed favourable characteristics from a wound healing perspective. In vitro release of borate and PVA were assessed in order to evaluate potential clinical dosing of free species originating from the hydrogel structure. Component diffusion was influenced by both concentration and molecular weight, where relevant, with up to 5% free PVA cumulative release observed after 30 min. The results of this study demonstrated the importance of poly(vinyl alcohol) selection for ensuring appropriate gel formation in PVA-THB hydrogels. The benefits of higher degrees of hydrolysis, in particular, included lower excipient release and reduced bioadhesion. The unique physical characteristics of these hydrogels make them an appealing delivery vehicle for chronic and acute wound management purposes.

Non-steroidal anti-inflammatory drug use and cervical cancer risk: a case-control study using the Clinical Practice Research Datalink

Non-steroidal anti-inflammatory drugs (NSAIDs) have many anticarcinogenic properties via the inhibition of cyclooxygenase 2 (COX-2). Only one study, a cohort study examining risk of all cancers, investigated their role in cervical cancer with inconsistent findings between non-aspirin NSAIDs and aspirin. The aim of this study was to further investigate NSAID/aspirin use and cervical cancer risk.

Potential Cellular Targets and Antibacterial Efficacy of Atmospheric Pressure Non-Thermal Plasma

Atmospheric pressure non-thermal plasma (APNTP) has been gaining increasing interest as a new alternative antibacterial approach. Although this approach has demonstrated promising antibacterial activity, its exact mechanism of action remains unclear. Mechanistic elucidation of the antimicrobial activity will facilitate development and rational optimisation of this approach for potential medical applications. In this study, the antibacterial efficacy of an in-house-built APNTP jet was evaluated alongside an investigation of the interactions between APNTP and major cellular components in order to identify the potential cellular targets involved in plasma-mediated bacterial destruction mechanisms. The investigated plasma jet exhibited excellent, rapid antibacterial activity against a selected panel of clinically significant bacterial species including Bacillus cereus, meticillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Pseudomonas aeruginosa, all of which were completely inactivated within 2 min of plasma exposure. Plasma-mediated damaging effects were observed, to varying degrees, on all of the investigated cellular components including DNA, a model protein enzyme, and lipid membrane integrity and permeability. The antibacterial efficacy of APNTP appears to involve a multiple-target mechanism, which potentially reduces the likelihood of emergence of microbial resistance towards this promising antimicrobial approach. However, cellular membrane damage and resulting permeability perturbation was found to be the most likely rate-determining step in this mechanism. Crown Copyright © 2013.

Microneedle-Iontophoresis Combinations for Enhanced Transdermal Drug Delivery

It has recently been proposed that the combination of skin barrier impairment using microneedles (MNs) coupled with iontophoresis (ITP) may broaden the range of drugs suitable for transdermal delivery as well as enabling the rate of delivery to be achieved with precise electronic control. However, few reports exist on the combination of ITP with in situ drug-loaded polymeric MN delivery systems. Our in vitro permeation studies revealed that MN enhances transdermal drug delivery. The combination of dissolving MN and ITP did not further enhance the extent of delivery of the low molecular weight drug ibuprofen sodium after short application periods. However, the extent of peptide/protein delivery was significantly enhanced when ITP was used in combination with hydrogel-forming MN arrays. As such, hydrogel-forming MN arrays show promise for the electrically controlled transdermal delivery of biomacromolecules in a simple, one-step approach, though further technical developments will be necessary before patient benefit is realized.

Fast-drying multi-laminate bioadhesive films for transdermal and topical drug delivery

No bioadhesive patch-based system is currently marketed. This is despite an extensive number of literature reports on such systems detailing their advantages over conventional pressure sensitive adhesive-based patches in wet environments and describing successful delivery of a diverse array of drug substances. This lack of proprietary bioadhesive patches is largely due to the fact that such systems are exclusively water-based, meaning drying is difficult. In this paper we describe, for the first time, a novel multiple lamination method for production of bioadhesive patches. In contrast to patches produced using a conventional casting approach, which took 48 hours to dry, bioadhesive films prepared using the novel multiple lamination method were dried in 15?min and were folded into formed patches in a further 10?min. Patches prepared by both methods had comparable physicochemical properties. The multiple lamination method allowed supersaturation of 5-aminolevulinic acid to be achieved in formed patch matrices. However, drug release studies were unable to show an advantage for supersaturation with this particular drug, due to its water high solubility. The multiple lamination method allowed greater than 90% of incorporated nicotine to remain within formed patches, in contrast to the 48% achieved for patches prepared using a conventional casting approach. The procedure described here could readily be adapted for automation by industry. Due to the reduced time, energy and ensuing finance now required, this could lead to bioadhesive patch-based drug delivery systems becoming commercially viable. This would, in turn, mean that pathological conditions occurring in wet or moist areas of the body could now be routinely treated by prolonged site-specific drug delivery, as mediated by a commercially produced bioadhesive patch.