Application of mesoporous silica for the oral delivery of poorly water-soluble drugs

The objective of this thesis was to improve the dissolution rate of the poorly waters-soluble drug, fenofibrate by processing it with a high surface area carrier, mesoporous silica. The subsequent properties of the drug – silica composite were studied in terms of drug distribution within the silica matrix, solid state and release properties. Prior to commencing any experimental work, the properties of unprocessed mesoporous silica and fenofibrate were characterised (chapter 3), this allowed for comparison with the processed samples studied in later chapters. Fenofibrate was a highly stable, crystalline drug that did not adsorb moisture, even under long term accelerated storage conditions. It maintained its crystallinity even after SC-CO2 processing. Its dissolution rate was limited and dependent on the characteristics of the particular in vitro media studied. Mesoporous silica had a large surface area and mesopore volume and readily picked up moisture when stored under long term accelerated storage conditions (75% RH, 40 oC). It maintained its mesopore character after SC-CO2 processing. A variety of methods were employed to process fenofibrate with mesoporous silica including physical mixing, melt method, solvent impregnation and novel methods such as liquid and supercritical carbon dioxide (SC-CO2) (chapter 4). It was found that it was important to break down the fenofibrate particulate structure to a molecular state to enable drug molecules enter into the silica mesopores. While all processing methods led to some increase in fenofibrate release properties; the impregnation, liquid and SC-CO2 methods produced the most rapid release rates. SC-CO2 processing was further studied with a view to optimising the processing parameters to achieve the highest drug-loading efficiency possible (chapter 5). In this thesis, it was that SC-CO2 processing pressure had a bearing on drug-loading efficiency. Neither pressure, duration or depressurisation rate affected drug solid state or release properties. The amount of drug that could be loaded onto to the mesoporous silica successfully was also investigated at different ratios of drug mass to silica surface area under constant SC-CO2 conditions; as the drug – silica ratio increased, the drug-loading efficiency decreased, while there was no effect on drug solid state or release properties. The influence of the number of drug-loading steps was investigated (chapter 6) with a view to increasing the drug-loading efficiency. This multiple step approach did not yield an increase in drug-loading efficiency compared to the single step approach. It was also an objective in this chapter to understand how much drug could be loaded into silica mesopores; a method based on the known volume of the mesopores and true density of drug was investigated. However, this approach led to serious repercussions in terms of the subsequent solid state nature of the drug and its release performance; there was significant drug crystallinity and reduced release extent. The impact of in vitro release media on fenofibrate release was also studied (chapter 6). Here it was seen that media containing HCl led to reduced drug release over time compared to equivalent media not containing HCl. The key findings of this thesis are discussed in chapter 7 and included: 1. Drug – silica processing method strongly influenced drug distribution within the silica matrix, drug solid state and release. 2. The silica surface area and mesopore volume also influenced how much drug could be loaded. It was shown that SC-CO2 processing variables such as processing pressure (13.79 – 41.37 MPa), duration time (4 – 24 h) and depressurisation rate (rapid or controlled) did not influence the drug distribution within the SBA- 15 matrix, drug solid state form or release. Possible avenues of research to be considered going forward include the development and application of high resolution imaging techniques to visualise drug molecules within the silica mesopores. Also, the issues surrounding SBA-15 usage in a pharmaceutical manufacturing environment should be addressed.

Exploring the Zionist evolution of Robert Briscoe: History and memory

Robert Briscoe was the Dublin born son of Lithuanian and German-Jewish immigrants. As a young man he joined Sinn Féin and was an important figure in the War of Independence due to a role as one of the IRA’s main gun-procuring agents. He took the anti-Treaty side during an internecine Civil War, mainly due to the influence of Eamon de Valera and retained a filial devotion towards him for the rest of his life. In 1926 he was a founding member of Fianna Fáil, de Valera’s breakaway republican party, which would dominate twentieth-century Irish politics. He was first elected as a Fianna Fáil T.D. (Teachta Dála, Deputy to the Dáil) in 1927, and successfully defended his seat eleven times becoming the first Jewish Lord Mayor of Dublin in 1956, an honour that was repeated in 1961. On this basis alone, it can be argued that Briscoe was a significant presence in an embryonic Irish political culture; however, when his role in the 1930s Jewish immigration endeavor is acknowledged, it is clear that he played a unique part in one of the most contentious political and social discourses of the pre-war years. This was reinforced when Briscoe embraced Zionism in a belated realisation that the survival of his European co-religionists could only be guaranteed if an independent Jewish state existed. This information is to a certain degree public knowledge; however, the full extent of his involvement as an immigration advocate for potential Jewish refugees, and the seniority he achieved in the New Zionist Organisation (Revisionists) has not been fully recognised. This is partly explicable because researchers have based their assessment of Briscoe on an incomplete political archive in the National Library of Ireland (NLI). The vast majority of documentation pertaining to his involvement in the immigration endeavor has not been available to scholars and remains the private property of Robert Briscoe’s son, Ben Briscoe. The lack of immigration files in the NLI was reinforced by the fact that information about Briscoe’s Revisionist engagement was donated to the Jabotinsky Institute in Tel Aviv and can only be accessed physically by visiting Israel. Therefore, even though these twin endeavors have been commented on by a number of academics, their assessments have tended to be based on an incomplete archive, which was supplemented by Briscoe’s autobiographical memoir published in 1958. This study will attempt to fill in the missing gaps in Briscoe’s complex political narrative by incorporating the rarely used private papers of Robert Briscoe, and the difficult to access Briscoe files in Tel Aviv. This undertaking was only possible when Mr.Ben Briscoe graciously granted me full and unrestricted access to his father’s papers, and after a month-long research trip to the Jabotinsky Institute in Tel Aviv. Access to this rarely used documentation facilitated a holistic examination of Briscoe’s complex and multifaceted political reality. It revealed the full extent of Briscoe’s political and social evolution as the Nazi instigated Jewish emigration crisis reached catastrophic proportions. He was by turn Fianna Fáil nationalist, Jewish immigration advocate and senior Revisionist actor on a global stage. The study will examine the contrasting political and social forces that initiated each stage of Briscoe’s Zionist awakening, and in the process will fill a major gap in Irish-Jewish historiography by revealing the full extent of his Revisionist engagement.

An exploration through interview and drawings of the experiences of patients diagnosed with oral cancer across their cancer trajectory

Background: The treatment of oral cancer is complex and lengthy. Curative treatment implies a combination of surgery, radiotherapy and chemotherapy. The main goal of treatment is to guarantee long-term tumour free survival with as little functional and cosmetic damage. Despite progress in developing these strategies, cancers of the oral cavity continue to have high mortality rates that have not improved dramatically over the past ten years. Aim: The aim of this study was to uniquely explore the dynamic changes in the physical, psychological, social and existential experiences of newly diagnosed patients with oral cancer at two points across their cancer illness trajectory i.e. at the time of diagnosis and at the end of treatment. Methodology: A qualitative prospective longitudinal design was employed. Non-probability purposive sampling allowed the recruitment of 10 participants. The principal data collection method used was a digital audio taped semi-structured interview along with drawings produced by the participants. Analysis: Data was analysed using latent content analyses. Summary: Three ‘dynamic’ themes, physical, psychosocial and existential experiences were revealed that interact and influence each other in a complex and compound whole. These experiences are present at different degrees and throughout the entire trajectory of care. Patients have a number of specific concerns and challenges that cannot be compartmentalised into unitary or discrete aspects of their daily lives. Conclusion & Implications: An understanding of the patient’s experience of their illness at all stages of the disease trajectory, is essential to inform service providers’ decision making if the delivery of care is to be client centred. Dynamic and fluctuating changes in the patient’s personal experience of the cancer journey require dynamic, energetic and timely input from health care professionals.

A river of memory: landscape, narrative and identity in the Lee Valley, Co. Cork, Ireland

In moments of rapid social changes, as has been witnessed in Ireland in the last decade, the conditions through which people engage with their localities though memory, individually and collectively, remains an important cultural issue with key implications for questions of heritage, preservation and civic identity. In recent decades, cultural geographers have argued that landscape is more than just a view or a static text of something symbolic. The emphasis seems to be on landscape as a dynamic cultural process – an ever-evolving process being constructed and re-constructed. Hence, landscape seems to be a highly complex term that carries many different meanings. Material, form, relationships or actions have different meanings in different settings. Drawing upon recent and continuing scholarly debates in cultural landscapes and collective memory, this thesis sets out to examine the generation of collective memory and how it is employed as a cultural tool in the production of memory in the landscape. More specifically, the research considers the relationships between landscape and memory, investigating the ways in which places are produced, appropriated, experienced, sensed, acknowledged, imagined, yearned for, appropriated, re-appropriated, contested and identified with. A polyvocal-bricoleur approach aims to get below the surface of a cultural landscape, inject historical research and temporal depth into cultural landscape studies and instil a genuine sense of inclusivity of a wide variety of voices (role of monuments and rituals and voices of people) from the past and present. The polyvocal-bricoleur approach inspires a mixed method methodology approach to fieldsites through archival research, fieldwork and filmed interviews. Using a mixture of mini-vignettes of place narratives in the River Lee valley in the south of Ireland, the thesis explores a number of questions on the fluid nature of narrative in representing the story and role of the landscape in memory-making. The case studies in the Lee Valley are harnessed to investigate the role of the above questions/ themes/ debates in the act of memory making at sites ranging from an Irish War of Independence memorial to the River Lee’s hydroelectric scheme to the valley’s key religious pilgrimage site. The thesis investigates the idea that that the process of landscape extends not only across space but also across time – that the concept of historical continuity and the individual and collective human engagement and experience of this continuity are central to the processes of remembering on the landscape. In addition the thesis debates the idea that the production of landscape is conditioned by several social frames of memory – that individuals remember according to several social frames that give emphasis to different aspects of the reality of human experience. The thesis also reflects on how the process of landscape is represented by those who re-produce its narratives in various media.

Religious memory as a conveyor of authoritative tradition: The necessary and essential component in a definition of religion

In a landmark book published in 2000, the sociologist Danièle Hervieu-Léger defined religion as a chain of memory, by which she meant that within religious communities remembered traditions are transmitted with an overpowering authority from generation to generation. After analysing Hervieu-Léger’s sociological approach as overcoming the dichotomy between substantive and functional definitions, this article compares a ritual honouring the ancestors in which a medium becomes possessed by the senior elder’s ancestor spirit among the Shona of Zimbabwe with a cleansing ritual performed by a Celtic shaman in New Hampshire, USA. In both instances, despite different social and historical contexts, appeals are made to an authoritative tradition to legitimize the rituals performed. This lends support to the claim that the authoritative transmission of a remembered tradition, by exercising an overwhelming power over communities, even if the memory of such a tradition is merely postulated, identifies the necessary and essential component for any activity to be labelled “religious”.

A corpus-driven error analysis of the oral and written production of Leaving Certificate Spanish learners

The Leaving Certificate (LC) is the national, standardised state examination in Ireland necessary for entry to third level education – this presents a massive, raw corpus of data with the potential to yield invaluable insight into the phenomena of learner interlanguage. With samples of official LC Spanish examination data, this project has compiled a digitised corpus of learner Spanish comprised of the written and oral production of 100 candidates. This corpus was then analysed using a specific investigative corpus technique, Computer-aided Error Analysis (CEA, Dagneaux et al, 1998). CEA is a powerful apparatus in that it greatly facilitates the quantification and analysis of a large learner corpus in digital format. The corpus was both compiled and analysed with the use of UAM Corpus Tool (O’Donnell 2013). This Tool allows for the recording of candidate-specific variables such as grade, examination level, task type and gender, therefore allowing for critical analysis of the corpus as one unit, as separate written and oral sub corpora and also of performance per task, level and gender. This is an interdisciplinary work combining aspects of Applied Linguistics, Learner Corpus Research and Foreign Language (FL) Learning. Beginning with a review of the context of FL learning in Ireland and Europe, I go on to discuss the disciplinary context and theoretical framework for this work and outline the methodology applied. I then perform detailed quantitative and qualitative analyses before going on to combine all research findings outlining principal conclusions. This investigation does not make a priori assumptions about the data set, the LC Spanish examination, the context of FLs or of any aspect of learner competence. It undertakes to provide the linguistic research community and the domain of Spanish language learning and pedagogy in Ireland with an empirical, descriptive profile of real learner performance, characterising learner difficulty.

Polymeric and monomeric IgA response in serum and milk after parenteral cholera and oral typhoid vaccination

SCOPUS: ar.j

Significant variations of Anti-Müllerian hormone serum levels during pregnancy and during oral contraception

info:eu-repo/semantics/nonPublished

Functional neuroimaging of autobiographical memory.

Functional neuroimaging studies of autobiographical memory have grown dramatically in recent years. These studies are important because they can investigate the neural correlates of processes that are difficult to study using laboratory stimuli, including: (i) complex constructive processes, (ii) recollective qualities of emotion and vividness, and (iii) remote memory retrieval. Constructing autobiographical memories involves search, monitoring and self-referential processes that are associated with activity in separable prefrontal regions. The contributions of emotion and vividness have been linked to the amygdala and visual cortex respectively. Finally, there is evidence that recent and remote autobiographical memories might activate the hippocampus equally, which has implications for memory-consolidation theories. The rapid development of innovative methods for eliciting personal memories in the scanner provides the opportunity to delve into the functional neuroanatomy of our personal past.

Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.

BACKGROUND: The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. METHODS AND FINDINGS: We immortalized IgG(+) memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. CONCLUSIONS: This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

Use of 16S ribosomal RNA gene analyses to characterize the bacterial signature associated with poor oral health in West Virginia.

BACKGROUND: West Virginia has the worst oral health in the United States, but the reasons for this are unclear. This pilot study explored the etiology of this disparity using culture-independent analyses to identify bacterial species associated with oral disease. METHODS: Bacteria in subgingival plaque samples from twelve participants in two independent West Virginia dental-related studies were characterized using 16S rRNA gene sequencing and Human Oral Microbe Identification Microarray (HOMIM) analysis. Unifrac analysis was used to characterize phylogenetic differences between bacterial communities obtained from plaque of participants with low or high oral disease, which was further evaluated using clustering and Principal Coordinate Analysis. RESULTS: Statistically different bacterial signatures (P<0.001) were identified in subgingival plaque of individuals with low or high oral disease in West Virginia based on 16S rRNA gene sequencing. Low disease contained a high frequency of Veillonella and Streptococcus, with a moderate number of Capnocytophaga. High disease exhibited substantially increased bacterial diversity and included a large proportion of Clostridiales cluster bacteria (Selenomonas, Eubacterium, Dialister). Phylogenetic trees constructed using 16S rRNA gene sequencing revealed that Clostridiales were repeated colonizers in plaque associated with high oral disease, providing evidence that the oral environment is somehow influencing the bacterial signature linked to disease. CONCLUSIONS: Culture-independent analyses identified an atypical bacterial signature associated with high oral disease in West Virginians and provided evidence that the oral environment influenced this signature. Both findings provide insight into the etiology of the oral disparity in West Virginia.

Chimpanzees and bonobos exhibit divergent spatial memory development.

Spatial cognition and memory are critical cognitive skills underlying foraging behaviors for all primates. While the emergence of these skills has been the focus of much research on human children, little is known about ontogenetic patterns shaping spatial cognition in other species. Comparative developmental studies of nonhuman apes can illuminate which aspects of human spatial development are shared with other primates, versus which aspects are unique to our lineage. Here we present three studies examining spatial memory development in our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (P. paniscus). We first compared memory in a naturalistic foraging task where apes had to recall the location of resources hidden in a large outdoor enclosure with a variety of landmarks (Studies 1 and 2). We then compared older apes using a matched memory choice paradigm (Study 3). We found that chimpanzees exhibited more accurate spatial memory than bonobos across contexts, supporting predictions from these species' different feeding ecologies. Furthermore, chimpanzees - but not bonobos - showed developmental improvements in spatial memory, indicating that bonobos exhibit cognitive paedomorphism (delays in developmental timing) in their spatial abilities relative to chimpanzees. Together, these results indicate that the development of spatial memory may differ even between closely related species. Moreover, changes in the spatial domain can emerge during nonhuman ape ontogeny, much like some changes seen in human children.

Cognitive training: the effects of working memory training

Gemstone Team Cognitive Training

Sikh Sabad Kirtan as a Musical Construction of Memory

The performance of devotional music in India has been an active, sonic conduit where spiritual identities are shaped and forged, and both history and mythology lived out and remembered daily. For the followers of Sikhism, congregational hymn singing has been the vehicle through which text, melody and ritual act as repositories of memory, elevating memory to a place where historical and social events can be reenacted and memorialized on levels of spiritual significance. This dissertation investigates the musical process of Shabad Kirtan, Sikh hymn singing, in a Sikh musical service as a powerful vehicle to forge a sense of identification between individual and the group. As an intimate part of Sikh life from birth to death, the repertoire of Shabad Kirtan draws from a rich mosaic of classical and folk genres as well as performance styles, acting as a musical and cognitive archive. Through a detailed analysis of the Asa Di Var service, Shabad Kirtan is explored as a phenomenological experience where time, place and occasion interact as a meaningful unit through which the congregation creates and recreates themselves, invoking deep memories and emotional experiences. Supported by explanatory tables, diagrams and musical transcriptions, the sonic movements of the service show how the Divine Word as Shabad is not only embodied through the Guru Granth Sahib, but also encountered through the human enactment of the service, aurally, viscerally and phenomenologically.