Bactericidal urea crown ethers target phosphatidylethanolamine membrane lipids.

An increasing number of people are infected with antibiotic-resistant bacteria each year, sometimes with fatal consequences. In this manuscript, we report a novel urea-functionalized crown ether that can bind to the bacterial lipid phosphatidylethanolamine (PE), facilitate PE flip-flop and displays antibacterial activity against the Gram-positive bacterium Bacillus cereus with a minimum inhibitory concentration comparable to that of the known PE-targeting lantibiotic duramycin.

Liposomes Enhance Dye Localization within the Mammary Ducts of Porcine Nipples.

Transductal and transepidermal diffusion are two distinct penetration routes of molecules administered via the nipple. To improve the therapeutic potential of this drug administration technique, drug penetration into the mammary ducts should be maximized, which may be accomplished through design optimization of drug delivery vehicles. In this study, we evaluated liposomes, ranging in size from 100 to 3000 nm, to improve ductal penetration of model fluorescent dyes using fluorescence microscopy and image analysis. Liposomes encapsulating a model fluorescent lipophilic dye, nile red, or hydrophilic dye, sulforhodamine B, were applied topically on porcine nipples for 6 h in vitro. Liposome encapsulation of sulforhodamine B significantly reduced the total amount of dye penetrating the nipple, while penetration of liposome-encapsulated nile red varied depending on vesicle size, as compared to their solution controls. However, the fluorescence intensity localized at the ductal epithelium was higher at extended nipple depths in tissues treated with liposomes versus dye solutions, suggesting a higher concentration of dye penetrating the nipple via the ducts. In contrast, the fluorescence intensity measured at the stratum corneum was reduced (sulforhodamine B) or unchanged (nile red) in nipples treated with liposomes versus dye solutions, suggesting a decrease or no change in dye penetration of the nipple via the stratum corneum. Furthermore, the limited penetration distance into the connective tissue beyond the ductal epithelium for both liposome-encapsulated nile red and sulforhodamine B suggests that liposomes remain intact over the 6 h duration of this study when penetrating through the ducts and enhance retention within the ductal lumen. However, the varied penetration profiles into the connective tissue beyond the stratum corneum between liposome-encapsulated nile red and sulforhodamine B suggests that the liposomes destabilize when penetrating the outer tissues layers of the nipple. Overall, liposomes, regardless of size, improved penetration into and retention within the mammary ducts, while limiting penetration into the stratum corneum, indicating their capacity to target the mammary ductal network.

Evaluation of Amphiphilic Star/Linear-Dendritic Polymer Reverse Micelles for Transdermal Drug Delivery: Directing Carrier Properties by Tailoring Core versus Peripheral Branching.

The reverse micelle self-assembly of lipophile-functionalized poly(ethylene glycol) (PEG) dendrimer hybrids is probed for applications in carrier-mediated transdermal drug delivery. Under investigation are topologically diverse amphiphiles featuring controlled branching motifs at either the polymer core (one-, two-, and four-arm PEG) and the polar/nonpolar interface (peripheral dendritic generations 0-2). Thus, a systematic investigation of the effect of branching location (core vs peripheral) on carrier properties is described. Dye-encapsulation experiments verify these materials are capable of forming well-defined aggregates and solubilizing polar compounds. Further quantification of reverse micelle critical micelle concentration and dye loading capacity for the branched amphiphile library was obtained through spectroscopy characterization. Both core and peripheral branching are shown to significantly influence dynamic encapsulation behavior, with evidence of location-based contributions extending beyond multiplicity of branching alone. Finally, the in vitro transdermal diffusion of the reverse micelle carriers was investigated through Franz diffusion cell experiments using physiologically relevant juvenile porcine dermis. The permeation results, combined with previously reported aggregate size trends, show the complex relationship between polymer branching and transdermal transport, with the lowest core- and highest peripherally-branched amphiphilic analogs exhibiting optimal transdermal permeation characteristics for this set of branched carriers.

The role of the mentor in evaluating learning.

This paper aims to give an overview of the role of the mentor within the sphere of the evaluation of learning, with particular emphasis on the intermediate interview and student reflection on their learning experience as formal tools for evaluation. Although the terms 'evaluation' and 'assessment' are often used in similar contexts, it is important to distinguish between the two concepts. The importance of evaluation of learning cannot be over emphasised as it is an important part of ensuring that students develop as expected (Nursing and Midwifery Council (NMC) 2008). Therefore, failure to evaluate learning can have a negative impact on the student and their learning throughout their programme of study.

The A subunit of Escherichia coli heat-labile enterotoxin functions as a mucosal adjuvant and promotes IgG2a, IgA, and Th17 responses to vaccine antigens.

Enterotoxigenic Escherichia coli (ETEC) produces both heat-labile (LT) and heat-stable (ST) enterotoxins and is a major cause of diarrhea in infants in developing countries and in travelers to those regions. In addition to inducing fluid secretion, LT is a powerful mucosal adjuvant capable of promoting immune responses to coadministered antigens. In this study, we examined purified A subunit to further understand the toxicity and adjuvanticity of LT. Purified A subunit was enzymatically active but sensitive to proteolytic degradation and unable to bind gangliosides, and even in the presence of admixed B subunit, it displayed low cyclic AMP (cAMP) induction and no enterotoxicity. Thus, the AB5 structure plays a key role in protecting the A subunit from proteolytic degradation and in delivering the enzymatic signals required for secretion. In contrast, the A subunit alone was capable of activating dendritic cells and enhanced immune responses to multiple antigens following intranasal immunization; therefore, unlike toxicity, LT adjuvanticity is not dependent on the AB5 holotoxin structure or the presence of the B subunit. However, immune responses were maximal when signals were received from both subunits either in an AB5 structure or with A and B admixed. Furthermore, the quality of the immune response (i.e., IgG1/IgG2 balance and mucosal IgA and IL-17 secretion) was determined by the presence of an A subunit, revealing for the first time induction of Th17 responses with the A subunit alone. These results have important implications for understanding ETEC pathogenesis, unraveling immunologic responses induced by LT-based adjuvants, and developing new mucosal vaccines.

Synthesis of amphiphilic star block copolymers and their evaluation as transdermal carriers.

Amphiphilic star polymers offer substantial promise for a range of drug delivery applications owing to their ability to encapsulate guest molecules. One appealing but underexplored application is transdermal drug delivery using star block copolymer reverse micelles as an alternative to the more common oral and intravenous routes. We prepared 6- and 12-arm amphiphilic star copolymers via atom transfer radical polymerization (ATRP) of sequential blocks of polar oligo (ethylene glycol)methacrylate and nonpolar lauryl methacrylate from brominated dendritic macroinitiators based on 2,2-bis(hydroxymethyl) propionic acid. These star block copolymers demonstrate the ability to encapsulate polar dyes such as rhodamine B and FITC-BSA in nonpolar media via UV/vis spectroscopic studies and exhibit substantially improved encapsulation efficiencies, relative to self-assembled "1-arm" linear block copolymer analogs. Furthermore, their transdermal carrier capabilities were demonstrated in multiple dye diffusion studies using porcine skin, verifying penetration of the carriers into the stratum corneum.

CPD for mentors: creating a portfolio.

It is a mandatory requirement for mentors to support and assess all pre-registration students in their practice areas. The role is time consuming and challenging, but can also be extremely rewarding. This article examines the roles and responsibilities of mentors and discusses the importance of continuing professional development for mentors. It also looks at how mentors can demonstrate they meet the standards required by the Nursing and Midwifery Council (2008b).

Liposomes in double-emulsion globules.

Tubular liposomes containing a hydrophilic model compound (fluorescein sodium salt, FSS) were entrapped inside the internal aqueous phase (W(1)) of water-in-oil-in-water (W(1)/O/W(2)) double-emulsion globules. Our hypothesis was that the oil membrane of double emulsions can function as a layer of protection to liposomes and their contents and thus better control their release. Liposomes were prepared in bulk, and their release was observed microscopically from individual double-emulsion globules. The liposomes containing FSS were released through external coalescence, and the behavior of this system was monitored visually by capillary video microscopy. Double-emulsion globules were stabilized with Tween 80 as the water-soluble surfactant, with Span 80 as the oil-soluble surfactant, while the oil phase (O) was n-hexadecane. The lipids in the tubular liposomes consist of L-alpha-phosphatidylcholine and Ceramide-VI. Variations of Tween 80 concentration in the external aqueous phase (W(2)) and Span 80 concentration in the O phase controlled the release of liposomes from the W(1) phase to the W(2) phase. The major finding of this work is that the sheer presence of liposomes in the W(1) phase is by itself a stabilizing factor for double-emulsion globules.

Protocol for a mixed methods study investigating the impact of investment in housing, regeneration and neighbourhood renewal on the health and wellbeing of residents: the GoWell programme.

BACKGROUND: There is little robust evidence to test the policy assumption that housing-led area regeneration strategies will contribute to health improvement and reduce social inequalities in health. The GoWell Programme has been designed to measure effects on health and wellbeing of multi-faceted regeneration interventions on residents of disadvantaged neighbourhoods in the city of Glasgow, Scotland. METHODS/DESIGN: This mixed methods study focused (initially) on 14 disadvantaged neighbourhoods experiencing regeneration. These were grouped by intervention into 5 categories for comparison. GoWell includes a pre-intervention householder survey (n = 6008) and three follow-up repeat-cross sectional surveys held at two or three year intervals (the main focus of this protocol) conducted alongside a nested longitudinal study of residents from 6 of those areas. Self-reported responses from face-to-face questionnaires are analysed along with various routinely produced ecological data and documentary sources to build a picture of the changes taking place, their cost and impacts on residents and communities. Qualitative methods include interviews and focus groups of residents, housing managers and other stakeholders exploring issues such as the neighbourhood context, potential pathways from regeneration to health, community engagement and empowerment. DISCUSSION: Urban regeneration programmes are 'natural experiments.' They are complex interventions that may impact upon social determinants of population health and wellbeing. Measuring the effects of such interventions is notoriously challenging. GoWell compares the health and wellbeing effects of different approaches to regeneration, generates theory on pathways from regeneration to health and explores the attitudes and responses of residents and other stakeholders to neighbourhood change.

Do Voluntary Lab-Based Active Learning Sessions Impact Medical Student Knowledge Retention?

BACKGROUND: Despite recent evidence demonstrating the benefits of case-based and active learning strategies in medical education, many medical schools have reduced or entirely eliminated teaching laboratories in medical microbiology courses. The objective of our investigation was to analyze the impact of a voluntary hands-on microbiology laboratory session on students' knowledge retention and ability to apply the underlying principles to exam questions in our Introduction to Infectious Diseases (IID) course. METHODS: We compared the performance of students participating in the wet labs with those who did not, analyzing scores on exam questions directly related to the concepts presented in the laboratory session and their overall scores on the IID module exam. The voluntary nature of our microbiology lab session provided a unique opportunity to assess its impact on knowledge retention independent of other factors, such as lecture and exam content, etc. Data were collected for 7 academic years and analyzed in aggregate. RESULTS: Students who attended voluntary lab sessions scored higher on exam questions related to lab exercises than students who did not attend (Mann-Whitney, p = 0.0074). These results support the benefit of reexamining material originally presented during classroom sessions in an active, collaborative learning environment. Course evaluation responses indicted that students valued the opportunity to visually reinforce concepts they had previously read in a textbook or heard in lectures. CONCLUSIONS: At a time when many medical schools are reducing or eliminating hands-on lab sessions in microbiology and other basic sciences, our results highlight the benefits of this teaching strategy. The laboratory session provided an opportunity for students to revisit concepts initially presented in the traditional classroom setting and to actively engage in applying these concepts to case-based scenarios. The improved educational outcomes will benefit students in future standardized exams as well as in their professional practice.

Highly aspherical silica nanoshells by templating tubular liposomes.

A dual-lipid liposome system consisting of a phospholipid and a skin ceramide extruded though a 100 nm membrane yields novel tubular and helical liposomes. These liposomes were used as templates to generate highly aspherical silica nanocapsules with length to diameter aspect ratios exceeding 10. Many of these nanocapsules have the morphology of a bulbous end attached to a long tip, mimicking microneedles attached to a reservoir. The fidelity of helical liposomes is transcribed to the silicas and the long tips indicate helically entwined left-handed silica structures. The silica coating is expected to protect and stabilize the internal contents of the liposomes, as well as enable surface functionalization for applications in drug or targeted delivery.

Nanoemulsions Enhance in vitro Transpapillary Diffusion of Model Fluorescent Dye Nile Red.

While the feasibility of transpapillary drug delivery has previously been established, localized transport via the mammary ducts may be improved with tailored drug delivery formulations. The objective of this study was to investigate the impact of nanoemulsion encapsulation on transpapillary delivery in vitro. Nanoemulsion formulations composed of isopropyl myristate and Tween 80 encapsulating a fluorescent dye were applied topically on porcine nipples using a Franz diffusion cell. A combination of dye extraction and fluorescence image analysis was used to quantify the total amount of dye retained within the nipple and to characterize the penetration routes. After diffusion for 6 hours, the amount of dye deposited in the nipple was proportional to the formulation's water concentration. The 90% water formulation deposited significantly more dye via both the stratum corneum and mammary ducts, while the 80% and 70% water formulations moderately increased ductal penetration, but minimally altered stratum corneum penetration as compared to the control solution. Similar trends were found after diffusion for 48 hours; however, the overall impact was diminished, likely due to the nanoemulsion's topical instability. This study indicates that drug delivery vehicles, nanoemulsions specifically, enhance delivery of encapsulated molecules via the stratum corneum and mammary ducts in a formulation-dependent basis.

Determination of permeation pathways of hydrophilic or hydrophobic dyes through the mammary papilla.

The transport pathways and permeation kinetics of lipophilic and hydrophilic fluorescent dyes through porcine mammary papillae were visualized and quantified. Porcine mammary papillae, removed from full-thickness abdominal tissue, were positioned in a Franz diffusion cell for passive diffusion studies. Solutions containing the fluorescent dyes were applied topically for time periods ranging from 30 min to 48 h. Dye concentrations in tissue and Franz diffusion compartments were analyzed using fluorescence microscopy and fluorimetry. Fluorescence micrographs elucidated two permeation pathways, transepidermal and transductal. Hydrophilic sulforhodamine B predominantly penetrated via the transepidermal route, while lipophilic nile red diffused mainly by the transductal route. An almost 4-fold higher amount of sulforhodamine B was retained within the nipple over time compared to nile red, despite both dyes permeating through the tissue at similar rates. Diffusion through the porcine nipple was 500-fold higher than through adjacent skin for both dyes, likely attributable to the two mammary ducts which provide an entry point and transport route through the tissue. These results, generated from both qualitative and quantitative evidence at a micro and macro scale, demonstrate that the mammary ducts provide a direct pathway that contributes significantly to passive transport through the nipple, particularly for lipophilic molecules.

Controlled release from a nanocarrier entrapped within a microcarrier.

This study illustrates the entrapment of the dye molecule fluorescein sodium salt (FSS) by hydrogel nanoparticles, which are in turn confined inside a water-in-oil-in-water double-emulsion globule, and its subsequent release by the action of the competing agent hydrochloric acid (HCl). Thus, a "double carrier" concept is being introduced in which a nanoscale delivery vehicle is being transported by a microscale delivery vehicle in order to simultaneously take advantage of both systems. This may facilitate storage and handling while protecting the active substance and improving its action upon application.

Attitudes of bariatric surgeons concerning adolescent bariatric surgery (ABS).

BACKGROUND: As the number of adolescents with clinically severe obesity has grown, so too have the number of adolescents seeking bariatric surgery. METHODS: The membership of the ASBS was contacted by e-mail with a 14-question survey to ascertain plans for development of adolescent bariatric surgery (ABS) programs. Results were tabulated and expressed as a percentage of total respondents. RESULTS: Of the 92 respondents, most (84%) performed >50 adult bariatric procedures per year. Over half (53%) had performed ABS. Nearly half (45%) had performed <10 ABS cases within the last year, and 70% were planning ABS in the upcoming year. 42% reported that they have already or were in the process of developing an adolescent bariatric treatment program with pediatric specialists in their community. The vast majority (84%) of respondents was willing to participate in a multi-center collection of outcomes data, and 65% reported having dedicated personnel for clinical data collection. CONCLUSIONS: There is increasing interest in developing ABS programs. Despite the perceived need for such services, information is lacking in the adolescent age group to guide decisions regarding optimal patient selection, choice of operation, and postoperative management. Rigorous evaluation of the outcomes of this intervention with detailed prospective data collection is needed to support decision-making regarding use of bariatric surgery for adolescents with morbid obesity.

Improved diagnostic effectiveness with a sequential diagnostic paradigm in idiopathic pediatric sensorineural hearing loss.

OBJECTIVES: To determine whether a stepwise diagnostic paradigm is more diagnostically efficient and cost-effective than a simultaneous testing approach in the evaluation of idiopathic pediatric sensorineural hearing loss (SNHL). DESIGN: Prospective prevalence study. SETTING: Tertiary referral children's hospital. PATIENTS: Consecutive children (n = 150) presenting with idiopathic SNHL in the last 2 years. INTERVENTIONS: All children were evaluated with full diagnostic evaluations including GJB2 screens, temporal bone computed tomography scans, and laboratory investigations. MAIN OUTCOME MEASURES: 1) Diagnostic yields of GJB2 screens, imaging, and laboratory results per SNHL category; 2) Cost analysis comparing a sequential versus a simultaneous testing approach. RESULTS: Overall, 12.0% of patients had biallelic mutations in the GJB2 gene, whereas 30% of patients had an abnormality on temporal bone scan. Laboratory testing did not reveal the SNHL etiology in any patient. While maintaining diagnostic accuracy, significant cost savings were inferred by using a sequential diagnostic algorithm. Our data show children with severe to profound SNHL should first be tested with a GJB2 screen, as opposed to those with milder SNHL, who should undergo imaging as the initial testing step. In patients with initially positive GJB2 or imaging screens, logistic regression analysis significantly predicted negative results on further testing. CONCLUSIONS: A stepwise diagnostic paradigm tailored to the level of the hearing loss in children with bilateral SNHL is more diagnostically efficient and cost effective than the more commonly used full, simultaneous testing approach. Laboratory investigation should not be routine but based on clinical history.

Neighbourhood demolition, relocation and health. A qualitative longitudinal study of housing-led urban regeneration in Glasgow, UK.

We conducted a qualitative longitudinal study to explore how adult residents of disadvantaged urban neighbourhoods (Glasgow, UK) experienced neighbourhood demolition and relocation. Data from 23 households was collected in 2011 and 2012. Some participants described moves to new or improved homes in different neighbourhoods as beneficial to their and their families' wellbeing. Others suggested that longstanding illnesses and problems with the new home and/or neighbourhood led to more negative experiences. Individual-level contextual differences, home and neighbourhood-level factors and variations in intervention implementation influence the experiences of residents involved in relocation programmes.

The novel adjuvant dmLT promotes dose sparing, mucosal immunity and longevity of antibody responses to the inactivated polio vaccine in a murine model.

One option for achieving global polio eradication is to replace the oral poliovirus vaccine (OPV), which has the risk of reversion to wild-type virulence, with the inactivated poliovirus vaccine (IPV) vaccine. Adjuvants and alternate routes of immunization are promising options that may reduce antigen dose in IPV vaccinations, potentially allowing dose sparing and cost savings. Use of adjuvants and alternate routes of immunization could also help promote mucosal immunity, potentially mimicking the protection against intestinal virus shedding seen with OPV. In the current study, we examined the impact of combining the novel adjuvant dmLT with trivalent IPV for dose sparing, induction of mucosal immunity and increasing longevity of anti-poliovirus (PV) responses in a mouse model following either intradermal (ID) or intramuscular (IM) delivery. We found that non-adjuvanted ID delivery was not superior to IM delivery for fractional dose sparing, but was associated with development of mucosal immunity. Vaccination with IPV+dmLT promoted serum anti-PV neutralizing antibodies with fractional IPV doses by either IM or ID delivery, achieving at least five-fold dose sparing above non-adjuvanted fractional doses. These responses were most noticeable with the PV1 component of the trivalent vaccine. dmLT also promoted germinal center formation and longevity of serum anti-PV neutralizing titers. Lastly, dmLT enhanced mucosal immunity, as defined by fecal and intestinal anti-PV IgA secretion, when included in IPV immunization by ID or IM delivery. These studies demonstrate that dmLT is an effective adjuvant for either IM or ID delivery of IPV. Inclusion of dmLT in IPV immunizations allows antigen dose sparing and enhances mucosal immunity and longevity of anti-PV responses.