Rationalising the management of individuals : theory, power and subjects in the thought of Michel Foucault.

Thesis (Ph.D.)-University of Natal, 1997.This thesis explores the implications of the work of Michel Foucault for the Enlightenment project. Specifically, it asks whether and how the modern drive to explain the world so as to guide political action and promote progressive change, can be defended in the light of Foucault's critique of Western philosophy, his reconceptualisation of power relations and his account of the subject. Firstly, it is shown how Foucault's genealogy, a hybrid and polemical approach, aims to call into question the theories and practices which underpin the present. Genealogy problematizes what we have come to take for granted, and in so doing it requires that we rethink not only the nature and history of Western philosophical thought but also the role of intellectuals. To attempt to write a history of truth is to ask what one can know of a concept which structures the very limits of our knowledge. It is to become aware of the forces and constraints involved in our production of truth, and thus to bring to light the complex relationship between knowledge and power. Secondly, Foucault argued that, since ancient times, forms of knowledge and relations of power, characterised by individualising and totalising tendencies, have steadily but discontinuously integrated into disciplinary technologies which have been instrumental in constituting the sovereign human individuals which philosophy assumes as given. Following Foucault's lead in focusing not on what power is, but on how it operates historically and in concrete ways, it is shown how Foucault reconceptualised relations of power as strategies of governance which depend on the existence of free subjects capable of resistance. Thirdly, the spotlight falls on the role of relations of power and knowledge, especially the human sciences, in manufacturing subjectivity (from souls and bodies to individual actors), which is in turn related to Foucault's call to irreverently question the limits of philosophy and to engage in aesthetic stylistic experimentation upon ourselves within and against the bounds imposed on us by our present. The thesis concludes by arguing that Foucault's iconoclastic genealogy of our limits and our possibilities leaves us with a rich set of analyses and strategies with which we might render modernity unfamiliar and available for refabrication

PINX1 and TERT are required for TNF-α-induced airway smooth muscle chemokine gene expression

Airway smooth muscle (ASM) cells contribute to asthmatic lung pathology with chemokine hypersecretion and increased ASM cell mass. With little recent progress in the development of asthma therapies, a greater understanding of lung inflammation mechanisms has become a priority. Chemokine gene expression in ASM cells is dependent upon NF-κB transcription factor activity. The telomerase/shelterin complex maintains chromosomal telomere ends during cell division. Telomerase is a possible cofactor for NF-κB activity, but its role in NF-κB activity in airway tissue inflammation is not known. In this study, we sought to address two key questions: whether telomerase is involved in inflammation in ASM cells, and whether components of the shelterin complex are also required for an inflammatory response in ASM cells. Telomerase inhibitors and telomerase small interfering RNA (siRNA) reduced TNF-α-induced chemokine expression in ASM cells. Telomerase siRNA and inhibitors reduced NF-κB activity. An siRNA screen of shelterin components identified a requirement for PIN2/TERF1 interacting-telomerase inhibitor 1 (PINX1) in chemokine gene expression. High-level PINX1 overexpression reduced NF-κB reporter activity, but low-level expression amplified NF-κB activity. Coimmunoprecipitation studies showed association of PINX1 and p65. Overexpression of the N terminus (2-252 aa) of PINX1, but not the C-terminal telomerase-inhibitor domain (253-328 aa), amplified TNF-α-induced NF-κB activity. GST pull-downs demonstrated that the N terminus of PINX1 bound more p65 than the C-terminal telomerase-inhibitor domain; these observations were confirmed in whole cells with N-terminal and C-terminal PINX1 immunoprecipitation. We conclude that telomerase and PINX1 are required for chemokine expression in ASM cells and represent significant new targets for future anti-inflammatory therapies for lung diseases, such as asthma

Oxidation of the Platinum (II) Anticancer Agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] to Platinum (IV) Complexes by Hydrogen Peroxide

PtIV coordination complexes are of interest as prodrugs of PtII anticancer agents, as they can avoid deactivation pathways owing to their inert nature. Here, we report the oxidation of the antitumor agent [PtII(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 (py = pyridine) to dihydroxidoplatinum(IV) solvate complexes [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].H2O, 2·H2O with hydrogen peroxide (H2O2) at room temperature. To optimize the yield, 1 was oxidized in the presence of added lithium chloride with H2O2 in a 1:2 ratio of Pt: H2O2, in CH2Cl2 producing complex 2·H2O in higher yields in both gold and red forms. Despite the color difference, red and yellow 2·H2O have the same structure as determined by single-crystal and X-ray powder diffraction, namely, an octahedral ligand array with a chelating organoamide, pyridine and chloride ligands in the equatorial plane, and axial hydroxido ligands. When tetrabutylammonium chloride was used as a chloride source, in CH2Cl2, another solvate, [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].0.5CH2Cl2, 3·0.5CH2Cl2, was obtained. These PtIV compounds show reductive dehydration into PtII [Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H over time in the solid state, as determined by X-ray powder diffraction, and in solution, as determined by 1H and 19F NMR spectroscopy and mass spectrometry. 1H contains an oxidized coordinating ligand and was previously obtained by oxidation of 1 under more vigorous conditions. Experimental data suggest that oxidation of the ligand is favored in the presence of excess H2O2 and elevated temperatures. In contrast, a smaller amount (1Pt:2H2O2) of H2O2 at room temperature favors the oxidation of the metal and yields platinum(IV) complexes

Successful use of axonal transport for drug delivery by synthetic molecular vehicles

We report the use of axonal transport to achieve intraneural drug delivery. We constructed a novel tripartite complex of an axonal transport facilitator conjugated to a linker molecule bearing up to a hundred reversibly attached drug molecules. The complex efficiently enters nerve terminals after intramuscular or intradermal administration and travels within axonal processes to neuron cell bodies. The tripartite agent provided 100-fold amplification of saturable neural uptake events, delivering multiple drug molecules per complex. _In vivo_, analgesic drug delivery to systemic and to non-targeted neural tissues was greatly reduced compared to existing routes of administration, thus exemplifying the possibility of specific nerve root targeting and effectively increasing the potency of the candidate drug gabapentin 300-fold relative to oral administration

Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Kirsch and colleagues show that, in antidepressant trials, there is a greater difference in efficacy between drug and placebo amongst more severely depressed patients. However, this difference seems to result from a poorer response to placebo amongst more depressed patients

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Risk perception influences athletic pacing strategy.

PURPOSE: The objective of this study is to examine risk taking and risk perception associations with perceived exertion, pacing, and performance in athletes. METHODS: Two experiments were conducted in which risk perception was assessed using the domain-specific risk taking (DOSPERT) scale in 20 novice cyclists (experiment 1) and 32 experienced ultramarathon runners (experiment 2). In experiment 1, participants predicted their pace and then performed a 5-km maximum effort cycling time trial on a calibrated Kingcycle mounted bicycle. Split times and perceived exertion were recorded every kilometer. In experiment 2, each participant predicted their split times before running a 100-km ultramarathon. Split times and perceived exertion were recorded at seven checkpoints. In both experiments, higher and lower risk perception groups were created using median split of DOSPERT scores. RESULTS: In experiment 1, pace during the first kilometer was faster among lower risk perceivers compared with higher risk perceivers (t(18) = 2.0, P = 0.03) and faster among higher risk takers compared with lower risk takers (t(18) = 2.2, P = 0.02). Actual pace was slower than predicted pace during the first kilometer in both the higher risk perceivers (t(9) = -4.2, P = 0.001) and lower risk perceivers (t(9) = -1.8, P = 0.049). In experiment 2, pace during the first 36 km was faster among lower risk perceivers compared with higher risk perceivers (t(16) = 2.0, P = 0.03). Irrespective of risk perception group, actual pace was slower than predicted pace during the first 18 km (t(16) = 8.9, P < 0.001) and from 18 to 36 km (t(16) = 4.0, P < 0.001). In both experiments, there was no difference in performance between higher and lower risk perception groups. CONCLUSIONS: Initial pace is associated with an individual's perception of risk, with low perceptions of risk being associated with a faster starting pace. Large differences between predicted and actual pace suggest that the performance template lacks accuracy, perhaps indicating greater reliance on momentary pacing decisions rather than preplanned strategy.This is the author accepted manuscript. The final version is available from Wolters Kluwer via http://dx.doi.org/10.1249/MSS.000000000000050

Effects of helicobacter pylori infection on iron metabolism genes in patients with iron deficiency anaemia

This is an accepted manuscript of an article published by BMJ in Gut on 08/06/2018, available online: http://dx.doi.org/10.1136/gutjnl-2018-BSGAbstracts.282 The accepted version of the publication may differ from the final published version.Published versio

Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: The role of p38 MAPK and ROS

Due to narrow therapeutic window of cancer therapeutic agents and the development of resistance against these agents, there is a need to discover novel agents to treat breast cancer. The antitumor activities of thymoquinone (TQ), a compound isolated from Nigella sativa oil, were investigated in breast carcinoma in vitro and in vivo. Cell responses after TQ treatment were assessed by using different assays including MTT assay, annexin V-propidium iodide staining, Mitosox staining and Western blot. The antitumor effect was studied by breast tumor xenograft mouse model, and the tumor tissues were examined by histology and immunohistochemistry. The level of antioxidant enzymes/molecules in mouse liver tissues was measured by commercial kits. Here, we show that TQ induced p38 phosphorylation and ROS production in breast cancer cells. These inductions were found to be responsible for TQ’s anti-proliferative and pro-apoptotic effects. Moreover, TQ-induced ROS production regulated p38 phosphorylation but not vice versa. TQ treatment was found to suppress the tumor growth and this effect was further enhanced by combination with doxorubicin. TQ also inhibited the protein expression of anti-apoptotic genes, such as XIAP, survivin, Bcl-xL and Bcl-2, in breast cancer cells and breast tumor xenograft. Reduced Ki67 and increased TUNEL staining were observed in TQ-treated tumors. TQ was also found to increase the level of catalase, superoxide dismutase and glutathione in mouse liver tissues. Overall, our results demonstrated that the antiproliferative and pro-apoptotic effects of TQ in breast cancer are mediated through p38 phosphorylation via ROS generation

Roundtable Event : The Potential Value of CCUS to the Political Economy, Edinburgh 28 November 2018

The Centre for Energy Policy held a Roundtable on the potential value to the political economy of carbon capture, utilisation and storage (CCUS), in the margins of the Global CCUS Summit held in Edinburgh. This note summarises discussions and reflects on next steps. Participants are listed in the appendix. This note does not attribute comments or views to particular participants. Professor Graeme Sweeney chaired the Roundtable, with Professor Karen Turner, Director of the Centre for Energy Policy, kick-starting the discussion with a presentation on recent research on the potential value of CCUS to the political economy