Resistance to chemotherapy is a major obstacle in clinical oncology. Hypoxia is a hallmark of solid tumours as a result of poorly structured tumour neovasculature and is known to be a key contributor to cancer malignancy and reduced drug effectiveness. Hypoxia-inducible factor-1 (HIF-1) mediates the hypoxic response, bringing about adaptive responses to the change in microenvironment. This study investigated the effect of 24 h hypoxia on the sensitivity of SH-SY5Y neuroblastoma cells to 5-fluorouracil (5-FU). Cytotoxicity, apoptosis and membrane integrity cell-based assays were carried out to observe changes in cell viability alongside apoptotic and necrotic cell death to determine the molecular mechanisms underlying reduced drug sensitivity. Hypoxic cells showed no change in cell viability to 5-FU in comparison to normoxic controls, suggesting that hypoxia conferred reduced drug sensitivity. As a measure of apoptosis, caspase-3/7 levels were significantly higher in hypoxic cells treated with increasing 5-FU concentrations. However, this was associated with less cell necrosis, suggesting that despite increased hypoxia-induced apoptosis, a significant decrease in uncontrolled cell death accounted for the change in viability observed. This finding also implies that alternative cell survival mechanisms could also be activated.

Obstructive sleep apnoea (OSA) is a leading yet often undiagnosed cause of daytime sleepiness. It affects between 3 and 7% of the adult population, and the prevalence is expected to increase due to the obesity epidemic and ageing population. OSA is a sleep-related breathing disorder in which the airway completely (apnoea) or partly closes (hypopnea) during sleep at the end of expiration. This can lead to decreases in blood oxygen saturation and sleep fragmentation. Those who suffer with OSA are often unaware of their symptoms. Severe, untreated OSA can have serious implications such as an increased risk of cardiovascular disease, motor vehicle accidents, poor neurocognitive performance and increased mortality. Many patients are prescribed continuous positive airway pressure (CPAP) as a treatment, but compliance with CPAP is often low. We briefly review the diagnosis and prognosis for obstructive sleep apnoea. But the main focus of our review is the critical evaluation of the numerous treatment strategies available for sleep apnoea as a multi-comorbid and multi-factorial condition. We also highlight areas that need further research.

Although genetic analyses suggest that the Skyrian pony is unrelated to other breeds, it shares some physical features with Exmoor ponies, thought to originate in the primitive pony referred to as Pony Type 1, and the Caspian horse, thought to be descended from Horse Type 4. To test the hypothesis that the Skyrian shares the Exmoor’s origin in Pony Type 1, comparisons were made of defined physical characters and morphometric measurements amongst Skyrian ponies, Exmoor ponies and Caspian horses. The average mean character differences were 0.56 ± 0.12 between the Skyrians and Exmoors, 0.43 ± 0.15 between the Skyrians and Caspians and 0.83 ± 0.06 between the Caspians and Exmoors. This approximates to reports comparing other horse breeds and breeds in other species, confirming that the Skyrian is a distinct breed. Using two-way analysis of variance (ANOVA), Friedman’s ANOVA and post hoc tests, no significant differences were found between Skyrians and Caspians in the eye, neck, body and limb shape (P = 1.000) nor shoulder angle (P = 0.222) nor in the ratios of body length:elbow height, neck length:neck circumference and heart girth: height to withers. However, there were significant differences ( P < 0.001) between Skyrians and Exmoors for these physical characters and ratios. While significant differences existed between Skyrians and Caspians in cephalic profile, parietal crest and tail placement (P < 0.001) and there were similarities between Skyrians and Exmoors in these physical characters (P = 1.000 or 0.098), overall the Skyrians appeared phenotypically closer to the Caspian, but unrelated to either breed. This investigation enabled the evaluation of a methodology comprising systematic, comprehensive investigations of phenotype, with data reduced and analysed by appropriate statistical methods, to clarify equine breed ancestry and phylogeny. The studies confirmed that the analysis of phenotype has utility and potential for investigations of phylogeny in species where there may be a paucity of information from the genetic base. Moreover, this approach has been shown to support and augment knowledge derived from studies based on genetic testing and provide a cost-effective and easily performed method of determining relatedness amongst equine breeds.

Ixodes ricinus, the sheep tick, as a consequence of its habit of taking blood from mammalian hosts, can transmit disease from wild animals to humans. This is likely to be a particular problem in parks shared by humans and deer populations. These ticks were sampled, using cloth drags, from vegetation at 16 sites in Richmond Park, London, between 15 July and 22 August 2009. A total of 2436 ‘host-seeking’ ticks (2281 larvae, 151 nymphs and 4 adults; three males and one female) were collected, and attempts were made to identify the environmental factors affecting the distribution of these ectoparasites. Tick presence was closely related to soil moisture, light levels and humidity throughout the park. It is thought that improving our understanding of how these factors influence the presence of I. ricinus will facilitate methods of tick control and help to educate the public about where ‘hotspots’ for these parasites are likely to be within the park.

The use of HIV point of care tests (POCTs) is increasing rapidly in both laboratory and other settings. These tests are often performed by non-laboratory trained staff. At the present time there are no external quality assessment (EQA) providers in the UK offering proficiency testing schemes for HIV point of care testing. The aim of this study is to develop such an EQA scheme. Firstly, a selection of the most widely used POCTs was selected and their performance assessed using existing HIV-positive serology EQA specimens. All assays produced the correct results however intensity of results observed for the same specimen differed greatly between POCT devices. In addition the effect of various sub-groups of HIV-1 serum samples on the HIV POCT assays was investigated and no difference between the results on the POCTs was observed. Ultimately four serum specimens, two HIV-1 and one HIV-2 positive, one HIV negative, were chosen and sent to NHS laboratories and sexual health clinics for testing as part of a pilot EQA scheme for HIV POCT. Results were excellent with 97% of participants reporting correct results (n= 20). The study highlighted a lack of awareness of EQA particularly in non-laboratory settings, although recommendations (ISO 22870:2006) are in place for the users of such devices. In conclusion, the need for EQA for providers of point of care testing is an integral part of ensuring reliability of results and quality of care for the patient.

The Earth's ecosystems supply human society with a stream of services, the sustained delivery of which remains crucial to our health, economic prosperity and personal and national security. Ecosystem services provide these benefits across a range of geographical scales (local, regional and global) and to many different groups (individuals, businesses and governments). In spite of this, ecosystem services are continually underrepresented and undervalued within decision-making situations. As a result, the capacity of ecosystems to supply a number of services—including the supply of food and freshwater, the regulation of disease and protection from natural hazards—has been degraded worldwide, with serious consequences for human wellbeing. The actions of man are unwittingly depleting the planet's natural capital and putting such strain on the environment that the capacity of Earth's ecosystems to support future generations can no longer be taken for granted. To address this we need a new approach to the way that decisions are made at the interface of the environment and society—one where the benefits and services provided by ecosystems are understood, evaluated and appropriately represented within the decision-making arena. By drawing attention to the failures and consequences of past and present attitudes in decision-making and resource management, this article frames a way forward to help avoid such problems in the future. Specifically, it outlines the rationale behind the need for an ecosystem service approach to decision-making and highlights some of the research needs that will help in selecting policies that sustain ecosystem services.

This study explores the role of the phosphatase Pp2A in regulation of anaphase onset in human cells. During the mitotic cell cycle, cells replicate their DNA in S-phase giving sister chromatids. These chromatids remain tethered together by the cohesin ring until anaphase. The onset of anaphase is triggered by the activation of separase, a protease which cleaves the cohesin ring structure, thereby allowing the sister chromatids to be pulled to opposite ends of the spindle. Prior to anaphase, separase is held in check by one of two inhibitors, namely securin or cyclin B1. Recently, it has been shown that securin-bound separase also binds the protein phosphatase, Pp2A. Importantly, the binding of Pp2A is regulated by separase autocleavage; upon activation, separase autocleaves and releases Pp2A. Strikingly, expression of a non-cleavable separase induces premature sister chromatid separation. Here, we show that the ability of non-cleavable separase to prematurely induce chromatid disjunction requires its catalytic activity. These data lend weight to a handover model whereby separase is initially inhibited by securin; then as securin is degraded, separase autocleaves, Pp2A is released thereby allowing cyclin B1 binding; this in turn maintains separase inhibition until cyclin B1 is degraded. One exciting extension of this model is that the release of Pp2A provides a burst of phosphatase activity just prior to chromatid separation, perhaps to ‘forewarn’ the cell that anaphase onset is imminent. For example, Pp2A activation may ensure that kinetochore–microtubule interactions are stabilized to ensure that all the chromatids are locked onto their K-fibres at the point when sister chromatid cohesion is lost. This study has important implications in understanding how defects in separase regulation can lead to aneuploidy and diseases such as cancer.

Leishmania are obligate intracellular vector-borne parasites that cause significant morbidity and mortality in many countries worldwide. There are several species of the parasite which vary according to geographical location and cause a variety of clinical syndromes ranging from self-limiting cutaneous lesions to potentially fatal infection of the viscera. The disease manifested is dependent on both the species of the parasite and the immune response of the host. Depending on the species of the parasite, resistance to infection is generally associated with a T-helper-1 immune response that activates macrophages to kill intracellular Leishmania in a nitric oxide-dependent manner. Conversely, disease progression is generally associated with a T-helper-2 response that activates humoral immunity. Chemotherapeutic treatments for leishmaniasis exist but are expensive, toxic and ineffective against resistant strains. A vaccine against leishmaniasis is feasible since most individuals that were once infected become resistant to clinical infection when later exposed. However, despite the wealth of information regarding the genetics of the parasite and the experimental immunology of the disease, there is currently no vaccine against Leishmania. A multitude of vaccine strategies have been pursued including the use of killed and genetically modified parasites. Immunization with naked plasmid DNA encoding Leishmania antigens represents a new approach to a Leishmania vaccine and confers several advantages over the more traditional vaccination methods. In order to develop an effective vaccine against leishmaniasis, it is important to understand the mechanisms of the immune response to Leishmania infection. This review discusses such immune mechanisms in detail and also explores several of the Leishmania vaccination strategies employed to date, with particular emphasis on DNA vaccines.

Catheter-associated urinary tract infections (CAUTI) have frequently been studied in monocultures in vitro. However, many CAUTI are due to the presence of a mixed microbial community and not just a single population, especially within patients subjected to long-term catheterization. This can potentially have important clinical implications in regards to treatment strategy and outcome. This study revealed that when Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) (both commonly found in CAUTI) were grown together as a mixed culture within a CAUTI model in comparison to their respective monocultures, accelerated biofilm development was observed. Virulence gene expression analysis within P. aeruginosa and MRSA monoculture and mixed biofilms was performed through use of real-time quantitative PCR. It was revealed that production of P. aeruginosa exotoxin A was increased 1839-fold when P. aeruginosa and MRSA were grown together as a mixed biofilm. Significant expression of α-haemolysin by MRSA was not observed in either culture. It is proposed that both the biofilm-forming capability and virulence gene expression of microbes within CAUTI mixed biofilms may differ substantially to the respective microbial monocultures. This highlights the importance of developing specific treatment strategies for CAUTI when polymicrobial communities are present.