The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus

The aim of this study was to examine the diffusion of commonly administered analgesics, ibuprofen and paracetamol, through gastric mucus. As ibuprofen and paracetamol are often formulated with alkalising excipients, or are commonly co-administered with antacids that have been demonstrated to alter their absorption, diffusion was also studied in the presence of a range of soluble and insoluble antacids or buffering agents. The effect of pH, which has been demonstrated to modify the properties of mucus, was also studied. Mucus was a significant barrier to diffusion for both drugs, compared to an unstirred aqueous layer with diffusion rates significantly lower in the presence of a mucus barrier for both drugs; ibuprofen diffusion also demonstrated a significant increase in the lag time. Paracetamol diffusion was not significantly affected by addition of any antacid, whereas ibuprofen rates were affected and the diffusion lag time for ibuprofen was significantly reduced in all cases. Isolated increases in pH increased the rate and reduced the lag time for ibuprofen diffusion. It was shown that mucus acts as a passive barrier in the case of paracetamol diffusion, and an interactive barrier to ibuprofen diffusion. Changes in mucus viscosity at different pH values may be responsible for the observed changes in ibuprofen diffusion rate. © 2004 Elsevier B.V. All rights reserved.

The breakdown of plant cell biomass by fungi

Three species of fungi Sporotrichum thermophile, Botrytis cinerea and Trichoderma viride were assessed for their ability to utilize a variety of plant cell substrates (methanol extracted), Catharanthus roseus, Daucus carota, re-autoclaved C. roseus, re-autoclaved D. carota) which preliminary studies had indicated contained the necessary nutrients for fungal growth. Incubated in a suitable manner all three fungal species were able to grow on C. roseus and D. carota plant cell biomass in addition to material which had undergone methanol extraction or a re-autoclaving process to remove soluble components. Fungal biomass yields were markedly influenced by substrate, with each fungal species demonstrating a preference for particular plant cell material. Incubation conditions i.e. static or shaken and temperature also proved important. Release of glucose (i.e. values higher than Day 0) promoted by fungal breakdown of plant cell biomass was only noted with methanol extracted, re-autoclaved C. roseus and re-autoclaved D. carota material. A re-autoclaved substrate was also generally associated with high fungal C1, Cx, B-glucosidase and endo-polygalacturonase activity. In addition for each enzyme highest values were usually obtained from a particular fungal species. Buffering cultures at pH 3 or 5 further influenced enzyme activity, however in a majority of cases when flasks were unbuffered and the pH rose naturally to alkaline values higher enzyme activity was recorded. Likewise Tween 80 addition had only a limited beneficial effect. Finally filtrates containing glucose produced both from the re-autoclaving process and through fungal activity on plant cell biomass were utilized for Fusarium oxysporum, Saccharomyces cerevisiae and C. roseus plant cell culture. Although reasonable fungal biomass was obtained the use of such filtrates proved unsuitable for plant cell growth.

Work stressors, strains and hospital unit performance

Hospital employees who work in an environment with zero tolerance to error, face several stressors that may result in psychological, physiological, and behavioural strains, and subsequently, in suboptimal performance. This thesis includes two studies which investigate the stressor-to-strain-to-performance relationships in hospitals. The first study is a cross-sectional, multi-group investigation based on secondary data from 65,142 respondents in 172 acute/specialist UK NHS trusts. This model proposes that senior management leadership predicts social support and job design which, in turn, moderate stressors-to-strains across team structure. The results confirm the model's robustness. Regression analysis provides support for main effects and minimal support for moderation hypotheses. Therefore, based on its conclusions and inherent limitations, study one lays the framework for study two. The second study is a cross-sectional, multilevel investigation of the strain-reducing effects of social environment on externally-rated unit-level performance based on primary data from 1,137 employees in 136 units, in a hospital in Malta. The term "social environment" refers to the prediction of the moderator variables, which is to say, social support and decision latitude/control, by transformational leadership and team climate across hospital units. This study demonstrates that transformational leadership is positively associated with social support, whereas team climate is positively associated with both moderators. At the same time, it identifies a number of moderating effects which social support and decision latitude/control, both separately and together, had on specific stressor-to-strain relationships. The results show significant mediated stressor-to-strain-to-performance relationships. Furthermore, at the higher level, unit-level performance is positively associated with shared unit-level team climate and with unit-level vision, the latter being one of the five sub-dimension of transformational leadership. At the same time, performance is also positively related to both transformational leadership and team climate when the two constructs are tested together. Few studies have linked the buffering effects of the social environment in occupational stress with performance. Therefore, this research strives to make a significant contribution to the occupational stress and performance literature with a focus on hospital practice. Indeed, the study highlights the wide-ranging and far-reaching implications that these findings provide for theory, management, and practice.

Investigating the modulation of oral drug absorption using in vitro models

Dipeptides can be absorbed into cells via the dipeptide transporter (which also transported tripeptides and dipeptide derivatives). The optimum conditions for measuring the inhibition of Gly-Pro uptake in Caco-2 cells were identified. A number of structure-activity relationships were identified. These included the effects of increasing the amino-acid chain-length, and the presence of a thiol or hydroxyl group in the side-chain increased IC50 while the presence of a hydroxyl group did not. The benzyl esters had lower or equal IC50 values compared to the parent dipeptides while the methyl esters had higher values. These results indicated that while molecular properties did affect IC50, the size, charge and composition of three particular groups caused the most significant effects, supporting the structure-activity relationship identified. An assay was developed using calcein-AM to show the inhibition of p-glycoprotein activity. There was no significant change due to the presence of mannitol but there was in the presence of clyclosporin A (p<0.01). Incubating the cells with the test solution for 30 minutes before the addition of the ester resulted in a significant (p<0.001) difference. The assay was specific for p-glycoprotein, as the presence MRP inhibitors had no effect (p>0.05). The modified protocol allowed the identification of p-glycoprotein inhibitors quickly and simply using a cell suspension of unmodified cells. The clinically relevant buffering of grapefruit juice to pH 7 led to a four-fold increase in intracellular calcein and hence significant inhibition of p-glycoprotein. Buffered orange and lemon juices had no effect on the assay. Flavone derivatives had previously been found to be inhibitors of CYP3A4 yet neither naringin nor naringenin had any significant effect at concentrations found in grapefruit juice. Of the other (non-grapefruit) flavone derivatives tested, hesperidin, found in orange juice, had no significant effect, kaempferol and rutin also had no effect while genistein significantly inhibited p-glycoprotein (results that support previous studies). Hydroxycinnamic acids had no effect on p-glycoprotein. Studies on other compounds found that the balance between inhibiting p-glycoprotein and disrupting cell membranes depends on the compound containing an oxygen atom and the size of the negative charge on it, as well as three-dimensional arrangement of the atoms.

All-optical regenerative memory using a single device

In recent years the optical domain has been traditionally reserved for node-to-node transmission with the processing and switching achieved entirely in the electrical domain. However, with the constantly increasing demand for bandwidth and the resultant increase in transmission speeds, there is a very real fear that current electronic technology as used for processing will not be able to cope with future demands. Fuelled by this requirement for faster processing speeds, considerable research is currently being carried out into the potential of All-optical processing. One of the fundamental obstacles in realising All-optical processing is the requirement for All-optical buffering. Without all-optical buffers it is extremely difficult to resolve situations such as contention and congestion. Many devices have been proposed to solve this problem however none of them provide the perfect solution. The subject of this research is to experimentally demonstrate a novel all-optical memory device. Unlike many previously demonstrated optical storage devices the device under consideration utilises only a single loop mirror and a single SOA as its switch, whilst providing full regenerative capabilities required for long-term storage. I will explain some of the principles and characteristics of the device, which will then be experimentally demonstrated. The device configuration will then be studied and investigated as to its suitability for Hybrid Integrated Technology.

The effect of care solutions on the bulk and surface properties of soft contact lenses

Purpose: Soft contact lenses for continuous wear require the use of cleaning regimes which utilise hydrogen peroxide systems or multipurpose cleaning solutions (MPS). The compositions of MPS are becoming increasingly complex and often include disinfectants, cleaning agents, preservatives, wetting agents, demulcents, chelating and buffering agents. Recent research on solution–lens interactions has focused on specific ocular parameters such as corneal staining. However the effect of a solution on the lens, particularly silicone hydrogel lenses, itself has received less attention. The purpose of this work was to establish and understand the effects that care solutions have on selected bulk and surface material properties. Methods: Selected bulk and surface properties of each material (etafilcon A, vifilcon A, balafilcon A, senofilcon A, lotrafilcon A and lotrafilcon B, galyfilcon A) were measured after a 24 h soak in a variety of care solutions. Additionally the lenses were soaked for 24 h in hyperosmolar (680 mOsm L-1) and hyposmolar (170 mOsm L-1) PBS. A bulk property parameter the total diameter (TD) was measured using an Optimec contact lens analyser. The surface property related CoF of soaked lenses was measured on a nano-tribometer with conditions of load 30 mN, at a distance of 20 mm and speed 30 mm/min. Results: In terms of bulk properties, change is related to the EWC of the lens, the higher the EWC of the lens the greater the TD changes. Silicone hydrogel lenses have EWCs of <47% and little or no TD changes were observed; lotrafilcon A exhibited no change irrespective of the cleaning solution. Conventional contact lenses have higher EWCs (58% for etafilcon A and 55% for vifilcon A) and the TD was seen to change to a greater extent, for example the etafilcon A material in ReNu MPS had an increase to 14.45± 0.07 mm from the cited 14.2 mm. Other lenses increased or decreased in TD depending on the solution used. The osmolarity of the solution although important is not the only factor governing change in the TD, for example soaking senofilcon A in hyperosmolar PBS (680 mOsm L-1) for 24 h increased the TD of the lens (+0.25 ± 0.07 mm), however when the same lens type was soaked for 24 h in a MPS with a lower osmolarity there was a similar effect. Biotribology measurements demonstrated that some solution–lens combinations can reduce the CoF by 55%, when compared with biotribology with the native packing solution. An increase in the CoF was observed for other solution–lens combinations. Conclusions: There is a dramatic difference in bulk and surface performance of specific lens materials with particular care solutions. Individual components of the care solutions have effects on the bulk and surface properties of contact lenses. The affects are not as great with the silicone hydrogel as compared with conventional hydrogels.

The effect of flying and low humidity on the admittance of the tympanic membrane and middle ear system

Many passengers experience discomfort during flight because of the effect of low humidity on the skin, eyes, throat, and nose. In this physiological study, we have investigated whether flight and low humidity also affect the tympanic membrane. From previous studies, a decrease in admittance of the tympanic membrane through drying might be expected to affect the buffering capacity of the middle ear and to disrupt automatic pressure regulation. This investigation involved an observational study onboard an aircraft combined with experiments in an environmental chamber, where the humidity could be controlled but could not be made to be as low as during flight. For the flight study, there was a linear relationship between the peak compensated static admittance of the tympanic membrane and relative humidity with a constant of proportionality of 0.00315 mmho/% relative humidity. The low humidity at cruise altitude (minimum 22.7 %) was associated with a mean decrease in admittance of about 20 % compared with measures in the airport. From the chamber study, we further found that a mean decrease in relative humidity of 23.4 % led to a significant decrease in mean admittance by 0.11 mmho [F(1,8) = 18.95, P = 0.002], a decrease of 9.4 %. The order of magnitude for the effect of humidity was similar for the flight and environmental chamber studies. We conclude that admittance changes during flight were likely to have been caused by the low humidity in the aircraft cabin and that these changes may affect the automatic pressure regulation of the middle ear during descent. © 2013 Association for Research in Otolaryngology.

The influence of pH and fluid dynamics on the antibacterial efficacy of 45S5 Bioglass

In recent years, there has been considerable interest in the potential antibacterial properties that bioactive glasses may possess. However, there have been several conflicting reports on the antibacterial efficacy of 45S5 Bioglass®. Various mechanisms regarding its mode of action have been proposed, such as changes in the environmental pH, increased osmotic pressure, and ‘needle like’ sharp glass debris which could potentially damage prokaryotic cell walls and thus inactivate bacteria. In this current study, a systematic investigation was undertaken on the antibacterial efficacy of 45S5 Bioglass® on Escherichia coli NCTC 10538 and Staphylococcus aureus ATCO 6538 under a range of clinically relevant scenarios including varying Bioglass® concentration, direct and indirect contact between Bioglass® and microorganisms, static and shaking incubation conditions, elevated and neutralised pH environments. The results demonstrated that under elevated pH conditions, Bioglass® particles has no antibacterial effect on S. aureus whilst, a concentration dependent antibacterial effect against E. coli was observed. However, the antibacterial activity ceased when the pH of the media was neutralised. The results of this current study therefore suggest that the mechanism of antibacterial activity of Bioglass® is associated with changes in the environmental pH; an environment that is less likely to occur in vivo due to buffering of the system.

The antecedents and consequences of anticipatory identification

The aim of this thesis was to investigate anticipatory identification: newcomers’ identification with an organisation prior to entry; in particular by exploring the antecedents and consequences of the construct. Although organisational identification has been frequently investigated over the past 25 years, surprisingly little is known about what causes an individual to identify with a new organisation before entry and whether this has an impact on their relationship with the organisation after formally taking up membership. Drawing on a Social Identity approach to organisational identification, it was hypothesised that newcomers would more closely identify with an organisation prior to entry when the organisation was seen as a source of positive social identity and was situationally relevant and meaningful to the newcomer, i.e. salient, during the pre-entry period. It was also hypothesised that anticipatory identification would have post-entry consequences and would predict newcomers’ post-entry identification, turnover intentions and job satisfaction. An indirect relationship between anticipatory identification and post-entry identification through post-entry social identity judgements (termed a “feedback loop” mechanism) was additionally proposed. Finally anticipatory identification was also predicted to moderate the relationship between post-entry social identity judgements and post-entry identification (termed a “buffering” mechanism). Four studies were conducted to test these hypotheses. Study One served as a pilot study, using a retrospective self-report design with s sample of 124 university students to initially test the proposed conceptual model. Studies Two and Three adopted experimental designs. Each used a unique sample of 72 staff and students from Aston University to respectively test the hypothesised positive social identity motive and salience antecedents of anticipatory identification. Study Four explored the relationship between anticipatory identification, its antecedents and consequences longitudinally, using an organisational sample of 45 employees. Overall, these studies found support for a social identity motive antecedent of anticipatory identification, as well as more limited evidence that anticipatory identification was associated with the salience of an organisation prior to entry. Support was inconsistent for a direct relationship between anticipatory identification and post-entry identification and there was no evidence that anticipatory identification was a significant direct predictor of turnover intention and job satisfaction. Anticipatory identification was however found to act as a buffer in the relationship between post-entry social identity judgements and post-entry identification in all but one of the four samples measured. A feedback loop mechanism was observed within the experimental designs of Studies Two and Three, but not within the organisational samples of Studies One and Four. Overall the findings of these four studies highlight key ways through which anticipatory identification can develop prior to entry into an organisation. Moreover, the research observed several important post-entry consequences of anticipatory identification, indicating that an understanding of post-entry identification may be enriched by attending more closely to the extent to which newcomers identify with an organisation prior to entry.

Web-based report generators, data visualization, and Web-to-database connectivity

Because some Web users will be able to design a template to visualize information from scratch, while other users need to automatically visualize information by changing some parameters, providing different levels of customization of the information is a desirable goal. Our system allows the automatic generation of visualizations given the semantics of the data, and the static or pre-specified visualization by creating an interface language. We address information visualization taking into consideration the Web, where the presentation of the retrieved information is a challenge. ^ We provide a model to narrow the gap between the user's way of expressing queries and database manipulation languages (SQL) without changing the system itself thus improving the query specification process. We develop a Web interface model that is integrated with the HTML language to create a powerful language that facilitates the construction of Web-based database reports. ^ As opposed to other papers, this model offers a new way of exploring databases focusing on providing Web connectivity to databases with minimal or no result buffering, formatting, or extra programming. We describe how to easily connect the database to the Web. In addition, we offer an enhanced way on viewing and exploring the contents of a database, allowing users to customize their views depending on the contents and the structure of the data. Current database front-ends typically attempt to display the database objects in a flat view making it difficult for users to grasp the contents and the structure of their result. Our model narrows the gap between databases and the Web. ^ The overall objective of this research is to construct a model that accesses different databases easily across the net and generates SQL, forms, and reports across all platforms without requiring the developer to code a complex application. This increases the speed of development. In addition, using only the Web browsers, the end-user can retrieve data from databases remotely to make necessary modifications and manipulations of data using the Web formatted forms and reports, independent of the platform, without having to open different applications, or learn to use anything but their Web browser. We introduce a strategic method to generate and construct SQL queries, enabling inexperienced users that are not well exposed to the SQL world to build syntactically and semantically a valid SQL query and to understand the retrieved data. The generated SQL query will be validated against the database schema to ensure harmless and efficient SQL execution. (Abstract shortened by UMI.)^

Mangrove tannins in aquatic ecosystems: Their fate and possible influence on dissolved organic carbon and nitrogen cycling

We describe the fate of mangrove leaf tannins in aquatic ecosystems and their possible influence on dissolved organic nitrogen (DON) cycling. Tannins were extracted and purified from senescent yellow leaves of the red mangrove (Rhizophora mangle) and used for a series of model experiments to investigate their physical and chemical reactivity in natural environments. Physical processes investigated included aggregation, adsorption to organic matter-rich sediments, and co-aggregation with DON in natural waters. Chemical reactions included structural change, which was determined by excitation–emission matrix fluorescence spectra, and the release of proteins from tannin–protein complexes under solar-simulated light exposure. A large portion of tannins can be physically eliminated from aquatic environments by precipitation in saline water and also by binding to sediments. A portion of DON in natural water can coprecipitate with tannins, indicating that mangrove swamps can influence DON cycling in estuarine environments. The chemical reactivity of tannins in natural waters was also very high, with a half-life of less than 1 d. Proteins were released gradually from tannin–protein complexes incubated under light conditions but not under dark conditions, indicating a potentially buffering role of tannin– protein complexes on DON recycling in mangrove estuaries. Although tannins are not detected at a significant level in natural waters, they play an important ecological role by preserving nitrogen and buffering its cycling in estuarine ecosystems through the prevention of rapid DON export/loss from mangrove fringe areas and/or from rapid microbial mineralization.

*Adoption status: A risk factor or protective factor for children of divorced families

This study examined two competitive hypotheses: the double jeopardy hypothesis and the buffering effect hypothesis on whether parental divorce affects adopted children and non-adopted children similarly or differently. The double jeopardy hypothesis suggests that when adopted children experience their parents' divorce, they perform worse because they carry two risk factors, adoption status and parental divorce, while their non-adopted counterparts carry only the risk factor of their parents' divorce. The buffering effect hypothesis suggests that, being adopted children, their previous experiences of parental loss help them better deal with the later loss of their parents' divorce so their adoption status is a protective factor rather than a risk factor. ^ Secondary analyses of a nation-wide data set were executed using different statistical methods such as ANOVA and Chi-square on different outcome variables. The results indicated that there was no evidence supporting the double-jeopardy hypothesis. That is, adopted children from divorced families did not perform significantly worse than the non-adopted children from divorced families on any outcome variable. The results also indicated that there was only weak evidence supporting the buffering effect hypothesis. The general conclusion based on the results from most of the outcome variables suggest that adopted children from divorced families do not perform differently than the biological children from divorced families. ^

Effects of in situ CO2 enrichment on structural characteristics, photosynthesis, and growth of the Mediterranean seagrass Posidonia oceanica

Seagrass is expected to benefit from increased carbon availability under future ocean acidification. This hypothesis has been little tested by in situ manipulation. To test for ocean acidification effects on seagrass meadows under controlled CO2/pH conditions, we used a Free Ocean Carbon Dioxide Enrichment (FOCE) system which allows for the manipulation of pH as continuous offset from ambient. It was deployed in a Posidonia oceanica meadow at 11 m depth in the Northwestern Mediterranean Sea. It consisted of two benthic enclosures, an experimental and a control unit both 1.7 m**3, and an additional reference plot in the ambient environment (2 m**2) to account for structural artifacts. The meadow was monitored from April to November 2014. The pH of the experimental enclosure was lowered by 0.26 pH units for the second half of the 8-month study. The greatest magnitude of change in P. oceanica leaf biometrics, photosynthesis, and leaf growth accompanied seasonal changes recorded in the environment and values were similar between the two enclosures. Leaf thickness may change in response to lower pH but this requires further testing. Results are congruent with other short-term and natural studies that have investigated the response of P. oceanica over a wide range of pH. They suggest any benefit from ocean acidification, over the next century (at a pH of 7.7 on the total scale), on Posidonia physiology and growth may be minimal and difficult to detect without increased replication or longer experimental duration. The limited stimulation, which did not surpass any enclosure or seasonal effect, casts doubts on speculations that elevated CO2 would confer resistance to thermal stress and increase the buffering capacity of meadows.

Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics

Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.

Geochemistry and radiogenic isotope ratios of the volcanic sequences from Izu-Bonin Arc, Japan

New radiogenic isotope and trace element data are presented for the volcanic sequences along 600 km of the active Izu-Bonin arc, the Oligocene Izu arc, and their associated rift basins. As with many intra-oceanic island arcs, the Pliocene-Recent Izu-Bonin frontal-arc lavas are highly depleted in Zr, Nb and the rare-earth elements relative to typical mid-ocean ridge basalt (MORB), indicating that the mantle wedge source has undergone a previous episode of melting. Ratios between these elements (such as Nb/Zr and La/Sm), as well as 143Nd/144Nd, do not vary significantly along the length of the frontal-arc. These parameters suggest that each of the arc volcanoes is derived from similar melt fractions of the mantle wedge. However, Ba/Zr, Ba/Rb and 87Sr/86Sr increase along the frontal-arc to the north. This leads us to propose that a variable enrichment in Ba and radiogenic Sr is superimposed on the mantle wedge. Sr-Nd and Pb-Nd isotope variation indicate that both Sr and Pb become more radiogenic after fluid addition. However, Pb isotope ratios do not correlate with increases in Pb concentration or ratios such as Ba/Zr and Nb/Pb. In other words, the Pb isotopic composition of the arc lavas appears to be independent of the amount of Pb introduced by subduction fluids into the mantle source. This buffering of Pb isotopes along the frontal-arc means that the isotopic composition of the lavas is indistinguishable from that of the fluid. Isotopic mixing models presented for the arc are only illustrative of the many plausible combinations of components and quantities. Despite this, we are able to determine that the mantle wedge has isotopic characteristics similar to Indian Ocean MORB, and that the subduction-fluid solute is primarily derived from subducted oceanic basalt with a <2% contribution from subducted sediment. Lavas in the Oligocene Izu arc and fore-arc basin were derived from a mantle wedge of similar composition to the active arc. Despite levels of Pb enrichment comparable to those of the modern arc, the Pb isotopes of the Oligocene volcanics indicate a lower sediment input into the melting region.