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The effects of smoking on color vision have been scarcely studied. To bridge such gap, this study examined if there were differences in chromatic discrimination between heavy and light smokers. The psychophysical Trivector test was used to evaluate chromatic discrimination in healthy controls ( = 36), heavy smokers ( = 29), and light smokers ( = 32). The subject's task was to identify the orientation of the Landolt C ring gap - presented and randomized in one of the four positions (e.g., up, down, right, and left). The thresholds for Protan (red), Deutan (green) and Tritan (blue) were higher in heavy smokers compared to nonsmokers but not to light smokers. The results confirm that heavy smoking and chronic exposure to its harmful compounds affect color discrimination when compared to light smoking; and this is more pronounced in heavy smokers than light smokers. This is particularly important to understand the differences among smokers on visual and multisensory processing.

BackgroundLow uptake of sexually transmitted infection testing by sexually active young people is a worldwide public health problem. Screening in non-medical settings has been suggested as a method to improve uptake. The “Test n Treat” feasibility trial offered free, on-site rapid chlamydia/gonorrhoea tests with same day treatment for chlamydia (and gonorrhoea treatment at a local clinic,) to sexually active students (median age 17 years) at six technical colleges in London. Despite high rates of chlamydia (6% prevalence), uptake of testing was low (MethodsIn 2016–17 we conducted a qualitative study in the interpretative tradition using face to face or telephone semi-structured interviews with students (n = 26), teaching staff (n = 3) and field researchers (n = 4). Interviews were digitally recorded, transcribed and thematically analysed.ResultsFrom the student perspective, feelings of embarrassment and the potential for stigma were deterrents to sexually transmitted infection testing. While the non-medical setting was viewed as mitigating against stigma, for some students volunteering to be screened exposed them to detrimental judgements by their peers. A small financial incentive to be screened was regarded as legitimising volunteering in a non-discrediting way. Staff and researchers confirmed these views. The very low level of knowledge about sexually transmitted infections influenced students to not view themselves as candidates for testing. There were also suggestions that some teenagers considered themselves invulnerable to sexually transmitted infections despite engaging in risky sexual behaviours. Students and researchers reported the strong influence peers had on uptake, or not, of sexually transmitted infection testing.ConclusionsThis study offers new insights into the acceptability of college-based sexually transmitted infection screening to young, multi-ethnic students. Future studies in similar high risk, hard to reach groups should consider linking testing with education about sexually transmitted infections, offering non stigmatising incentives and engaging peer influencers.

Alginate hydrogels are cross-linked polymers with high water content, tuneable chemical and material properties, and a range of biomedical applications including drug delivery, tissue engineering, and cell therapy. However, their similarity to soft tissue often renders them undetectable within the body using conventional bio-medical imaging techniques. This leaves much unknown about their behaviour in vivo, posing a challenge to therapy development and validation. To address this, we report a novel, fast, and simple method of incorporating the nuclear imaging radio-metal 111In into the structure of alginate hydrogels by utilising its previously-undescribed capacity as an ionic cross-linking agent. This enabled non-invasive in vivo nuclear imaging of hydrogel delivery and retention across the whole body, over time, and across a range of model therapies including: nasal and oral drug delivery, stem cell transplantation, and cardiac tissue engineering. This information will facilitate the development of novel therapeutic hydrogel formulations, encompassing alginate, across disease categories.

Basic research creates new knowledge that fuels technological advances. However, budgetary concerns and escalating R&D prices are challenging organizations to show returns from investments in scientific research. Few attempts are made to analyse research that leads to pharmaceutical innovation. In particular, the financial contribution of public and private organizations to the riskiest stage of biomedical discovery has remained unclear and partially unexplored. This study is a first attempt to shed light on the financial support to basic research by public and private sectors using publications data. We conducted an exploratory analysis of funding acknowledgments on publications authored by the founding scientists of 91 ‘drug originator’ companies in United Kingdom. The nature and distribution of the support acknowledged to the research conducted before the company creation was analysed and the impact of publications and type of support were statistically tested. We found the majority of publications acknowledged public institutions, whereas, commercial organisations were likely to support those with privately affiliated authors. Based on these findings, we discussed the need to foster collaborative research and to set adequate incentives for shared risks and benefits from investments in knowledge creation.

Although helminth parasites cause enormous suffering worldwide we know little of how protein phosphorylation, one of the most important post-translational modifications used for molecular signalling, regulates their homeostasis and function. This is particularly the case for schistosomes. Herein, we report a deep phosphoproteome exploration of adult Schistosoma mansoni, providing one of the richest phosphoprotein resources for any parasite so far, and employ the data to build the first parasite-specific kinomic array. Complementary phosphopeptide enrichment strategies were used to detect 15,844 unique phosphopeptides mapping to 3,176 proteins. The phosphoproteins were predicted to be involved in a wide range of biological processes and phosphoprotein interactome analysis revealed 55 highly interconnected clusters including those enriched with ribosome, proteasome, phagosome, spliceosome, glycolysis, and signalling proteins. 93 distinct phosphorylation motifs were identified, with 67 providing a ‘footprint’ of protein kinase activity; CaMKII, PKA and CK1/2 were highly represented supporting their central importance to schistosome function. Within the kinome, 808 phosphorylation sites were matched to 136 protein kinases, and 68 sites within 37 activation loops were discovered. Analysis of putative protein kinase-phosphoprotein interactions revealed canonical networks but also novel interactions between signalling partners. Kinomic array analysis of male and female adult worm extracts revealed high phosphorylation of transformation:transcription domain associated protein by both sexes, and CDK and AMPK peptides by females. Moreover, eight peptides including protein phosphatase 2C gamma, Akt, Rho2 GTPase, SmTK4, and the insulin receptor were more highly phosphorylated by female extracts, highlighting their possible importance to female worm function. We envision that these findings, tools and methodology will help drive new research into the functional biology of schistosomes and other helminth parasites, and support efforts to develop new therapeutics for their control., Author summary Schistosomes are formidable parasites that cause the debilitating and life-threatening disease human schistosomiasis. We need to better understand the cellular biology of these parasites to develop novel strategies for their control. Within cells, a process called protein phosphorylation controls many aspects of molecular communication or ‘signalling’ and is central to cellular function and homeostasis. Here, using complementary strategies, we have performed the first in-depth characterisation and functional annotation of protein phosphorylation events in schistosomes, providing one of the richest phosphoprotein resources for any parasite to date. Using this knowledge, we have developed a novel tool to simultaneously evaluate signalling processes in these worms and highlight sex-biased differences in adult worm protein phosphorylation. Several proteins were found to be more greatly phosphorylated by female worm extracts, suggesting their possible importance to female worm function. This work will help drive new research into the fundamental biology of schistosomes, as well as related parasites, and will support efforts to develop new drug or vaccine-based therapeutics for their control.

Monoclonal antibody (mAb) technology is an excellent tool for the discovery of overexpressed cell surface tumour antigens and the development of targeting agents. Here, we report the development of two novel mAbs against CFPAC-1 human pancreatic cancer cells. Using ELISA, flow cytometry, immunoprecipitation, mass spectrometry, Western blot and immunohistochemistry, we found that the target antigens recognised by the two novel mAbs KU44.22B and KU44.13A, are integrin α3 and CD26 respectively, with high levels of expression in human pancreatic and other cancer cell lines and human pancreatic cancer tissue microarrays. Treatment with naked anti-CD26 mAb KU44.13A did not have any effect on the growth and migration of cancer cells nor did it induce receptor downregulation. In contrast, treatment with anti-integrin α3 mAb KU44.22B inhibited growth in vitro of Capan-2 cells, increased migration of BxPC-3 and CFPAC-1 cells and induced antibody internalisation. Both novel mAbs are capable of detecting their target antigens by immunohistochemistry but not by Western blot. These antibodies are excellent tools for studying the role of integrin α3 and CD26 in the complex biology of pancreatic cancer, their prognostic and predictive values and the therapeutic potential of their humanised and/or conjugated versions in patients whose tumours overexpress integrin α3 or CD26.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40–69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid tumours and more effective therapy is urgently needed. The stroma is thought to play a critical role in tumour development and metastasis, and high stromal expression of the matricellular protein SPARC has been robustly associated with poor patient prognosis. However, the precise role of SPARC has been highly controversial, with multiple studies demonstrating tumour-suppressor properties of this protein 'in vitro'. This conflicting data has been a barrier to the development of new therapeutic approaches targeting SPARC, despite current interest in stromal-therapy.\ud \ud We show conclusively that SPARC acts directly on cancer cells to promote pancreatic cancer cell proliferation. This contradicts previous 'in vitro' studies, but is consistent with the observed clinical association between SPARC expression and poor patient prognosis. However, depletion of fibronectin switches the activity of SPARC from promoting cancer cell proliferation to growth inhibition and induction of apoptosis. Thus, targeting the interaction between SPARC and fibronectin could be used to turn the highly expressed tumour protein SPARC against the tumour to induce tumour cytotoxicity, and is a novel target for PDAC therapy.

BACKGROUND The accurate determination of vitamin D in skin is of considerable importance in evaluating penetration of skin health products through the different layers of the skin. OBJECTIVE We report on the characterisation and quantitation of vitamin D in an idealised sample and in complex mixtures which mimic that of a typical skin cream, using qNMR, 2D NMR and DOSY techniques. METHODS The characterisation and quantitation conditions were acquired over several heterogeneous samples, allowing for analysis of how the dynamic range and complexity of the different sample mixtures affect the limits of detection (LOD) and limits of quantitation (LOQ) of vitamin D. NMR is of particular value to this task as it is non-destructive, uses a primary ratio method for quantification, and tolerates a wide variety of hydrophilic and hydrophobic components within a given matrix. RESULTS In this investigation, we have attained a trueness level

Background:\ud \ud Oncogenic human papilloma viruses (HPV) are the cause of various types of cancer, specifically cervical cancer. L1 protein is the main protein of HPV capsid which targeted in many vaccine-producing attempts. However, they have not enough coverage on the various high risk HPV types. Therefore, having a low cost potent HPV vaccine to protect against all members of the ɑ-papillomaviridea family will be promising. In this study, L1 protein-based peptide vaccine was designed using immunoinformatics methods which provides physicochemical properties such as stability in room temperature, potential of antigenicity, non-allergic properties and no requirement with eukaryotic host system.\ud \ud Results:\ud \ud The designed vaccine has two HPV conserved epitopes with lengths 18 and 27 amino acids in all members of α-papillomaviridea. These peptides promote humoral and cellular immunity and INF-γ responses. In order to ensure strong induction of immune responses, Flagellin, a Toll like receptor 5(TLR-5) agonist, and a short synthetic toll like receptor 4 (TLR-4) agonist were also joined to the epitopes. Structure of the designed- vaccine was validated using Rampage and ERRAT and a high quality 3D structure of the vaccine protein was provided. Docking studies demonstrated an appropriate and stable interaction between the vaccine and TLR-5.\ud \ud Conclusions:\ud \ud The vaccine is expected to have a high quality structure and suitable properties including high stability, solubility and a high potential to be expressed in 'E.coli'. High potentiality of the vaccine in inducing humoral and cellular immune responses, may be considered as an anti-tumor vaccine.

Working effectively within multidisciplinary\ud teams is an important employability skill\ud common in postgraduate working life, but\ud opportunities to develop this are limited in\ud many undergraduate taught programmes. The\ud projects reported here offered twelve level 5\ud undergraduate students from a range of\ud science disciplines the opportunity to work with\ud each other and staff on a specific research\ud question. This paper explores the experience\ud of cross-disciplinary research from both the\ud student and staff research partners’\ud perspectives. In particular the employability\ud skills gained from such partnership working,\ud the potential for developing and demonstrating\ud leadership skills, and the benefits and\ud disadvantages are discussed.

Background: Objective cough frequency measurements are increasingly applied in clinical research. Technological advances enable automated detection and counting of cough events from sound recordings of many hours’ duration. A possible limitation of sound-based cough frequency measurement is the contamination of recordings by environmental coughs (coughs from persons other than the patient). This study aimed to investigate the accuracy of a sound-based cough monitor for detecting and discriminating patient cough from environmental cough. Methods: As part of a stroke trial (ISRCTN40298220), patients on a hospital ward underwent 15-minute recordings using the Leicester Cough Monitor (LCM), a sound-based cough monitor (‘semi-automated counts’). Participants and other persons in the environment were prompted to cough. An observer present in the room recorded the number of patient and environmental coughs (‘live counts’). LCM counts were also compared against a manual cough count, the most commonly used gold standard to determine accuracy (‘manual sound counts’ from listening to recordings), by a blinded assessor who cross-referenced timed cough events from the respective methods. Data for automated, manual and live cough counts were analyzed using agreement statistics. Results: On sound recordings from five patients, there were 65 patient coughs and 78 environmental coughs (manual counts). Absolute agreement for patient cough count between all three measurement methods (LCM automated, live, and manual sound counts) was high, with intra-class correlation coefficient of 0.94 [95% confidence intervals (CI): 0.74, 0.99]. The proportion of exact agreements for patient cough between LCM and manual count was 0.92, and kappa was 0.84 (95% CI: 0.75, 0.93). The LCM showed sensitivity of 0.94 (95% CI: 0.84, 0.98), specificity of 0.91 (95% CI: 0.82, 0.96), positive predictive value of 0.90 (95% CI: 0.79, 0.95) and negative predictive value of 0.95 (95% CI: 0.86, 0.98) for detecting patient coughs. Conclusions: This preliminary study supports the validity of the cough monitor for detecting and discriminating patient from environmental cough. Further validation is recommended, to describe the level of accuracy with greater precision.

Objective To evaluate the frequency of HLA class I and II alleles associated with traditional forms of inflammatory arthritis in patients with immune checkpoint inhibitor (ICI)-induced inflammatory arthritis as compared with population controls. Methods High-resolution HLA typing was performed on 27 patients with ICI-induced inflammatory arthritis and 726 healthy controls. Genotyping at the shared epitope (SE) locus (HLA DRB1) was performed on 220 RA cases. Allele-positivity rates and frequency of having at least one SE allele were compared using Fisher’s exact test between ICI-induced inflammatory arthritis and healthy controls. Frequency of having at least one SE allele was also compared between ICI-induced inflammatory arthritis and RA cases. Results Twenty-six patients with ICI-induced inflammatory arthritis were of European descent, and one was African American. In those 26 patients, 16 (61.5%) had at least one SE allele, significantly different from healthy controls of European descent, in whom 299 (41.2%) had at least one SE allele (odds ratio 2.3, P = 0.04). The allele-positivity rate of DRB1*04: 05 was also higher in the ICI-induced inflammatory arthritis group. The ICI-induced inflammatory arthritis population and RA patients of European descent did not differ in frequency of having at least one SE allele, but ICI-induced inflammatory arthritis patients were more likely to be autoantibody-negative for RF and anti-CCP antibodies. Conclusion Patients with ICI-induced inflammatory arthritis of European descent were more likely to have at least one SE allele than healthy controls. Further studies are needed to validate these findings and investigate whether a unique immunogenetic framework increases risk for different immune-related adverse events.

Transition to higher education is challenging, and may be more difficult for some groups than others. The transition from level 3 foundation year into level 4 offers the opportunity to explore student perspectives. Qualitative survey and focus group data were collected from current and previous Level 3 students, to ascertain student perceptions about induction, level of belonging, confidence about Level 4 and to identify useful support sources. Over a third of eligible Level 3 students (n=102) participated, but numbers of eligible participants from Levels 4, 5 and 6 were limited. Despite the heterogeneous nature of Level 3 students the majority of students recognised the value of the foundation year. Data suggested that Level 3 students did not identify with the university. Those who did highlighted the importance of social outlets such as clubs and societies. A major cause of dissatisfaction was perceived lack of clarity about the foundation year, including the programme, subjects and physical location of the course. This was apparent across all ethnicities, age groups and both genders. Among previous Level 3 students, personal sources of support were uniformly valued although the precise source varied by year of study. Support from academic staff, via office hours and as personal tutors, was rated as most important. Enabling academic staff to offer support to students throughout their study, and clear consistent information available throughout an ongoing transition, may help to minimise these issues.

Healthcare programmes tend to neglect exploring self-care strategies for students whilst they are\ud on their clinical placements. There is evidence that students experience placements as\ud challenging because of the long hours, and endeavouring to meet the needs of many patients\ud across diverse challenging settings. Mindfulness is a potential self-management strategy to\ud enable students to manage the challenges and resultant stress during these times, and to work\ud optimally within their competences. This study explores the role of mindfulness in attempting to\ud meet these challenges. Purposive sampling was used to recruit nineteen MSc pre-registration\ud physiotherapy students who received a two-hour mindfulness intervention prior to commencing\ud their placement, and were encouraged to practice mindfulness for 30 minutes three times a week\ud with a CD whilst on placement or in their own time. Additionally, they were asked to practice for\ud 10-15 minutes ‘mindfulness of the breath’ during this period. A qualitative approach that\ud incorporated thematic analysis was used to analyse the audio-recorded and transcribed pre- and\ud post-placement focus groups. Perceived benefits from practising mindfulness were: a lessening\ud of intrinsic stress, and an ability to cope with extrinsic stress with increased clarity and objectivity.\ud The CD proved burdensome amongst the students, largely owing to time constraints, but this did\ud not deter their desire to implement mindfulness during this time, and they devised alternative and\ud individual modes of practicing this mind-body-based approach. This study lends evidence to\ud support inclusion of mindfulness into the physiotherapy curriculum as a self

Purpose Dementia cafés (also known as Alzheimer’s or memory cafés) have been running in the UK since 2000. The purpose of this paper is to report on the recommendations from recent research that interviewed family carers on their experiences of using the cafés. Design/methodology/approach The research was carried out in cafés in and around London, and focussed on informal, unpaid carers’ experiences of using them. In total, 11 carers from five different dementia cafés were interviewed, using semi-structured questionnaires. The results were thematically analysed. Findings The findings showed that carers had an overwhelming appreciation of the cafés and what they offered, but several of the findings led to the recommendations about the recruitment and training of café co-ordinators; how cafés present themselves and their services and how they can offer dedicated support to informal carers. Originality/value These recommendations will be of use to café organisers and commissioners, especially considering the dearth of information currently available in this area.

Personal health & wellbeing are rated more highly in those with higher educational qualifications than those without, and good health & wellbeing are likely to impact upon student attendance and hence attainment at university. It is important to understand factors which may affect perceived health and wellbeing from a student perspective in order to develop university-specific campaigns to correct misinformation. In addition, multidisciplinary working is characteristic in the post-graduation world, but is difficult to truly replicate within formal university teaching. This project had two aims. First, through a cross-disciplinary staff-student collaboration, to explore student perceptions of health and wellbeing in Kingston University. Second, to enable students from a range of disciplines to work in active partnership with each other and with academic staff. A quiz was completed by almost 300 undergraduate students. Results from this and focus group discussions demonstrated reasonable knowledge of a range of lifestyle risk factors affecting health, but misinformation about the safety of vaccines and the importance of nutrition, activity and adequate sleep for maximising health, wellbeing and thus, potentially, university attainment. Future work is planned with Kingston University undergraduate students to address identified misconceptions. Student partners highly rated the opportunity for active learning, partnership working with staff and being part of a cross-disciplinary project team.

Glomerular filtration rate (GFR) is usually determined by estimation of iothalamate (IOT) clearance. We have developed and validated an accurate and robust method for the analysis of IOT in human plasma and urine. The mobile phase consisted of methanol and 50 mM sodium phosphate (10:90; v/v). Flow rate was 1.2 mL/min on a C18 reverse phase column, Synergi-hydro (250 × 4.6 mm) 4 µm 80 Å, with an ultraviolet detector set to 254 nm. Acetonitrile was used for the deproteination and extraction of IOT from human plasma and urine. Precision and accuracy were within 15% for IOT in both plasma and urine. The recoveries of IOT in urine and plasma ranged between 93.14% and 114.74 and 96.04–118.38%, respectively. The linear range for urine and plasma assays were 25–1500 and 1–150 µg/mL respectively. The lower limits of detection were 0.5 µg/mL for both urine and plasma, with no interference from plasma and urine matices. This method has been fully validated according to FDA guidelines and the new HPLC assay has been applied to a new formulation of IOT (Conray™ 43), to calculate GFR in healthy volunteers. The new method is simple, less expensive and it would be instrumental in future clinical and pharmacokinetic studies of iothalamate in kidney patients.

Purpose: The UK standard operating procedures mandate that trained pharmacists supervise the safe handling and preparation of hazardous drugs in healthcare settings. Researchers often handle cytotoxic drugs classified as hazardous in the laboratories of universities during their experiments, in the absence of special guidelines for these settings. The aim of this UK national survey is to gauge the current practice of cytotoxic handling in these cytotoxic academic research laboratories (CARLs).\ud \ud Methods: The survey used a 36-item online questionnaire targeting Health and Safety officers (H&SO) of academic institutions researching cytotoxic drugs. Invitations to participate in the survey, participant information sheets, and a link to complete the survey were all sent to the aforementioned officers.\ud \ud Results: 48.8% of H&SO (19/39) mentioned that the top two personnel groups that access the CARL are researchers and cleaning staff. Also, 48.8% of H&SO (19/39) disclosed that the latter are not aware of any special cleaning procedures required for these laboratories. 45.9% H&SO (17/37) reported that the staff at the reception point for cytotoxic drugs is neither aware of their risk nor notified of the content of the delivery. According to the H&SO, the required personal protective equipment in these laboratories was as follows; gloves (94.9%, 37/39), impermeable gown (59%, 23/39), mask (25.6%, 10/39), shoe cover (41%, 16/39), goggles (87.2%, 34/39).\ud \ud Conclusion: This audit reflects the repercussions of the lack of distinctive recommendations relating to cytotoxic manipulations in CARL. Professional pharmaceutical organizations are urged to set strategic plans to control unwanted cytotoxic contamination within academic institutions.

Schistosoma mansoni cercariae display specific behavioural responses to abiotic/biotic stimuli enabling them to locate and infect the definitive human host. Here we report the effect of such stimulants on signalling pathways of cercariae in relation to host finding and invasion. Cercariae exposed to various light/temperature regimes displayed modulated protein kinase C (PKC), extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) activities, with distinct responses at 37°C and intense light/dark, when compared to 24°C under normal light. Kinase activities were localized to regions including the oral sensory papillae, acetabular ducts, tegument, acetabular glands, and nervous system. Furthermore, linoleic acid (LA) modulated PKC and ERK activities concurrent with the temporal release of acetabular gland components. Attenuation of PKC, ERK and p38 MAPK activities significantly reduced gland component release, particularly in response to LA, demonstrating the importance of these signalling pathways to host penetration mechanisms.

Eukaryotic protein kinases are well conserved through evolution. The genome of Schistosoma mansoni, which causes intestinal schistosomiasis, encodes over 250 putative protein kinases with all of the main eukaryotic groups represented. However, unraveling functional roles for these kinases is a considerable endeavour, particularly as protein kinases regulate multiple and sometimes overlapping cell and tissue functions in organisms. In this article, elucidating protein kinase signal transduction and function in schistosomes is considered from the perspective of the state-of-the-art methodologies used and comparative organismal biology, with a focus on current advances and future directions. Using the free-living nematode Caenorhabditis elegans as a comparator we predict roles for various schistosome protein kinases in processes vital for host invasion and successful parasitism such as sensory behaviour, growth and development. It is anticipated that the characterization of schistosome protein kinases in the context of parasite function will catalyze cutting edge research into host-parasite interactions and will reveal new targets for developing drug interventions against human schistosomiasis.

OBJECTIVES: Interleukin-1 (IL-1) is a multifunctional proinflammatory cytokine. There have been studies suggesting a role in affecting growth and invasiveness of malignant breast cells by either blocking or stimulating growth of cultured MCF-7 breast cancer cells. This effect may be mediated by induction of COX-2. Aspirin is an inhibitor of COX-2 and has been implicated, with other non-steroidal anti-inflammatory drugs (NSAIDS) in prevention and treatment of breast cancer. In this study the in vitro effects of IL-1 and aspirin on growth of MCF-7 human breast cancer cells was examined. METHODS: MCF-7 cells were treated with various concentrations of IL-1 and aspirin alone and in combination. Cell growth was assessed by cell number measurement. RESULTS: Aspirin significantly decreased growth rate in a dose-dependent manner, alone and as a combined treatment with IL-1 with a maximum reduction in growth rate at 300 mg/ml (P < 0.05). Treatment with IL-1 alone showed no significant effect on growth rate of MCF-7 cells (P > 0.05). CONCLUSION: This study confirms that aspirin suppresses the proliferation rate of MCF-7 cells both as a single agent and in combination with IL-1. It also suggests that IL-1 alone does not stimulate or inhibit growth of MCF-7 cells.

Numerous studies have reported inverse associations between birth weight and a range of diseases in later life. These have led to the development of the foetal origins of adult disease hypothesis. However, many such studies have only been able to demonstrate a statistically significant association between birth weight and disease in later life by adjusting for current size. This has been interpreted as evidence that the impact of low birth weight on subsequent disease is somehow dependent on subsequent weight gain, and has led to a broadening of the hypothesis into the developmental origins of health and disease. Unfortunately, much of the epidemiological evidence used for both of these interpretations is prone to a statistical artefact known as the 'reversal paradox'. The aim of this paper is to illustrate why, using vector geometry.

Introduction\ud \ud Acute metabolic acidosis of non-renal origin is usually a result of either lactic or ketoacidosis, both of which are associated with a high anion gap. There is increasing recognition, however, of a group of acidotic patients who have a large anion gap that is not explained by either keto- or lactic acidosis nor, in most cases, is inappropriate fluid resuscitation or ingestion of exogenous agents the cause.\ud \ud Methods\ud \ud Plasma ultrafiltrate from patients with diabetic ketoacidosis, lactic acidosis, acidosis of unknown cause, normal anion gap metabolic acidosis, or acidosis as a result of base loss were examined enzymatically for the presence of low molecular weight anions including citrate, isocitrate, ?-ketoglutarate, succinate, malate and d-lactate. The results obtained from the study groups were compared with those obtained from control plasma from normal volunteers.\ud \ud Results\ud \ud In five patients with lactic acidosis, a significant increase in isocitrate (0.71 ± 0.35 mEq l-1), ?-ketoglutarate (0.55 ± 0.35 mEq l-1), malate (0.59 ± 0.27 mEq l-1), and d-lactate (0.40 ± 0.51 mEq l-1) was observed. In 13 patients with diabetic ketoacidosis, significant increases in isocitrate (0.42 ± 0.35 mEq l-1), ?-ketoglutarate (0.41 ± 0.16 mEq l-1), malate (0.23 ± 0.18 mEq l-1) and d-lactate (0.16 ± 0.07 mEq l-1) were seen. Neither citrate nor succinate levels were increased. Similar findings were also observed in a further five patients with high anion gap acidosis of unknown origin with increases in isocitrate (0.95 ± 0.88 mEq l-1), ?-ketoglutarate (0.65 ± 0.20 mEq l-1), succinate (0.34 ± 0.13 mEq l-1), malate (0.49 ± 0.19 mEq l-1) and d-lactate (0.18 ± 0.14 mEq l-1) being observed but not in citrate concentration. In five patients with a normal anion gap acidosis, no increases were observed except a modest rise in d-lactate (0.17 ± 0.14 mEq l-1).\ud \ud Conclusion\ud \ud The levels of certain low molecular weight anions usually associated with intermediary metabolism were found to be significantly elevated in the plasma ultrafiltrate obtained from patients with metabolic acidosis. Our results suggest that these hitherto unmeasured anions may significantly contribute to the generation of the anion gap in patients with lactic acidosis and acidosis of unknown aetiology and may be underestimated in diabetic ketoacidosis. These anions are not significantly elevated in patients with normal anion gap acidosis.\ud © 2005 Forni et al.; licensee BioMed Central Ltd.

BACKGROUND: The control of proliferation, differentiation and survival of normal and malignant cells in the tumour microenvironment is under the control of a wide range of different factors, including cell:cell interactions, cytokines, growth factors and hormonal influences. However, the ways in which these factors interact are poorly understood. In order to compare the effects of multiple variables, experimental design becomes complex and difficult to manage. We have therefore evaluated the use of a novel approach to multifactorial experimental design, the Taguchi methods, to approach this problem. METHOD: The Taguchi methods are widely used by quality engineering scientists to compare the effects of multiple variables, together with their interactions, with a simple and manageable experimental design. In order to evaluate these methods, we have used a simple and robust system to compare a traditional experimental design with the Taguchi Methods. The effect of G-CSF, GM-CSF, IL3 and M-CSF on daunorubicin mediated cytotoxicity in K562 cells was measured using the MTT assay. RESULTS: Both methods demonstrated that the same combination of growth factors at the same concentrations minimised daunorubicin cytotoxicity in this assay. CONCLUSIONS: These findings demonstrate that Taguchi methods may be a valuable tool for the investigation of the interactions of multiple variables in the tumour microenvironment.

Clinical research helps in improving patient care and quality of life through translation of findings from basic research (laboratory based) into actual benefit to patients. The huge advancements in the field of clinical research are accompanied by increase in demand for infrastructure, funding and regulations to ensure the safe conduct of research. There are many barriers faced by researchers around the world that affect the initiation and progress of their clinical research projects and eventually lead to wastage of effort and resources. Many studies in literature assessed these barriers from the researchers’ perspective. Nevertheless, the aim of this study was to identify the barriers as seen by research managers in Qatar. The study also had a retrospective aspect where the database of funded projects was analyzed for frequency of suspensions and terminations and if they were related to the identified barriers. Five research managers from different research institutions in Qatar were interviewed for their opinion about the barriers to conducting clinical research in Qatar. The interviews were recorded, transcribed and a thematic analysis model was applied to generate common themes. The major barriers identified could be categorized into four major themes – scientific / professional, financial, administrative and regulatory. A retrospective analysis of the grants awarded to Hamad Medical Corporation (HMC) confirmed that most reasons for the suspensions and terminations were related to these barriers. We believe that this study provided very important insight into the barriers faced by researchers in Qatar. The outcomes will be communicated to the policy makers in Qatar to focus on addressing these issues for a better utilization of the available resources and infrastructure to support clinical research in Qatar. The study also paves the way for a future study where barriers will be assessed by the researchers.

37 million people are currently living with HIV worldwide. With the development of Antiretroviral Therapy (ART) AIDS mortality has reduced, with cardiovascular disease (CVD) now the leading cause of HIV deaths. HIV associated CVD has been linked to chronic immune activation through the association of inflammatory biomarkers, clinical events and asymptomatic atherosclerosis; even from a young age. Microparticles (MPs), markers of cellular activation and injury, are also elevated in adults with HIV, and demonstrate the capacity to contribute to inflammation, endothelial dysfunction and coagulation. Monocytes play a key role in atherosclerosis initiation and display an activated, pro-inflammatory phenotype in paediatric HIV. Monocytic MPs (MMPS) are elevated in adults with HIV, thus the aim of this thesis was to quantify MMPS in HIV infected children and investigate their effects on monocytic function.\ud \ud A novel negative isolation method was first optimised to enable the study of human monocyte function 'ex vivo'. This isolation procedure allowed the negative enrichment of all three circulating monocyte subsets (Classical, Non-classical and Intermediate), with high purity and minimal activation. Extracted monocytes displayed minimal alterations in marker expression while retaining their phagocytic, migratory and cytokine secretion function 'ex vivo'.\ud \ud Using a monocytic cell line (THP-1), MP release under different stimulatory and apoptotic conditions was investigated. Under stimulatory conditions with cytokines and a calcium ionophore (A23187), MPs were released in a concentration-dependent manner, with endotoxin stimulation resulting in the highest quantity. Furthermore, MPs displayed a similar trend in surface marker expression in comparison to their parent cell. Next, we investigated the effects of THP-1 derived MMPS on human monocyte function employing the isolation method established. MMPS evoked the release of pro-inflammatory cytokines in addition to enhancing CD11b expression, adherence and transendothelial migration. This work demonstrates that MMPS activates monocytes and enhances endothelial migration, presenting a mechanism that contributes to atherosclerosis pathogenesis.\ud \ud Finally, MMPS and MPs from an endothelial, platelet and T cell origin were enumerated in children with HIV infection pre/post ART initiation and healthy sex-age-matched controls. Plasma samples were collected during the CHAPAS-3 CV sub-study, from which we analysed 16 children receiving ART (≥2 years), 11 treatment-naïve children and 15 controls. Circulating MPs from an endothelial, platelet and T cell origin found in children with HIV infection normalised to levels found in healthy controls, following ART initiation and experience. MMPS were elevated within the treatment-naïve cohort and remained elevated despite treatment intervention; this elevation was also observed in the treatment-experienced cohort. The persistence of elevated MMPS indicates consistent monocyte activation despite successful viral suppression, supporting the activated phenotype reported in literature.\ud \ud This data combined with the functional implications of MMPS on monocytic function described in this thesis elucidates a mechanism that contributes to elevated vascular inflammation reported within this population.

Aim: The aim of this thesis is to collate and reflect on my published studies exploring the variations within the anatomic, clinical, anthropometric and other aspects of different structures of the human body. \ud \ud Background: The anatomy of living organisms is diverse within each species, including the humans. The scope of anatomical variations cannot be just limited to variants or anomalies; it encompasses the interesting field of “normal variations” among individuals. Anatomical variations need to be considered as an integral component of anatomy teaching because the knowledge of common variants reflects the ability to recognise the diverse clinical reality of anatomy with important surgical and other medical implications. \ud \ud A series of scientific papers published by myself and my colleagues addresses different variations in the human body morphology and function. Therefore, the proposed work scrutinises and critically appraises the published work in the abovementioned area of interest. The objective (or main theme) in this thesis is to understand and address the implications that the identified variations in structure and function might have in health and clinical management. \ud \ud Methods: A common introduction to the published work which focuses on the anatomical and functional morphology and the related variations is presented using selected published articles and case reports. The material and methods section of all the selected papers are reviewed and the salient findings highlighted. Four key themes have been identified in my published work. These are: \ud \ud Theme 1: variations in the foramina of human skull and case reports related to the head and neck region. \ud \ud Theme 2: variations in muscles, knee menisci and height prediction in musculoskeletal system. \ud \ud Theme 3: variations and case reports related to organs.\ud \ud Theme 4: variations and case reports related to blood vessels of circulatory system. \ud \ud Discussion: One question that is often asked today is whether publications and studies of anatomical variations have relevance and clinical significance for medicine and biology of the 21st century, or do they rather represent an exhausted topic with little insignificant implications. The main themes in this thesis discuss the objective response to this valid question and highlight the fact that medical progress needs more accurate knowledge of the variability of the human morphology to improve diagnosis and therapeutic management. Moreover, the advances in the new imaging and surgical techniques (Echography, MRI, CT, Endoscopy, and reconstructive, minimal invasive surgery) have opened new fields of research for the descriptive anatomy that is considered promising. Anatomical variations will always have relevance and applications in the medical and biological fields and developments. \ud \ud As variant anatomy, at least in part contributes to a significant number of malpractice claims, there is a need to improve the basis of anatomical knowledge among practicing physicians and surgeons. This thesis highlights the importance of carefully assessing the quality and reviewing and scrutinising the designs, interpretation and conclusions made, in the light of the clinical interest and clinical implications.

Background Motile cilia are essential to the survival and reproduction of many eukaryotes; they are responsible for powering swimming of protists and small multicellular organisms and drive fluids across respiratory and reproductive surfaces in mammals. Although tremendous progress has been made to comprehend the biochemical basis of these complex evolutionarily-conserved organelles, few protein kinases have been reported to co-ordinate ciliary beat. Here we present evidence for p38 mitogen-activated protein kinase (p38 MAPK) playing a role in the ciliary beat of a multicellular eukaryote, the free-living miracidium stage of the platyhelminth parasite Schistosoma mansoni. Results Fluorescence confocal microscopy revealed that non-motile miracidia trapped within eggs prior to hatching displayed phosphorylated (activated) p38 MAPK associated with their ciliated surface. In contrast, freshly-hatched, rapidly swimming, miracidia lacked phosphorylated p38 MAPK. Western blotting and immunocytochemistry demonstrated that treatment of miracidia with the p38 MAPK activator anisomycin resulted in a rapid, sustained, activation of p38 MAPK, which was primarily localized to the cilia associated with the ciliated epidermal plates, and the tegument. Freshly-hatched miracidia possessed swim velocities between 2.17 - 2.38 mm/s. Strikingly, anisomycin-mediated p38 MAPK activation rapidly attenuated swimming, reducing swim velocities by 55% after 15 min and 99% after 60 min. In contrast, SB 203580, a p38 MAPK inhibitor, increased swim velocity by up to 15% over this duration. Finally, by inhibiting swimming, p38 MAPK activation resulted in early release of ciliated epidermal plates from the miracidium thus accelerating development to the post-miracidium larval stage. Conclusions This study supports a role for p38 MAPK in the regulation of ciliary-beat. Given the evolutionary conservation of signalling processes and cilia structure, we hypothesize that p38 MAPK may regulate ciliary beat and beat-frequency in a variety of eukaryotes.