siRNA Inhibition of Endocytic Pathways to Characterize the Cellular Uptake Mechanisms of Folate-Functionalized Glycol Chitosan Nanogels.

Glycol chitosan nanogels have been widely used in gene, drug, and contrast agent delivery in an effort to improve disease diagnosis and treatment. Herein, we evaluate the internalization mechanisms and intracellular fate of previously described glycol chitosan nanogels decorated with folate to target the folate receptor. Uptake of the folate-decorated nanogel was impaired by free folate, suggesting competitive inhibition and shared internalization mechanisms via the folate receptor.

Learning ability is a key outcome determinant of GSK-3 inhibition on visuospatial memory in rats.

Learning aptitude has never been a focus of visuospatial performance studies, particularly on memory consolidation and reconsolidation. The aim of this study was to determine the consequences of learning ability on memory consolidation/reconsolidation following inhibition of glucose synthase kinase-3 (GSK-3) by 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The anxiety-like nature of rats was characterized in the elevated plus maze.

Disulfiram-induced cytotoxicity and endo-lysosomal sequestration of zinc in breast cancer cells.

Disulfiram, a clinically used alcohol-deterrent has gained prominence as a potential anti-cancer agent due to its impact on copper-dependent processes. Few studies have investigated zinc effects on disulfiram action, despite it having high affinity for this metal. Here we studied the cytotoxic effects of disulfiram in breast cancer cells, and its relationship with both intra and extracellular zinc.

Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with α-synuclein aggregates which incite parkinsonian-like symptoms.

Alpha-synuclein (α-syn) toxic aggregates delivered by the nasal vector have been shown to modify the neurochemistry of dopamine (DA) which is associated with parkinsonian-like motor symptoms. The aim was therefore to study the intranasal effects of α-syn oligomers, fibrils or their combination on the motor behavior of aged mice in relation to possible noradrenergic and serotonergic correlates. In vitro generated α-syn oligomers and fibrils were verified using atomic force microscopy and the thioflavin T binding assay.

Resistance to and killing by the sporicidal microbicide peracetic acid.

Objectives: To elucidate the mechanisms of spore resistance to and killing by the oxidizing microbicide peracetic acid (PAA).

Methods: Mutants of Bacillus subtilis lacking specific spore structures were used to identify resistance properties in spores and to understand the mechanism of action of PAA. We also assessed the effect of PAA treatment on a number of spore properties including heat tolerance, membrane integrity and germination.

Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning.

Pre-, post-, and remote conditioning of the myocardium are well described adaptive responses that markedly enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and provide therapeutic paradigms for cardioprotection. Nevertheless, more than 25 years after the discovery of ischemic preconditioning, we still do not have established cardioprotective drugs on the market. Most experimental studies on cardioprotection are still undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of cardiovascular risk factors.

Extraction and sensitive detection of toxins A and B from the human pathogen Clostridium difficile in 40 seconds using microwave-accelerated metal-enhanced fluorescence.

Clostridium difficile is the primary cause of antibiotic associated diarrhea in humans and is a significant cause of morbidity and mortality. Thus the rapid and accurate identification of this pathogen in clinical samples, such as feces, is a key step in reducing the devastating impact of this disease. The bacterium produces two toxins, A and B, which are thought to be responsible for the majority of the pathology associated with the disease, although the relative contribution of each is currently a subject of debate.

Distal phenylalanine modification for enhancing cellular delivery of fluorophores, proteins and quantum dots by cell penetrating peptides.

For cell penetrating peptides (CPPs) to fulfil their promise as effective delivery vectors we need a better understanding of their mechanisms of cell binding and uptake. This is especially the case when they are linked to different types of cargo. Here we describe new studies based on our previous findings suggesting that, for peptide-CPP chimeras, distal hydrophobic residues upstream of the CPP sequence can have profound effects on the way they interact with cells.

Best practice in healthcare environment decontamination.

There is now strong evidence that surface contamination is linked to healthcare-associated infections (HCAIs). Cleaning and disinfection should be sufficient to decrease the microbial bioburden from surfaces in healthcare settings, and, overall, help in decreasing infections. It is, however, not necessarily the case.

Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates.

Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with α-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries.

Natriuretic peptides modulate ATP-sensitive K(+) channels in rat ventricular cardiomyocytes.

B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and (Cys-18)-atrial natriuretic factor (4-23) amide (C-ANF), are cytoprotective under conditions of ischemia-reperfusion, limiting infarct size. ATP-sensitive K(+) channel (KATP) opening is also cardioprotective, and although the KATP activation is implicated in the regulation of cardiac natriuretic peptide release, no studies have directly examined the effects of natriuretic peptides on cardiac KATP activity. Normoxic cardiomyocytes were patch clamped in the cell-attached configuration to examine sarcolemmal KATP (sKATP) activity.

Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes.

Activation of myofibroblast rich stroma is a rate-limiting step essential for cancer progression. The responsible factors are not fully understood, but TGFβ1 is probably critical. A proportion of TGFβ1 is associated with extracellular nano-vesicles termed exosomes, secreted by carcinoma cells, and the relative importance of soluble and vesicular TGFβ in stromal activation is presented.

The dermatology outpatient discharge decision: understanding a critical but neglected process.

Discharge from dermatology outpatients is a critical endpoint of patient care. Despite this, there has been very little research concerning the discharge process and factors influencing the discharge decision. To identify the factors influencing discharge decisions, articles from 1970 to April 2013 were searched in MEDLINE via Ovid, CINAHL, PROQUEST and Google Scholar using the keywords 'patient discharge', 'discharge decision', 'factors influencing discharge', 'clinical decision making', 'discharge decision making', 'process of discharge decision', 'outpatient', 'follow up', 'skin disease' and 'dermatology'.

Chronic disease influences over 40 major life-changing decisions (MLCDs): a qualitative study in dermatology and general medicine.

Background: Chronic disease not only impairs patients' psycho-social well-being but also influences major life-changing decisions (MLCDs). There is little information about the types of MLCDs affected and the long-term consequences.

Objectives: The aims were to identify the MLCDs influenced by chronic disease, to define 'MLCD' and to suggest support strategies for patients taking MLCDs.

Caveolin-1 in renal cell carcinoma promotes tumour cell invasion, and in co-operation with pERK predicts metastases in patients with clinically confined disease.

Background: Up to 40% of patients initially diagnosed with clinically-confined renal cell carcinoma (RCC) and who undergo curative surgery will nevertheless relapse with metastatic disease (mRCC) associated with poor long term survival. The discovery of novel prognostic/predictive biomarkers and drug targets is needed and in this context the aim of the current study was to investigate a putative caveolin-1/ERK signalling axis in clinically confined RCC, and to examine in a panel of RCC cell lines the effects of caveolin-1 (Cav-1) on pathological processes (invasion and growth) and select signalling pathways.

Methods: Using immunohistochemistry we assessed the expression of both Cav-1 and phosphorylated-ERK (pERK) in 176 patients with clinically confined RCC, their correlation with histological parameters and their impact upon disease-free survival.

Stability and purity of a bacteriophage cocktail preparation for nebulizer delivery.

Unlabelled: The aim of this study was to determine the stability and purity of a phage cocktail to be delivered by nebulization. A cocktail of three phages active against Pseudomonas aeruginosa isolates from cystic fibrosis patients was developed for a potential nebulized formulation. The individual phages were examined for their retention of activity over time, while the phage cocktail was analysed for bacterial contaminant and endotoxin level according to regulatory requirements for nebulized products.

Evaluation of new in vitro efficacy test for antimicrobial surface activity reflecting UK hospital conditions.

Background: Antimicrobial surfaces aim to reduce microbial bioburden and improve hygiene. The current antimicrobial surface efficacy test (ISO22196) is an initial screening test but its conditions, high temperature (37°C) and relative humidity (RH) (100%) bear little relationship to in-use conditions.

Aim: To develop an antimicrobial surface efficacy test providing a realistic second-tier test, simulating in-use conditions.

The development of a sensitive methodology to characterise hard shell capsule puncture by dry powder inhaler pins.

In order for hard-shell capsules to function effectively as drug reservoirs in dry powder inhalers, the capsule must be punctured with sharpened pins to release the powdered medicament upon inspiration. Capsule performance in this setting is poorly understood. This study aims to develop a methodology to characterise hard shell capsule penetration by needles from commercial dry powder inhalers, to determine whether changes to capsule materials impact on their performance.

The effect of cationic microbicide exposure against Burkholderia cepacia complex (Bcc); the use of Burkholderia lata strain 383 as a model bacterium.

Aim: The extensive use of microbicides in a wide range of applications has been questioned with regard to their role in the development of bacterial resistance to antimicrobials. This study aims to measure the phenotypic and genotypic changes in Burkholderia lata strain 383 exposed to chlorhexidine gluconate (CHG) and benzalkonium chloride (BZC), two commonly used cationic microbicides.

Methods And Results: The susceptibility of B.

Concept of major life-changing decisions in life course research.

Chronic diseases can severely impair patients' quality of life but little information is available about the long-term impact of chronic diseases. The chronic nature of disease may decrease patients' psychosocial well-being, may change their attitude towards life goals and influence major life-changing decisions (MLCDs). Understanding of the impact on MLCDs is largely missing from health outcomes research.

Does microbicide use in consumer products promote antimicrobial resistance? A critical review and recommendations for a cohesive approach to risk assessment.

The increasing use of microbicides in consumer products is raising concerns related to enhanced microbicide resistance in bacteria and potential cross resistance to antibiotics. The recently published documents on this topic from the European Commission have spawned much interest to better understand the true extent of the putative links for the benefit of the manufacturers, regulators, and consumers alike. This white paper is based on a 2-day workshop (SEAC-Unilever, Bedford, United Kingdom; June 2012) in the fields of microbicide usage and resistance.

Clinical experience and psychometric properties of the Children's Dermatology Life Quality Index (CDLQI), 1995-2012.

The Children's Dermatology Life Quality Index (CDLQI) is a widely used questionnaire to measure the quality of life of children aged from 4 to 16 years. The purpose of this review is to summarize all published data regarding the clinical experience of the CDLQI and its psychometric properties as a single reference source for potential users. A literature search was carried out to identify all articles describing the use of the CDLQI from 1995 to November 2012.