Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, and pathologically by neuronal degeneration, plaques (insoluble β-amyloid (Aβ) protein) and neurofibrillary lesions (abnormally phosphorylated tau protein). The mechanisms by which cells die in AD remain largely unknown and controversial. There is some evidence to suggest that cell death in AD brains may occur by apoptosis, and that Aβ might be involved in this process. Apoptosis, a type of cell death characterised by distinct morphological and biochemical features, is often the result of 'programmed cell death' (PCD). Many gene families have been proposed to be involved in the PCD pathway, including the caspase family, inducible transcription factor (ITF) family (including Jun, Fos and Krox genes), and members of the Bcl-2 gene family (including the death promoting gene Bax). It is possible, therefore, that some of these genes may play a role in cell death in AD. The hippocampus is one of the first regions of the brain to be affected in AD, showing cell loss mainly in the CA1-2 pyramidal cell layer. In this thesis, the hippocampus from AD and Control cases has been examined for markers of apoptosis and genes thought to be involved in PCD. In addition, the actions of Aβ, human amylin (a structurally similar protein to Aβ) and the Aβ precursor protein (APP) have been examined in cell culture in an attempt to elucidate their mechanisms of action and relate this to the pathogenesis of AD. AD hippocampi showed increased DNA fragmentation as assessed by TdT-mediated dUTP-biotin nick end labelling (TUNEL), but TUNEL-positive cells in AD generally did not exhibit 'typical' apoptotic morphology, and there was no evidence of the oligonucleosomal DNA fragmentation characteristic of apoptosis. This indicates that 'typical' apoptosis may not be the predominant cell death mechanism in AD. However, there was some evidence of atypical 'broken' nuclei, which may represent a form of apoptosis that presents with a different morphology in aging tissue. This study found no conclusive evidence of increased expression of Fos or Jun family members in the CA1 region of AD hippocampi, however there were increased levels of the putative 'apoptosis-specific protein' and krox24 mRNA in this area which could be related to the cell death. There was no change in Bax expression in the CA1 region of AD brains (although increased Bax expression was observed in this region in a rat hypoxic-ischemia model where the CA1 neurons die by apoptosis). However, there was a decrease in Bax expression in the granule cells of AD hippocampi which could be related to the relative preservation of these cells in AD. Bax and ITF expression was observed in tangles, senile plaques and Hirano bodies in AD hippocampi, which may be related to the formation of these features and/or the pathogenesis of AD. There appeared to be changes in the cellular location of proteins in post-mortem tissue that made determination of ITF levels extremely difficult. In addition, patterns of ITF expression differed when different antisera directed at the same protein were used. These observations indicate that caution must be exercised when studying protein changes in post-mortem tissue. Application of insoluble Aβ to cultured cells, and overexpression of APP or familial AD-linked APP mutants in cultured cells, did not cause toxicity or alter c-Jun gene expression. However, human amylin was toxic to cultured cells, and had different effects on c-Jun gene expression depending on the cell type. This shows that structurally similar proteins do not always act by a similar mechanism, and that care must be taken when choosing a cell culture system to study disease-related events. The finding that neither insoluble Aβ nor APP/AD-linked APP mutants caused acute toxicity to cultured cells, coupled with the lack of relationship between TUNEL staining and Aβ deposits in post-mortem AD tissue, indicates that deposited insoluble Aβ and/or increased amounts of Aβ may not represent the toxic event in AD. This thesis provides a detailed investigation of several factors that could be involved in the cell death process in the hippocampus in AD. The results presented find no conclusive evidence for ‘classical’ apoptosis and/or increased ITF expression in the hippocampus in AD, but the changes in expression of krox24 mRNA, ‘apoptosis-specific protein’ and Bax suggest that programmed cell death may well be a mechanism which is involved in the pathogenesis of AD. / Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Related published articles. MacGibbon GA, Cooper GJS, Dragunow M. Acute application of human amylin, unlike β-amyloid peptides, kills undifferentiated PC12 cells by apoptosis. NeuroReport 1997; 8:3945-3950. MacGibbon GA, Lawlor PA, Walton M, et al. Expression of Fos, Jun and Krox family proteins in Alzheimer's disease. Exp Neurol 1997; 147:316-332. MacGibbon GA, Lawlor PA, Sirimanne E et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997; 750:223-234

No description available.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is characterised clinically by dementia and progressive memory loss, and pathologically by neuronal degeneration, plaques (insoluble β-amyloid (Aβ) protein) and neurofibrillary lesions (abnormally phosphorylated tau protein). The mechanisms by which cells die in AD remain largely unknown and controversial. There is some evidence to suggest that cell death in AD brains may occur by apoptosis, and that Aβ might be involved in this process. Apoptosis, a type of cell death characterised by distinct morphological and biochemical features, is often the result of 'programmed cell death' (PCD). Many gene families have been proposed to be involved in the PCD pathway, including the caspase family, inducible transcription factor (ITF) family (including Jun, Fos and Krox genes), and members of the Bcl-2 gene family (including the death promoting gene Bax). It is possible, therefore, that some of these genes may play a role in cell death in AD. The hippocampus is one of the first regions of the brain to be affected in AD, showing cell loss mainly in the CA1-2 pyramidal cell layer. In this thesis, the hippocampus from AD and Control cases has been examined for markers of apoptosis and genes thought to be involved in PCD. In addition, the actions of Aβ, human amylin (a structurally similar protein to Aβ) and the Aβ precursor protein (APP) have been examined in cell culture in an attempt to elucidate their mechanisms of action and relate this to the pathogenesis of AD. AD hippocampi showed increased DNA fragmentation as assessed by TdT-mediated dUTP-biotin nick end labelling (TUNEL), but TUNEL-positive cells in AD generally did not exhibit 'typical' apoptotic morphology, and there was no evidence of the oligonucleosomal DNA fragmentation characteristic of apoptosis. This indicates that 'typical' apoptosis may not be the predominant cell death mechanism in AD. However, there was some evidence of atypical 'broken' nuclei, which may represent a form of apoptosis that presents with a different morphology in aging tissue. This study found no conclusive evidence of increased expression of Fos or Jun family members in the CA1 region of AD hippocampi, however there were increased levels of the putative 'apoptosis-specific protein' and krox24 mRNA in this area which could be related to the cell death. There was no change in Bax expression in the CA1 region of AD brains (although increased Bax expression was observed in this region in a rat hypoxic-ischemia model where the CA1 neurons die by apoptosis). However, there was a decrease in Bax expression in the granule cells of AD hippocampi which could be related to the relative preservation of these cells in AD. Bax and ITF expression was observed in tangles, senile plaques and Hirano bodies in AD hippocampi, which may be related to the formation of these features and/or the pathogenesis of AD. There appeared to be changes in the cellular location of proteins in post-mortem tissue that made determination of ITF levels extremely difficult. In addition, patterns of ITF expression differed when different antisera directed at the same protein were used. These observations indicate that caution must be exercised when studying protein changes in post-mortem tissue. Application of insoluble Aβ to cultured cells, and overexpression of APP or familial AD-linked APP mutants in cultured cells, did not cause toxicity or alter c-Jun gene expression. However, human amylin was toxic to cultured cells, and had different effects on c-Jun gene expression depending on the cell type. This shows that structurally similar proteins do not always act by a similar mechanism, and that care must be taken when choosing a cell culture system to study disease-related events. The finding that neither insoluble Aβ nor APP/AD-linked APP mutants caused acute toxicity to cultured cells, coupled with the lack of relationship between TUNEL staining and Aβ deposits in post-mortem AD tissue, indicates that deposited insoluble Aβ and/or increased amounts of Aβ may not represent the toxic event in AD. This thesis provides a detailed investigation of several factors that could be involved in the cell death process in the hippocampus in AD. The results presented find no conclusive evidence for ‘classical’ apoptosis and/or increased ITF expression in the hippocampus in AD, but the changes in expression of krox24 mRNA, ‘apoptosis-specific protein’ and Bax suggest that programmed cell death may well be a mechanism which is involved in the pathogenesis of AD. / Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Related published articles. MacGibbon GA, Cooper GJS, Dragunow M. Acute application of human amylin, unlike β-amyloid peptides, kills undifferentiated PC12 cells by apoptosis. NeuroReport 1997; 8:3945-3950. MacGibbon GA, Lawlor PA, Walton M, et al. Expression of Fos, Jun and Krox family proteins in Alzheimer's disease. Exp Neurol 1997; 147:316-332. MacGibbon GA, Lawlor PA, Sirimanne E et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res 1997; 750:223-234

<div><b>Background:</b> Bupropion, an atypical antidepressant and smoking cessation aid, is associated with wide inter-subject variability in its efficacy and safety. Variability in response to bupropion therapy is thought to be driven by variability in metabolism. Bupropion undergoes complex phase 1 and 2 stereoselective metabolism. Though bupropion`s pharmacology is not fully understood, much of it is thought to be due to its metabolites, specially, S, S-hydroxybupropion. In vitro studies (functional assays measuring IC50 at dopamine transporter-DAT, norepinephrine transporter-NET, various subtypes of nicotinic receptors-nAChR) and mouse models (forced swim test to assess antidepressant effect, antinociceptive models to assess antagonism of nicotine effects) indicate S, S-hydroxybupropion to contribute more towards efficacy as an antidepressant and smoking cessation aid than racemic bupropion and R, R-hydroxybupropion, respectively. Both pharmacokinetics (PK) and pharmacodynamics (PD) of bupropion and its metabolites are complex and reported to be stereoselective. As bupropion is known to act on multiple central nervous system (CNS) targets (DAT, NET nAChR), understanding CNS disposition (target site) is critical to explain variability in bupropion`s therapeutic and toxic effects. </div><div><b>Objective: </b>The objective of our study was to characterize the exposure of bupropion enantiomers and corresponding phase 1 metabolite diastereomers in plasma and brain in a surrogate non-clinical species, and to subsequently develop animal-to-human-translational population-PK and Physiologically Based PK (PBPK) models to predict human brain concentrations of bupropion and its active metabolite S, S-hydroxybupropion. Application of these PK modeling approaches to map the time course of unbound brain concentration can then be compared to in vitro potency measures at DAT, NET and nAChRs to predict target engagement over time (PD). Establishing relationships between plasma PK, target site PK along with PD would elucidate possible cause(s) of inter-patient variability to bupropion therapy. </div><div><b>Methods: </b>The first step towards development of a CNS model was to identify a nonclinical species with phase 1 metabolism closest to humans. To accomplish this, hepatic microsomal incubations of four species-rat, mouse, non-human primates (NHPs) and humans were conducted separately for the R- and S-bupropion enantiomers, and the formation of enantiomer-specific metabolites was determined using LC-MS/MS. Intrinsic formation clearance (CLint) of metabolites across the four species (rats, mice, NHPs, humans) was determined from the formation rate versus substrate concentration relationship. </div><div>Racemic bupropion (10 mg/kg) and preformed S, S-hydroxybupropion (2 mg/kg) were administered subcutaneously to adult male Sprague Dawley rats (n = 24/compound). Brain and plasma were collected from rats (n = 3) at eight time points for 6 hours and analyzed using a chiral LC-MS/MS method. Rat plasma protein and brain homogenate binding studies were conducted for all analytes to correct for unbound fraction using equilibrium dialysis method.</div><div>A plasma-brain compartmental pharmacokinetic approach was used to describe the blood–brain-barrier transport of both bupropion and S, S-hydroxybupropion. Also, a 2-compartment permeability-limited brain model consisting of brain blood, brain mass compartments was developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) parent-metabolite model for bupropion and S, S-hydroxybupropion. Both population PK and PBPK modeling approaches were subsequently translated to humans to predict human plasma and brain site exposure and its relationship to DAT and NET IC50 potencies.</div><div><b>Results: </b>The total clearance of S-bupropion was higher than that of R-bupropion in monkey and human liver microsomes. The contribution of hydroxybupropion to the total racemic bupropion clearance was 38%, 62%, 17%, and 96% in human, monkey, rat, and mouse, respectively. In the same species order, threohydrobupropion contributed 53%, 23%, 17%, and 3%, and erythrohydrobupropion contributed 9%, 14%, 66%, and 1.3%, respectively, to racemic bupropion clearance. Hepatic microsomal incubation studies indicated non-human primates to be the appropriate species to model CNS disposition. However, the cost and limited pharmacokinetic and pharmacodynamic data in NHPs were insurmountable barriers to conducting in vivo studies in NHPs. After considering multiple factors, such as the formation of reductive metabolites (higher in rats than mice), which are also thought to contribute to bupropion`s therapeutic efficacy, availability of microdialysis data measuring bupropion and dopamine, norepinephrine levels in brain extracellular fluid (ECF) and other in vitro potency evaluations in rats, rat was chosen as the surrogate species to model bupropion`s disposition.</div><div>In rats, unbound plasma and brain exposures and plasma clearances of both R and S-bupropion were similar. The exposure to parent was higher (50 to 100-fold) than to metabolites. The exposure of oxidative metabolites (R, R- and S, S-hydroxybupropion) was 2 to 3-fold higher in brain and plasma than reductive metabolites (R, R- and S, S-threohydrobupropion, S, R- and R, S-erythrohydrobupropion). Hepatic clearances of R- and S-bupropion scaled from in vitro rat hepatic microsomal incubation studies were 3-fold and 25-fold lower than their respective in vivo unbound apparent clearances. This could possibly be due to substantial contribution of metabolic pathways not characterized in this in vivo study and/or possible extrahepatic disposition in the rat. The unbound brain to unbound plasma AUC0-6h ratio (Kp,uu) of R- and S-bupropion were 0.43 and 0.38 respectively. Kp,uu of oxidative metabolites (R, R- and S, S-hydroxybupropion) and reductive metabolites (R, R- and S, S-threohydrobupropion) were close to 1. Kp,uu of S, R-erythrohydrobupropion was 0.43 and that of pre-formed S, S-hydroxybupropion was 5.</div><div>With respect to population PK modeling of both bupropion and S, S-hydroxybupropion, a plasma-brain compartmental model structure with time dependent change in brain influx clearance was required to adequately characterize the BBB transport of parent and this active metabolite. Using a physiologically-based pharmacokinetic model (PBPK) approach too, incorporation of active efflux and carrier mediated uptake terms in addition to passive permeability was necessary to adequately characterize brain disposition of bupropion and S, S-hydroxybupropion. Both modeling approaches (population-PK and PBPK) when translated to humans indicated that the predicted human brain exposures fall below the reported DAT and NET IC50 measures of bupropion and S, S-hydroxybupropion. </div><div><b>Conclusion: </b>Specific to our work in the rat, the discrepancy between in vitro scaled hepatic clearance and in vivo plasma clearance of R and S-bupropion suggests alternative non-CYP mediated clearance pathways and/or extra hepatic disposition of bupropion. Both translational PK models indicate active process such as efflux transporter or carrier mediated uptake could be involved in bupropion`s disposition in the brain. Variability in expression of these speculated active/carrier mediated transporters could possibly cause variability in response. Also, other CNS targets could contribute to bupropion`s therapeutic efficacy, elucidation of which would require further investigation.</div><div><br></div>

<p>Prostate cancer is the most frequently diagnosed cancer and the second leading causes of cancer-related death in men in the United States. Despite high overall incidence, the disease is relatively well controlled due to slow progression and early detection. However, surgical resection and external beam radiation therapy, first lines of defense, are the only potentially curative options in the clinic. Radiation resistant and metastatic prostate cancer are treated with androgen signaling inhibition (ASI) therapy to target the major growth/proliferation signaling axis that drives prostate cancer cells, but resistance invariably develops. Further, as ASI therapeutic compounds become more potent and are approved for use as neoadjuvant therapeutic options, up to 25% of prostate cancer patients on ASI therapy develop neuroendocrine prostate cancer (NEPC) that is actually induced by the ASI therapy itself. NEPC is resistant to taxane and platinum-based therapies, has no curative or specific targeting options clinically, results in mean overall survival under 9 months in some patient cohorts, and represents a significant unmet clinical need.</p> <p>Protein arginine methyltransferase 5 (PRMT5) is a methyltransferase with histone (epigenetic) and non-histone (non-epigenetic) substrates. PRMT5 is a critical mediator of stemness-associated genes as well as epigenetic regulation of cell fate determination. Further, PRMT5 is a validated therapeutic target in multiple hematological and solid tumor malignancies with multiple clinical trials ongoing. The Hu lab has recently demonstrated that 1) PRMT5 drives androgen receptor (AR) expression in hormone naïve prostate cancer (HNPC) cells, 2) PRMT5 positively regulates DNA damage response gene expression to confer radiation resistance in prostate cancer cells, 3) PRMT5 cooperates with cofactor pICln to drive AR expression in  castration resistant prostate cancer (CRPC) cells, and 4) targeting PRMT5 inhibits development of radiation-induced NEPC development, and that PRMT5 is a valid therapeutic target for prevention of radiation-induced neuroendocrine differentiation (NED). </p> <p>The research presented in this thesis demonstrates that PRMT5 and MEP50 are required for ASI-induced NED in prostate cancer cells, that the PRMT5:MEP50 protein:protein interaction can be pharmacologically targeted, and that ASI-induced NED occurs in an AR-dependent manner. Further, this work contributes a novel class of PRMT5:MEP50 PPI inhibitors in addition to a single-cell, time-resolved model system for interrogating pharmacological targeting of ASI-induced NED <em>in vitro</em>.</p>

<p dir="ltr">Torsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia associated with QT interval prolongation. Female sex and age > 65 years are risk factors for QT prolongation and TdP, possibly due to the effect of sex hormones. Progesterone shortens QT interval, while estrogen lengthens QT interval in females. Preclinical and clinical evidence indicates that progesterone has protective effects against drug-induced QT interval prolongation. J-Tpeak (JTp) and Tpeak-Tend (Tpe) intervals are biomarkers of early and late repolarization. Population pharmacokinetic/pharmacodynamic (PK/PD) models can be used to describe exposure-response relationships and identify sources of variability. In this study, data were pooled from four clinical trials with similar study design investigating the effect of progesterone on ibutilide-induced ventricular repolarization lengthening in healthy premenopausal women during menses or ovulation phase and healthy postmenopausal women. A nonlinear mixed effect model of ibutilide - QTc interval was first developed with preliminary data from 33 subjects. The model was then updated with new data from a total of 52 subjects, assessing the effect of progesterone on drug-induced QTc interval lengthening and identifying sources of variability through covariate analysis. Finally, two PK/PD models of ibutilide - baseline corrected JTpc (ΔJTpc) interval and Tpe (ΔTpe) interval were developed to assess the effect of progestogen on ibutilide-induced early and late repolarization lengthening. Progesterone showed protective effect against ibutilide-induced QTc interval lengthening, mainly through the shortening of pre-ibutilide baseline QTc interval. Body weight, age, race, hypertension, electrocardiogram (ECG) type and estradiol concentration were not significant covariates. Progesterone attenuates ibutilide-induced lengthening of late ventricular repolarization but did not show significant effect on ibutilide-induced early repolarization lengthening. Higher estradiol concentration was related to higher ibutilide-induced early repolarization lengthening. Black race was related to lower ibutilide-induced late repolarization lengthening.</p>

Emergency Departments (EDs) deliver urgent treatment at the ‘front-door' of acute hospitals. In Scotland, occupational therapists have had an increasing presence in EDs, an emerging role with limited evidence to guide its development. There are no predetermined philosophies or existing theories of ED occupational therapy. Therefore, this exploratory study examined the lived experience of ED occupational therapists in order to make an original contribution to knowledge, and to inform practice. Ethical approval was granted from Glasgow Caledonian University. Research methods were framed by Interpretative Phenomenological Analysis (IPA), and purposive sampling was used to recruit nine ED occupational therapists from across Scotland. Individual, semi-structured interviews were audio-recorded and transcribed verbatim. Interview transcripts were analysed line-by-line and interpreted using IPA methods. Two over-arching themes emerged from the data. Theme 1: 'On the Factory Floor' captured the experience of working in an ED. EDs are highly organised, likened to factory production-lines, but also unpredictable, even chaotic. The participants contributed their professional skills to make sense of both the order and the chaos. Theme 2: 'A Stranger in a Strange Land' encapsulated what it was like to enter the ED environment, and the participants were still discovering how they might acculturate. They experienced EDs as challenging environments, which potentially threatened the delivery of occupational therapy in terms of its core-constructs. However, they were able to maintain the values of occupational therapy, though they applied them with constraints. In addition, challenges placed clinicians at high risk of burn-out. Despite this, there were personal and professional rewards, especially enjoyment, being valued and being recognised. Occupational therapy is still emerging in the ED context, professional identity is forming and models of practice are not fully developed. Implications arising from the study are discussed in relation to health policy, future research, occupational therapy practice and occupational therapy education.

Intervertebral discs (IVD) degenerate earlier than many other musculoskeletal tissues and will continue to degenerate with aging. IVD degeneration affects up to 80 percent of the adult population and is a major contributing factor to low back pain. Anti-sclerostin antibody is an FDA-approved treatment for osteoporosis in postmenopausal women at high-risk for fracture and, as a systemic stimulant of the Wnt/LRP5/b-Catenin signaling pathway, may impact the IVD. Stabilization of b-Catenin in the IVD increases Wnt signaling and is anabolic to the extracellular matrix (ECM), while deletion of b-catenin or LRP5 decreases Wnt signaling and is catabolic to the ECM. Here, we hypothesized that a reduction of Sost would stimulate ECM anabolism. Lumbar and caudal (tail) IVD and vertebrae of Sost KO and WT (wildtype) mice (n=8 each) were harvested at 16 weeks of age and tested by MRI, histology, immunohistochemistry, Western Blot, qPCR, and microCT. Compared to WT, Sost KO reduced sclerostin protein and Sost gene expression. Next, Sost KO increased the hydration of the IVD and the proteoglycan stain in the nucleus pulposus and decreased the expression of genes associated with IVD degeneration, e.g., heat shock proteins. However, deletion of Sost was compensated by less unphosphorylated (active) b-Catenin protein in the cell nucleus, upregulation of Wnt signaling inhibitors Dkk1 and sFRP4, and catabolic ECM gene expression. Consequently, notochordal and early chondrocyte-like cells (CLCs) were replaced by mature CLCs. Overall, Sost deletion increased hydration and proteoglycan protein content, but activated a compensatory suppression of Wnt signaling that may trigger chondrogenesis and may potentially be iatrogenic to the IVD in the long-term.

<p dir="ltr">Previous research shows that the prevalence rates for alcohol use disorder, opioid use disorder, and chronic pain are high worldwide. Additional work has demonstrated that the most used pain medications are potentially addictive and not suitable for chronic use. Recent research suggests that inhibiting adenylyl cyclase type 1 (AC1) may be an alternative, non-addictive, method for reducing pain. The purpose of this study was to explore the effects of a novel AC1 inhibitor (CMPD84) on pain threshold and alcohol reward-related behavior in high-alcohol preferring male and female mice (HAP). No research to date has investigated the effects of AC1 inhibition on pain threshold and alcohol-induced conditioned place preference (CPP) in HAP mice, making this the first study to do so. Two manual von Frey experiments were run to explore the effects of CMPD84 (compared to alcohol and morphine) on pain threshold. Three CPP experiments were run to assess the effects of CMPD84 on the expression and acquisition of alcohol-induced CPP. Brain samples were taken from the NAc shell and vlPAG to assess levels of PKCε after the pain threshold experiments and the acquisition CPP experiment. PKCε has previously been shown to be linked to alcohol reward-behavior and pain relief. Results show that CMPD84 was more efficacious in increasing pain threshold in HAP mice compared to morphine and alcohol. CMPD84 also reduced the acquisition and expression of alcohol-induced CPP. AC1 inhibition reduced levels of PKCε in the brain, which matched behavioral results that reduced the expression and acquisition of alcohol-induced CPP, as well as increased pain threshold. These results suggest that PKCε may be linked to AC1 inhibition, pain threshold, and alcohol reward-related behaviors. </p>

This thesis is a user study within library and information science on participatory practices of a professional group in work activity. This has been investigated only to a minor extent in previous library and information science research. The qualitative empirical focus alternates between physicians‟ engagements in work practice and workplace learning within patient care. The overall research problem was to learn how people in workplaces interacted with information that was embedded, intricately intertwined, and tightly bound to the ongoing routines of their everyday work. This thesis aims at understanding information practices of professionals in occupational settings as exemplified by a team of physicians in a Nigerian teaching hospital. In this thesis, the focus was on the collective work activity, and the specific goals identified include how physicians interact and make meaning in the context of the social activities in the workplace, how professionals individually or collectively gather, understand, produce, share and use information, and how workplace learning influences information practices. Information practices are viewed as sociocultural practices that occur inside other practices. The thesis focuses on a nuanced, contextualized understanding of the interplay between the participating actors in activity, the activity per se, and the intermediary role of tools and artefacts. The epistemological point of departure is the sociocultural perspective that emphasizes the dynamic interdependence of the individual with the social and collective development focusing on mediation through tools and artefacts in cultural, institutional, and historical situations. I have chosen cultural-historical activity theory and the practice theories to analyse the dynamic processes in the context of patient care. Their underlying principles guided the empirical study, facilitating extrapolations and illustrations in the analysis. The cultural-historical activity theory was used to understand contextual issues that influence information practices in work activity: the object and subject of activity, division of labour, rules and norms, community, tools and artefacts, as well as the activity system itself and the hierarchical structure of the activity. Theories and concepts employed from a practice perspective on learning were considered useful for understanding the participatory modes in workplace and the influence of social learning communities on diverse information processes. In so doing, the study strives to provide a holistic understanding of information practices, workplace learning, and the relationships between them.The empirical data was gathered through a qualitative case study that lasted over a period of two years. Direct observation was the dominant data collection technique 5 used throughout the preliminary and main empirical studies to capture physicians‟ information practices and experiences. The observation focused on the Clinical Pharmacology and Therapeutics (CPT) team‟s encounters with patients; the interactions they had amongst themselves, and events and situations surrounding patient care. During the main study, other data collection techniques were employed alongside the observation method. In-depth open-ended interviews were conducted with 17 physicians and 9 non-physicians who were selected to provide rich and varied descriptions of the phenomena under study. The interview time totalled at 1,535 minutes. Physical artefacts were another data collection technique employed: 30 patients‟ medical records were assessed during the empirical study. Finally, informal interactions in the research setting were an additional data collection technique used continuously throughout the two empirical periods. The results were analyzed through a combination of inductive and deductive methods of analysis. There are four parts to the empirical results in this thesis. In the first, contextual elements that showed how work environment can be an influencing factor in the information practices of a professional group are described from the perspective of cultural historical activity theory. In the second part, the nature of information access in the real-world information environment was portrayed. It was found that information sources and strategies contributed to the overarching goal of restoring patient health to normalcy. The information sources and strategies were also found useful for mediating the information environment both subjectively and intersubjectively. An equally important result concerns the authority issues related to information sources and strategies. In the third part, available tools and artefacts were presented as useful information aids that also played a mediating role. Tools were categorised into physical tools and language. Language was categorized according to the social situations or classes of speakers. The case notes were seen as useful artefact and occupied a central niche in the studied work activity. These tools and artefacts enabled affordances around which social practices were built on in the work activities. In the last part of the results, various information practices that mirror the participatory practices rather than those of isolated individuals are highlighted. Six dimensions made up and covered the most vital spectrum of the information processing: information gathering, meaning making, information sharing, information use, reading, and documentation. Furthermore, the study revealed that learning took place simultaneously with the work activity and that it influenced information practices at the same time. / <p>Academic dissertation for the Degree of Doctor of Philosophy in Library and Information Science at the University of Borås to be publicly defended on Friday 19 October 2012 at 13.00 in lecture room D 211, University of Borås, Allégatan 1, Borås.</p>