Ion-paired Drug Delivery: An Avenue for Bioavailability Improvement

Ion-pairing is reported to improve the lipophilicity and subsequently the transport rate of polar drugs across lipid membranes. Lipophilisation of ionic drugs with high aqueous solubilities by ion-pair formation with appropriate counter-ion have proven to be promising for several applications. The aim of this review is to present the usefulness of ion-pair for improving the poor bioavailability of ionic drugs through various routes. The review covers an update on the applications of this strategy to improve drug delivery through various routes of administration including ocular, oral, parenteral and transdermal. It is discussed how ion-pair complexes assist in introducing functionality that would allow formation of a neutral molecule which can be subsequently encapsulated into delivery systems to be distributed by various routes of administration.Keywords: Bioavailability, Counter-ion, Drug- delivery, Hydrophobic molecule, Ion-pair formatio

Early-stage adhesion of microbes onto oral biomaterials at the nanoscale

Despite much progress, the infection of oral biomaterials by bacterial and fungal cells remains an important problem in the clinic, affecting millions of patients worldwide. Although biofilm formation comprises a series of stages, the initial cell-surface interaction is crucial in determining infection of the biomaterial surface. By employing single-cell force spectroscopy (SCFS) and nanoindentation with the atomic force microscope (AFM), the biophysics of the bacteria-biomaterial surface interaction has been characterised for Streptococcus sanguinis, Staphylococcus aureus and Candida albicans. Initially, the development and optimisation of a protocol to harvest and immobilise living bacterial and fungal cells for AFM experimentation is described. In a next step, SCFS was utilised to explore the influence of implant surface nanotopography on the colonisation of S. aureus, utilising an in vitro polycarbonate implant model. Although nanotopography was not found to influence bacterial elasticity, it did increase the adhesion of S. aureus to the surface at early time points. Subsequently, the interaction between clinically relevant titanium (Ti) implant substrates and S. aureus and S. sanguinis cells was studied, which demonstrated strain-dependent differences in the unbinding patterns observed in AFM experiments. Worm-like chain (WLC) modelling of unbinding events was used to predict the length of the bacterial adhesins involved in the Ti-bacteria interaction, which were found to be different for S. aureus and S. sanguinis. Finally, the attachment of C. albicans to acrylic surfaces at the single-cell level was explored with AFM. C. albicans was found to exhibit morphology-dependent adhesion onto acrylic, with adhesion being increased in hyphal tubes compared to yeast cells. Also, experiments suggest a potential correlation between strain virulence and increased adhesion to surfaces. Future work should focus on utilising this in vitro AFM model to explore novel antiadhesive and antimicrobial approaches at the single-cell level

Inhibition of Fungi and Gram-Negative Bacteria by Bacteriocin BacTN635 Produced by Lactobacillus plantarum sp. TN635

The aim of this study was to evaluate 54 lactic acid bacteria (LAB) strains isolated from meat, fermented vegetables and dairy products for their capacity to produce antimicrobial activities against several bacteria and fungi. The strain designed TN635 has been selected for advanced studies. The supernatant culture of this strain inhibits the growth of all tested pathogenic including the four Gram-negative bacteria (Salmonella enterica ATCC43972, Pseudomonas aeruginosa ATCC 49189, Hafnia sp. and Serratia sp.) and the pathogenic fungus Candida tropicalis R2 CIP203. Based on the nucleotide sequence of the 16S rRNA gene of the strain TN635 (1,540 pb accession no FN252881) and the phylogenetic analysis, we propose the assignment of our new isolate bacterium as Lactobacillus plantarum sp. TN635 strain. Its antimicrobial compound was determined as a proteinaceous substance, stable to heat and to treatment with surfactants and organic solvents. Highest antimicrobial activity was found between pH 3 and 11 with an optimum at pH = 7. The BacTN635 was purified to homogeneity by a four-step protocol involving ammonium sulfate precipitation, centrifugal microconcentrators with a 10-kDa membrane cutoff, gel filtration Sephadex G-25, and C18 reverse-phase HPLC. SDS-PAGE analysis of the purified BacTN635, revealed a single band with an estimated molecular mass of approximately 4 kDa. The maximum bacteriocin production (5,000 AU/ml) was recorded after a 16-h incubation in Man, Rogosa, and Sharpe (MRS) medium at 30 °C. The mode of action of the partial purified BacTN635 was identified as bactericidal against Listeria ivanovii BUG 496 and as fungistatic against C. tropicalis R2 CIP203

A powerful bursting radio source towards the Galactic Centre

Transient astronomical sources are typically powered by compact objects and usually signify highly explosive or dynamic events. While radio astronomy has an impressive record of obtaining high time resolution observations, usually it is achieved in quite narrow fields-of-view. Consequently, the dynamic radio sky is poorly sampled, in contrast to the situation in the X- and gamma-ray bands in which wide-field instruments routinely detect transient sources. Here we report a new transient source, GCRT J1745-3009, detected in 2002 during a moderately wide-field radio transient monitoring program of the Galactic center (GC) region at 0.33 GHz. The characteristics of its bursts are unlike those known for any other class of radio transient. If located in or near the GC, its brightness temperature (~10^16 K) and the implied energy density within GCRT J1745-3009 vastly exceeds that observed in most other classes of radio astronomical sources, and is consistent with coherent emission processes rarely observed. We conclude that GCRT J1745-3009 is the first member of a new class of radio transient sources, the first of possibly many new classes to be identified through current and upcoming radio surveys.Comment: 16 pages including 3 figures. Appears in Nature, 3 March 200

Testing surfactants as additives for clay improvement: compaction and suction effects

Environmental Geotechnics (Joint TC106-TC215 Session)This paper presents an exploratory study on surfactants as additives to improve soil properties. It is hypothesized that surfactant molecules populate the air-water interfaces reducing surface tension and suction thus allowing a control of the mechanical response of the soil. Suction measurements by means of a high suction tensiometer, compaction tests and Atterberg limits were conducted in mixtures of sand and kaolin, with and without a surfactant solution. The results revealed a prominent effect on suction, but to a lesser extent on the Atterberg limits and compaction behavior (the maximum dry density). This targeted effect of the surfactants suggests its molecules populate, not only the air-water interfaces decreasing surface tension, but may be adsorbing to the clay particles and forming micelles in the pore water as well. Therefore the interplay between the three may influence the soil behavior.published_or_final_versio

EQ-5D-3L Derived Population Norms for Health Related Quality of Life in Sri Lanka

Background Health Related Quality of Life (HRQoL) is an important outcome measure in health economic evaluation that guides health resource allocations. Population norms for HRQoL are an essential ingredient in health economics and in the evaluation of population health. The aim of this study was to produce EQ-5D-3L-derived population norms for Sri Lanka. Method A population sample (n =  780) was selected from four districts of Sri Lanka. A stratified cluster sampling approach with probability proportionate to size was employed. Twenty six clusters of 30 participants each were selected; each participant completed the EQ-5D-3L in a face-to-face interview. Utility weights for their EQ-5D-3L health states were assigned using the Sri Lankan EQ-5D-3L algorithm. The population norms are reported by age and socio-economic variables. Results The EQ-5D-3L was completed by 736 people, representing a 94% response rate. Sixty per cent of the sample reported being in full health. The percentage of people responding to any problems in the five EQ-5D-3L dimensions increased with age. The mean EQ-5D-3L weight was 0.85 (SD 0.008; 95%CI 0.84-0.87). The mean EQ-5D-3L weight was significantly associated with age, housing type, disease experience and religiosity. People above 70 years of age were 7.5 times more likely to report mobility problems and 3.7 times more likely to report pain/discomfort than those aged 18-29 years. Those with a tertiary education were five times less likely to report any HRQoL problems than those without a tertiary education. A person living in a shanty was 4.3 more likely to have problems in usual activities than a person living in a single house. Conclusion The population norms in Sri Lanka vary with socio-demographic characteristics. The socioeconomically disadvantaged have a lower HRQoL. The trends of population norms observed in this lower middle income country were generally similar to those previously reported in high income countries

The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population

Background: The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. \ud \ud Methods: We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. \ud \ud Results: Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). \ud \ud Conclusion: This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group. \ud \ud Trial registration: UKADS Trial Registration: ISRCTN38297969

Nudging down theft from insecure vehicles. A pilot study

This report presents the preliminary findings of a pilot study to reduce thefts from cars committed against insecure vehicles, using the behavioural insights or ‘nudge approach’. The recipients of the ‘nudges’ were potential victims of theft from insecure vehicles living in high rate areas for this crime, where a bespoke leaflet campaign was developed to nudge vehicle owners into thinking more carefully when leaving their vehicles unattended, particularly when left on their driveways overnight. Although somewhat tentative at this stage, the preliminary findings indicate that the percentage of thefts committed against insecure vehicles in the two treatment areas was reduced significantly when compared with the two control group areas where no nudge interventions were introduced. This demonstrates that if appropriate nudges (grounded in psychological theory) are coupled with and delivered by appropriate messengers, the prosocial behavioural change can be encouraged which can lead to a reduction in criminal behaviour and opportunities for crim

Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.

Malnourished HIV-infected African adults are at high risk of early mortality after starting antiretroviral therapy (ART). We hypothesized that short-course, high-dose vitamin and mineral supplementation in lipid nutritional supplements would decrease mortality