Tesis: "Non-clinical studies"

1

Peterson, Colleen Margaret. "Couple Cohesion: Differences Between Clinical and Non-Clinical Mormon Couples". Diss., CLICK HERE for online access, 1988. http://patriot.lib.byu.edu/u?/MTNZ,10566.

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2

Reid, Tracey J. S. "Obsessions and compulsions : electrophysiological studies in a non-clinical population". Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282300.

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3

Axelsson, Birger. "Cardiac effects of non-adrenergic inotropic drugs : clinical and experimental studies". Doctoral thesis, Umeå universitet, Anestesiologi och intensivvård, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-68967.

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Background: Myocardial failure and dysfunction is not uncommon during critical illness and following cardiac surgery. For optimal treatment, a better understanding of the effects of inotropic drugs is needed. In this thesis, two non-adrenergic mediated inotropes, milrinone and levosimendan were studied in different models of myocardial dysfunction. The study aims were to assess the following: the effects of milrinone on blood flow in coronary artery bypass grafts during CABG surgery; the effects of milrinone on left ventricular diastolic function during post-ischaemic myocardial dysfunction; whether milrinone or levosimendan are protective or injurious during acute myocardial ischaemia, and if levosimendan potentiates myocardial function when added to milrinone in an experimental model of post-ischaemic (stunned) myocardium. Material and Methods: In Study I, 44 patients undergoing coronary artery bypass surgery(CABG) were included as subjects. Milrinone or saline was administrated in a single dose during cardio-pulmonary bypass (CPB) and coronary graft flow measurements were recorded after 10 and 30 min following CPB. In Study II; 24 patients undergoing CABG had estimations of peak ventricular filling rates made before and after CPB with administration of milrinone or saline as a single dose during CPB, performed by assessment of the rate of change in diastolic cross-sectional left ventricular area. In Study III, energy-metabolic effects of milrinone and levosimendan were measured in an anaesthetized porcine model during 45 minutes of regional myocardial ischemia. Microdialysis sampling of metabolites of local ischemic metabolism allowed assessment of glycolytic activity and the degree of myocardial calcium overload. In Study IV, in a porcine model of postischaemic myocardial stunning, ventricular pressure-volume relationships were analyzed when milrinone or a combination of milrinone and levosimendan were given together. Results: In Study I, there was a clear increase in non-sequential saphenous vein graft blood flow with milrinone at 10 minutes (64.5 ± 37.4 compared to placebo 43.6 ± 25.7 ml/min (mean ± SD).). A decreasing but still measureable flow increase was seen for milrinone at 30 minutes. In Study II, an increase in early left ventricular filling rate (ventricular cross-sectional area rate of change,dA/dt) was seen in the milrinone treated group. Pre-bypass milrinone group dA/dt 22.0 ± 9.5 changed to post-bypass values dA/dt 27.8 ± 11.5 cm2/sec). Placebo group pre-bypass dA/dt was 21.0 ± 8.7 and post-bypass 17.1 ± 7.1 cm2/sec. A milrinone effect was demonstrated in an adjusted regression model (p = 0.001). In Study III, neither milrinone nor levosimendan led to a change in energy-metabolic activity during ischemia as reflected by interstitial glucose, pyruvate, lactate orglycerol. Neither drug exacerbated the relative myocardial calcium overload during ischemia. In Study IV, milrinone improved active relaxation (tau) in post-ischemic stunned myocardium, but did not markedly improve systolic function by preload recruitable stroke work. Levosimendan added to milrinone showed minimal effect on active relaxation but a positive effect on systolic function in combination with milrinone. Conclusions: We conclude that milrinone treatment leads to an increase in blood flow in newly implanted coronary saphenous vein grafts, and improves ventricular relaxation post-cardiopulmonary bypass. Neither milrinone nor levosimendan, in this porcine model, negatively influence myocardial energy metabolism or calcium overload during acute ischaemia. Addition of levosimendan to milrinone treatment during post-ischaemic ventricular dysfunction may provide additive inotropic effects on systolic function but probably not for active relaxation.

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4

Pereira, Stephen Paul. "The pathogenesis and non-surgical treatment of gallstones : clinical and laboratory studies". Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271458.

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5

Ösby, Eva. "Clinical studies in aggressive non-Hodgkin's lymphoma with special reference to elderly patients /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-563-8/.

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6

Webb, M’Balu Alena. "Studies into the efficacy of using non-purified islets for clinical islet transplantation". Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/10071.

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Islet purification prior to allo transplantation currently forms the clinical gold standard, despite the fact that purification protocols result in significant islet losses and remove potential islet precursors and tissue that may provide islets with bio-trophic support Conversely, non-purified islet preparations retain endocrine mass and within the sphere of islet auto transplantation have been associated with excellent long-term graft function. This study comprises of an analysis of peri-operative factors and the long-term graft function of patients’ auto transplanted with either purified (n=14) or nonpurified islets (n=23). Complementary in-vitro studies were carried out to assess the effect of non-islet tissue on islet viability, integrity and function (n=8), whilst a histology-based study (n=23) assessed whether transplantation of non-islet cells, particularly islet precursors, had a long-term effect on graft function in the clinical setting. Clinically, non-purified islets did not significantly increase peri-transplant venous pressures and perioperative factors including ITU stay, blood loss and liver function were comparable in both groups. Analysis of the 5 year post-transplant period demonstrated that although insulin release in response to glucose was initially superior following transplant of purified islets, non-purified islets were associated with stable long-term function. In-vitro studies reiterated these findings, revealing that islet viability and function were comparable in both groups, however, retention of intracellular insulin was found to be superior within non-purified preparations with some evidence that ductal tissue provided islets with bio-trophic support. Histology-based analysis of patient pancreata suggested a positive role for islet precursors demonstrating significantly superior blood glucose, HbA1c and C-peptide values associated with the transplantation of ductal cells and non-islet PDX-1 and glucagon positive cells. The results of this study indicate that transplantation of non-purified islets can be performed safely and with comparable long-term graft function as purified islets. Additionally, these studies potentially suggest that ductal tissue may help to preserve islet integrity, whilst certain precursors cells found within the acinar parenchyma and ductal epithelium may improve long-term islet graft function.

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7

Moorthy, Ganesh. "Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment". University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033.

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8

Rafi, Imran. "Phase I clinical and pharmacological studies with the non-classical thymidylate synthase inhibitor AG337". Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265431.

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9

Twati, Wageh. "Studies on materials and techniques to enhance clinical outcomes for non-vital immature permanent incisors". Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/5339/.

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In this thesis three studies are presented all aimed at enhancing outcomes for the endodontic management of non-vital immature permanent incisors. Study 1. Aim: To study the effect of non-setting calcium hydroxide (NSCH) and mineral trioxide aggregate (MTA) on mechanical properties of dentine. Methodology: Approval was obtained from the Tissue bank of the Leeds Dental Institute for the use of human teeth for this study. Twenty-seven human premolar teeth were sectioned to give a total of 54 dentine slabs. Nine slabs used in each group for each of the two time periods: 3 months and 8 months. A thin layer of NSCH or MTA was applied to the slabs, whilst the control group had no application of a medicament. The total period of the study was eight months. Dentine fracture resistance was measured using nano-indentation and by impact test, after which the slabs were Map Scanned for softening after 3 months and then at 8 months. Results: Impact test showed a significant reduction in the fracture resistance of dentine (p<0.001) after 3 and 8 months of application of MTA and NSCH compared with the control group. MTA application had the worst effect on dentine followed by NSCH and control. Also the map scan showed softer areas in the MTA group than the other groups. Conclusion: There was a significant time dependant reduction in the hardness of dentine with NSCH and MTA application. Study 2 The aim: This study was undertaken to evaluate the most effective intra canal medicament against five bacteria commonly implicated in causation of endodontic infections. Methodology: Five bacteria, namely, Actinomyces odontolyticus (NCTC 9335) Porphyromonas gingivalis (W50), Fusobacterium nucleatum (ACTC 10953), Escherichia coli (NCTC 11954) and Enterococcus faecalis (NCTC 755) were selected for this study. The test materials used to evaluate their effect against the chosen bacteria were calcium hydroxide (CH), mineral trioxide aggregate (MTA) and the recently advocated antibiotics (Minocycline, Metronidazole and Ciprofloxicillin), individually and as a Triple mixture. E. coli and E. faecalis were grown in Brain Heart Infusion (BHI) broth under an atmosphere of 10% CO2 + air and incubated at 37ºC. P gingivalis, F. nucleatum and A. odontolytics were grown in BHI broth supplementd with haemin and menadione at a final concentration of 5 µg/ml and 1 µg/µl respectively, all three bacteria were incubated at 37ºC under anaerobic conditions (80% N2, 10% H2 and 10% CO2) in a Mark III anaerobic Work station (Don Whitley Scientific, Shipley, UK). The antimicrobial activity of test materials were determined in agar diffusion assays. Broth cultures of all five bacteria were adjusted in sterile BHI or BHI supplemented with haemin and menadione to an optical density at 540 nm corresponding to 1 x 106 colony forming units (CFU) per ml. Aliquots (100 µl) of bacterial suspensions were inoculated onto the surfaces of Columbia blood agar plates (pre-reduced for anaerobic bacteria). Wells of 3 mm diameter were cut in each plate using a sterile cork borer and test materials applied using a syringe. Zones of inhibition of bacterial growth were measured using a caliper gauge and the mean of three measurements of each zone was calculated, each experiment was carried out on three different occasions. Results: CH, MTA and Metronidazole were not effective against E. faecalis; whereas Ciprofloxacin and Minocycline showed large inhibition zones with all five types of bacteria used in the present study. When all three antibiotics were used as a mixture, they were found to be effective against all five types of bacteria. Conclusions: In the present study the application of triple antibiotic (TriBioDent) was effective against the five common types of bacteria that cause endodontic lesions. Study 3 Aim: To evaluate the toxicity of antibiotics used for regenerative antibiotic technique, both individually and in combination on pulp cell survival. Methodology: Human dental pulp cells obtained from three different donors from the tissue bank were grown until sub-confluence. These were then incubated for 24 hours with culture media supplemented with different antibiotics (50 mg/ml each) in five groups including: 1- Metronidazole, 2- Ciprofloxacin and 3- Minocycline, 4- Metronidazole + Ciprofloxacin and 5- Metronidazole + Ciprofloxacin + Minocycline. Cells grown in culture medium without any antibiotics were used as a control. The experiments were repeated three times and the cell viability was measured using three methods: Lactate Dehydrogenase (LDH) assay, Trypan blue cell counting and flow cytometery. Results: The three methods used to measure the effect of individual or mixed antibiotics on cell viability showed consistent results. Ciprofloxicillin showed a high cytotoxic when compared to the control group that was significantly different (p<0.00). However a combination of two antibiotics, i.e, Metronidazole and Ciprofloxicillin showed a slightly higher cell survival as compared with a combination of all three antibiotics as currently used for the regenerative endodontic technique. Conclusion: In the present study the application of antibiotics used in the regenerative endodontic technique (double or triple antibiotics) was considered to have no significant effect on the survival of pulp cells. There was no difference between using two or three antibiotics in combination.

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10

Booster, Maurits Harm. "The Non-Heart Beating donor, a new source of kidneys for transplantation clinical and experimental studies /". Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1995. http://arno.unimaas.nl/show.cgi?fid=6644.

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11

Persson, Per-Erik. "Heterotopic Ossification : Clinical and Experimental Studies on Risk Factors, Etiology and Inhibition by Non-steroidal Anti-inflammatory Drugs". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3908.

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12

Jungner, Måns. "Healing of endosseous implants with different surface characteristics in grafted and non-grafted bone : clinical and experimental studies". Doctoral thesis, Umeå universitet, Institutionen för odontologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-85884.

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Aims: This study uses radiological and clinical evaluations of the healing of endosseous titanium implants presented with different surface characteristics in the clinical situation (paper I-III) and experimentally to describe the early bone healing in maxillary sinus membrane elevation with and without the use of grafting material (paper IV). Material and methods: In paper I, 136 patients were treated with 394 dental implants – 199 were oxidized titanium implants (Nobel Biocare TiUnite) and 195 were turned titanium surface implants (Nobel Biocare Mark III). Implant survival rates were retrospectively investigated after a minimum of five months after functional loading of the implants. At the five-year follow-up (paper II), eight patients were deceased and 128 were invited. Twenty-five patients refrained from participating in the study. The remaining 103 patients (287 implants – 133 with a turned surface and 154 with an oxidized surface) were examined after at least five years of functional loading. Clinical examinations of bleeding on probing (BoP) and pocket depth (PD) were performed. Intraoral radiographs were used to assess marginal bone levels (MBLs). In paper III, 28 patients were subjected to autologous bone graft and delayed implant placement, with a total of 92 dental implants. Thirteen patients received 47 implants with a turned surface and 15 patients received 45 implants with an oxidized surface. After a minimum of five years of functional loading, all patients were clinically examined regarding PD and BoP. The MBL was measured in intraoral radiographs. Cone beam computed tomography (CBCT) was used to evaluate the apical bone level (ABL) of the implants and intra-sinus conditions. The experimental study (paper IV) used nine adult male tufted capuchin primates (Cebus apella). Eight animals were subjected to bilateral maxillary sinus membrane elevation using a lateral replaceable bone window technique. One oxidized dental implant was placed in the residual bone of the sinus floor, protruding into the maxillary sinus cavity on both sides. In four animals, one sinus was left without any additional treatment, while the contralateral sinus was filled with autologous bone grafts from the tibia. In two animals, the implants were inserted under the elevated sinus membrane on both sides. In two animals, the sinus membrane was totally removed bilaterally before placement of implants. The animals were euthanized after 10 (n=4) or 45 (n=4) days. One non-operated animal representing pristine tissue conditions served as the control. The maxillary sinuses with implants were retrieved and further processed to prepare light microscopic ground sections or decalcified sections for immunohistochemical analyses. Results: In paper I seven implants were lost in five patients – six in the maxilla and one in the mandible. All failed implants were Mark III turned implants. The overall implant survival rate was 98.2% with a survival rate of 96.4% for implants with turned surface after a minimum of five months after functional loading. In paper II, one additional oxidized implant failed, giving an overall cumulative survival rate of 94.7 and 99.4%, respectively, after at least five years of functional loading. There was no difference for BoP, PD, or MBL between turned and oxidized implants. A total of two implants, three oxidized and one turned, showed a PD > 3 mm, MBL > 4 mm, and BoP. However, none of these were associated with suppurative infection on examination. In paper III no difference was found between the two implants surfaces used in terms of PD, BoP, MBL, or ABL. Pathological reactions to the sinus membrane were seen in four of the patients (14%). Radiographic signs of sinus pathology were not correlated to either survival rate of the implants or any of the investigated parameters. In the experimental paper IV, bone formation started from the bottom of the sinus floor, sprouting into the granulation tissue along the implant surface under the elevated membrane irrespective of time and surgical technique. Bone formation was not seen in direct conjunction with the sinus membrane. A distinct expression of osteopontin was observed in the serous glands of deeper portion of the lamina propria in direct connection with the elevated sinus membrane and close to the implant within all groups. Conclusion: After more than five years of function in non-grafted patients, oxidized implants had a survival rate higher than turned implants, although this was not statistically significant. No difference was found in MBL, PD, or BoP. Grafting of the maxillary sinus floor with intra- orally harvested bone and delayed placement of either turned or oxidized implants resulted in equally high long-term survival rates, MBL, ABL, and BoP. Pathological findings in the maxillary sinus cavity, in terms of sinus membrane health, are few and not correlated to any of the other investigated parameters. In the experimental study bone formation after sinus membrane elevation with or without additional bone grafts started at the sinus floor and sprouted into the elevated space along the implant surface. Removal of the membrane resulted in less bone formation. The sinus membrane did not seem to present osteoinductive potential in sinus membrane elevation procedures.

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13

Ball, David L. "Clinical studies of the effect of radiotherapy dose and fractionation on survival in patients with limited non-small cell lung cancer /". Title page, table of contents and abstract only, 2001. http://web4.library.adelaide.edu.au/theses/09MD/09MDB187.pdf.

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14

Politis, Marios. "Clinical and PET imaging studies in Parkinson's disease motor and non-motor complications : serotonergic and dopamimergic mechanisms and applications in treatment". Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6137.

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The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies.

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15

Schädlich, Andreas Verfasser], Karsten [Akademischer Betreuer] [Mäder, Achim [Akademischer Betreuer] Göpferich y Jörg [Akademischer Betreuer] Kreßler. "Pre‐clinical in vivo studies of parenteral drug delivery systems using non‐invasive multispectral fluorescence imaging : [kumulative Dissertation] / Andreas Schädlich. Betreuer: Karsten Mäder ; Achim Göpferich ; Jörg Kreßler". Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2013. http://d-nb.info/1045194824/34.

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16

Flenet, Timothé. "Mesure non invasive de suivi des transferts de fluides liés aux activités cardiorespiratoires chez le rat : vers une «bague aortique virtuelle»". Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAS013/document.

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Il est avéré que les signaux de pléthysmographie par inductance comportent des composantes cardiaques et respiratoires pouvant présenter un intérêt pour un suivi physiologique. Cette technique est largement utilisée chez l’homme et chez les mammifères de taille moyenne, mais n’a jamais été mise en œuvre chez les petits rongeurs de laboratoire comme le rat. Cette thèse vise à apporter la preuve analytique et expérimentale (TRL3) d’une application cardiaque de la pléthysmographie cardiorespiratoire par inductance (PCRI) fondée sur le concept amont de « bague aortique virtuelle » (BAOV). La BAOV permet de mettre en œuvre une mesure externe des débits aortiques « instantanés » à l’aide de la PCRI en lieu et place d’un instrument positionné autour du vaisseau lui-même.La thèse a débuté par une phase de spécification et de conception guidée par l’interdépendance entre la physiologie et les contraintes instrumentales. Les performances métrologiques à atteindre sont dictées par un saut d’échelle entre l’homme et le rat. Le développement d’une chaine de mesure optimisée a permis de repousser les limites des systèmes existants en rendant possible la mesure de variations de volumes de quelques microlitres. En parallèle, l’identification de critères de validation, de méthodes de référence et la mise au point de protocoles expérimentaux ont conduit à la définition d’une stratégie de validation de l’instrument de mesure développé et du concept de BAOV.À l’issue de ces trois années, un système de PCRI à ultra-haute résolution a été mis au point. Après calibration, l’exactitude sur les mesures de variations de section est de 5 % sur un banc de test micrométrique. L’interchangeabilité de la mesure des variations de volume du thorax sur la gamme physiologique a été évaluée par rapport à une mesure pneumotachographique sur 9 animaux anesthésiés. Les limites d’agrément obtenues sont inférieures à 20 %. L’induction d’un challenge hémodynamique sur 11 animaux anesthésiés dont le débit aortique est mesuré en parallèle avec la PCRI et une bague de débit ultrasonique placée au niveau sous-diaphragmatique démontre l’équivalence entre les deux systèmes. Par ailleurs, la grande similitude entre les signaux de débits des deux méthodes valide le concept de bague aortique virtuelle proposé
It is recognized that inductive plethysmographic signals contain cardiac and respiratory components, which can be of interest for physiological monitoring. This technology is widely used in humans and medium mammals, but it has never been implemented in small laboratory rodents. This PhD aims to provide the analytic and experimental proof (TRL3) of a cardiac application of the cardio-respiratory inductive plethysmography (CRIP), based on the upstream concept of an “virtual aortic probe” (VAP). The VAP allows to realize an extern measure of “instantaneous” aortic flows thanks to CRIP instead of an instrument located directly around the vessel.The PhD starts with a phase of specification and conception driven by the interdependency between physiology and instrumental constraints. The expected metrological performances are established by a scale jumping between man and rat. The development of an optimized acquisition line has enabled to stretch the limits of existing systems; it allows to measure volume variations of a few microliters. At the same time, validation criteria and reference methods have been identified and experimental protocols have been specified in order to define the validation strategy of the developed instrument and VAP concept.At the end of these 3 years, an ultra-high resolution CRIP system has been developed. After calibration, the accuracy on the section variation measurements is 5% on a micrometric test-bench. The interchangeability of the thorax volume variation measure on a physiological range has been evaluated by comparison with a pneumotachographic measure on 9 anesthetized animals and the limits of agreement are lower than 20%. A hemodynamic challenge has been induced on 11 anesthetized animals, and the aortic flow has been simultaneously measured by CRIP and with an ultrasonic flow probe at under diaphragm level. This demonstrates the equivalence between both systems. And the high similarity between flow signals from both methods validates the proposed concept of virtual aortic probe

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17

Nyström, Josefina. "Multivariate non-invasive measurements of skin disorders". Doctoral thesis, Umeå University, Chemistry, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-865.

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The present thesis proposes new methods for obtaining objective and accurate diagnoses in modern healthcare. Non-invasive techniques have been used to examine or diagnose three different medical conditions, namely neuropathy among diabetics, radiotherapy induced erythema (skin redness) among breast cancer patients and diagnoses of cutaneous malignant melanoma. The techniques used were Near-InfraRed spectroscopy (NIR), Multi Frequency Bio Impedance Analysis of whole body (MFBIA-body), Laser Doppler Imaging (LDI) and Digital Colour Photography (DCP).

The neuropathy for diabetics was studied in papers I and II. The first study was performed on diabetics and control subjects of both genders. A separation was seen between males and females and therefore the data had to be divided in order to obtain good models. NIR spectroscopy was shown to be a viable technique for measuring neuropathy once the division according to gender was made. The second study on diabetics, where MFBIA-body was added to the analysis, was performed on males exclusively. Principal component analysis showed that healthy reference subjects tend to separate from diabetics. Also, diabetics with severe neuropathy separate from persons less affected.

The preliminary study presented in paper III was performed on breast cancer patients in order to investigate if NIR, LDI and DCP were able to detect radiotherapy induced erythema. The promising results in the preliminary study motivated a new and larger study. This study, presented in papers IV and V, intended to investigate the measurement techniques further but also to examine the effect that two different skin lotions, Essex and Aloe vera have on the development of erythema. The Wilcoxon signed rank sum test showed that DCP and NIR could detect erythema, which is developed during one week of radiation treatment. LDI was able to detect erythema developed during two weeks of treatment. None of the techniques could detect any differences between the two lotions regarding the development of erythema.

The use of NIR to diagnose cutaneous malignant melanoma is presented as unpublished results in this thesis. This study gave promising but inconclusive results. NIR could be of interest for future development of instrumentation for diagnosis of skin cancer.

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18

Prudon, Nicolas. "Integrative study, from the cell to the animal model, of the development of a cell therapy for Parkinson's disease". Electronic Thesis or Diss., Bordeaux, 2024. http://www.theses.fr/2024BORD0071.

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Un ensemble d'études précliniques soutient désormais le développement de thérapies de remplacement cellulaire dérivées de cellules souches pluripotentes pour soulager les symptômes moteurs chez les patients parkinsoniens. Le remplacement de la principale population cellulaire dysfonctionnelle au sein de la maladie, les neurones dopaminergiques A9, est l'objectif principal de ces thérapies. Pour y parvenir, la plupart des approches thérapeutiques impliquent la greffe de suspensions cellulaires de progéniteurs dopaminergiques. Cependant, une quantité considérable de cellules meurent pendant le processus de transplantation, les cellules étant confrontées à l'anoïkis. Une potentielle solution consiste à greffer des préparations solides, c'est-à-dire adopter un format cellulaire 3D. La cryopréservation de ce format reste un obstacle majeur et n'est pas exempte de causer des retards dans le délai avant l'apparition des effets, comme observé avec l'utilisation de suspensions unicellulaires de progéniteurs dopaminergiques cryopréservés. Le travail de cette thèse se concentre sur le développement de microtissus neuraux 3D en tant que thérapie cellulaire pour la maladie de Parkinson. L'utilisation d'une technologie d'encapsulation cellulaire à haut débit associée à des bioréacteurs pour fournir un environnement de culture 3D a permis la différenciation dirigée des hiPSC en microtissus neuraux. La différenciation correcte des microtissus neuraux vers une identité mésencéphalique a été confirmée à l'aide de méthodes orthogonales, en utilisant notamment la qRT-PCR, le RNAseq, la cytométrie en flux et la microscopie fluorescente. L'efficacité des microtissus neuraux a été démontrée de manière dose-dépendante dans des études précliniques, en utilisant le modèle de rat hémiparkinsonien lésé par la 6-OHDA. Les greffes ont été caractérisées par une analyse histologique post-mortem, démontrant la présence de neurones dopaminergiques humains projetant dans le striatum hôte. Le travail présenté ici est la première bioproduction d'une thérapie cellulaire pour la maladie de Parkinson dans un bioréacteur mis à échelle, conduisant à une récupération fonctionnelle complète des animaux 16 semaines après la transplantation d’un format cellulaire 3D cryopréservé
A breadth of preclinical studies is now supporting the rationale of pluripotent stem cell-derived cell replacement therapies to alleviate motor symptoms in Parkinsonian patients. Replacement of the primary dysfunctional cell population in the disease, i.e. the A9 dopaminergic neurons, is the major focus of these therapies. To achieve this, most therapeutical approaches involve grafting single-cell suspensions of DA progenitors. However, a considerable number of cells die during the transplantation process, as cells face anoïkis. One potential solution to address this challenge is to graft solid preparations, i.e. adopting a 3D format. Cryopreserving such format remains a major hurdle and is not exempt from causing delays in the time to effect, as observed with the use of cryopreserved single-cell DA progenitors. The work of this thesis focus on the development of 3D neural microtissues as a cell therapy for PD. The use of a high-throughput cell-encapsulation technology coupled with bioreactors to provide a 3D culture environment enabled the directed differentiation of hiPSCs into neural microtissues. The proper patterning of these neural microtissues into a midbrain identity was confirmed using orthogonal methods including qPCR, RNAseq, flow cytometry and immunofluorescent microscopy. The efficacy of the neural microtissues was demonstrated in a dose-dependent manner in non-clinical studies, using the 6-OHDA-lesioned hemiparkinsonian rat model. The grafts were characterized by post-mortem histological analysis, demonstrating the presence of human dopaminergic neurons projecting into the host striatum. The work reported here is the first bioproduction of a cell therapy for Parkinson’s disease in a scalable bioreactor, leading to a full behavioural recovery 16 weeks in the animal model after transplantation using cryopreserved 3D cell format

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19

Hawley, Anna R. "A Longitudinal Analysis of Psychosocial Coping, Religious/Spiritual Appraisals, and Religious/Spiritual Coping in Predicting College Students’ Adjustment to Non-Marital Breakup". Bowling Green State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1431551368.

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20

Merandi, Gabrielle. "Transgender and Gender Diverse Students' Accounts of College Life". Bowling Green State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1470228047.

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21

Robbie, Maxine Ann. "Studies of the mechanisms of resistance of non-cycling cells to amsacrine and related antitumour drugs". Thesis, University of Auckland, 1988. http://hdl.handle.net/2292/3198.

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Several studies have shown that non-cycling cells are resistant to the cytotoxic effects induced by amsacrine (m-AMSA; 4'-(9-acridinylamino)methanesulphon-m-anisidide). This resistance may limit the activity of m-AMSA and related 9-anilinoacridine antitumour agents against solid tumours. The biochemical mechanism(s) for this resistance have been investigated using spontaneously transformed Chinese hamster fibroblast (AA8 cells) in log- and plateau-phase spinner cultures. In early plateau phase most cells entered a growth-arrested state with a G1-G0 DNA content and showed a marked decrease in sensitivity to cytotoxicity after a 1-h exposure to m-AMSA or its solid tumour-active analogue, CI-921. Studies with radiolabelled m-AMSA demonstrated that changes in sensitivity to m-AMSA-induced cell killing were not due to a difference in uptake or retention of drug by log- and plateau-phase cells, and there was no significant metabolism of drug by either log- or plateau-phase cells. Thus, after a 1-h exposure to [3H]-m-AMSA at 37°C, a small proportion (1%) of cell-associated radioactivity was covalently bound to macromolecules, but most of the cell-associated radioactivity represented unchanged m-AMSA. There was no evidence for any oxidative metabolism to reactive quinoidal species in these tumour cells. However, studies with a fluorescence assay for DNA unwinding indicated that plateau-phase cells were 3 to 4 times less sensitive to m-AMSA-induced DNA breakage than log-phase cells, and changes in sensitivity to m-AMSA-induced DNA breakage correlated with changes in sensitivity to cell killing by m-AMSA as cell progressed from log to plateau phase. Further studies showed that the decrease in sensitivity to m-AMSA-induced DNA stand breakage correlated with a decrease in sensitivity to covalent DNA-protein complex formation in plateau-phase cells after m-AMSA treatment. Combined with evidence that the DNA lesions rapidly disappeared from both log- and plateau-phase cells following the removal of m-AMSA (half-time approx. 4 min), this indicated that the lesions detected by the FADU assay probably arose from the stimulation of DNA-topoisomerase II (topo II) cleavable complex formation by m-AMSA. K+/SDS precipitation assays with [32p] 3’-end-labelled pBR322 DNA indicated that nuclear extracts containing topo II activity from plateau-phase cells were 3- to 4-fold less sensitive to stimulation of DNA-topo II complex formation by m-AMSA than nuclear extracts from log-phase cells. This change in sensitivity to m-AMSA-induced DNA-topo II complex formation was therefore similar to that observed with intact cells. However, P4 unknotting assays indicated that topo II activity in nuclear extracts from plateau-phase cells was only 2-fold lower than that in nuclear extracts from log-phase cells. Resistance to treatment with m-AMSA may therefore reflect a decrease in topo II activity and/or a decrease in sensitivity of topo II enzymes to stimulation of cleavable complex formation by m-AMSA in non-cycling cells.

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22

Taponen, S. (Saara). "Metabolic and clinical characteristics of women with self-reported symptoms of polycystic ovary syndrome". Doctoral thesis, University of Oulu, 2004. http://urn.fi/urn:isbn:9514273176.

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Abstract Oligomenorrhea (menstrual disturbances) and hirsutism (excessive growth of body hair) are typical symptoms of polycystic ovary syndrome, a common endocrine disorder with long-term health risks among fertile-age women. Associations between body size development and polycystic ovary syndrome symptoms in a cohort design (528 symptomatic and 1479 asymptomatic women) and endocrine, metabolic and clinical characteristics of women with self-reported symptoms of oligomenorrhea or hirsutism in a nested case-control design (518 cases and 1036 controls) were investigated in this general population-based study. Gynecologic ultrasonographic examinations were performed in 196 cases and 67 controls to assess the morphology of the ovaries and its relationship to biochemical and clinical parameters. The study population was derived from the Northern Finland Birth Cohort 1966, which included all births with expected birth dates in 1966 in Northern Finland and is well representative of the general female population. Polycystic ovary syndrome symptoms in adulthood were associated with obesity, particularly abdominal obesity, in adolescence and in adulthood, but not with birth weight or being small for gestational age. Hormonal changes typical of polycystic ovary syndrome, i.e. higher circulating concentrations of testosterone, luteinizing hormone (LH) and insulin and lower levels of sex hormone-binding globulin (SHBG), were detected in women with self-reported symptoms of oligomenorrhea and/or hirsutism compared with the controls. Less favorable metabolic cardiovascular disease risk factor profiles, higher body mass index (BMI), waist-hip ratio (WHR), and triglyceride and C-reactive protein (CRP) concentrations and lower high density lipoprotein cholesterol (HDL-C) levels, were detected in women with symptoms, being the most severe among women who reported both hirsutism and oligomenorrhea. Unfavorable characteristics were pronounced in the presence of overweight or obesity. Women with symptoms more often had features characteristic of polycystic ovarian morphology associated with an endocrine and clinical profile reflecting polycystic ovary syndrome. This study shows that questioning in regard to symptoms of oligomenorrhea and hirsutism is useful in detecting women at risk of polycystic ovary syndrome and associated health risks. Avoidance of being overweight is important among young women to prevent the development of insulin resistance. Systematic follow-up of women with symptoms of oligomenorrhea and hirsutism is justified for prevention and early detection of long-term health risks.

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23

Gogusetti, Vivek Shashank Nag. "Functions of ATR Kinase in Terminally Differentiated Human Epidermal Keratinocyles and in Human Ex-Vivo Skin After Exposure to Ultraviolet B Radiation". Wright State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=wright1622357540982634.

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24

Kain, Megan Marie. "Bind, Tether, and Transcend: Achieving Integration Through Extra-Therapeutic Dance". Antioch University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=antioch1466901499.

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25

Szabó, Zoltán. "Diabetes and coronary surgery : metabolic and clinical studies on diabetic patients after coronary surgery with special reference to cardiac metabolism and high-dose GIK /". Linköping : Univ, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-5219.

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26

Fouchet, Philippe. "Le phénomène épileptique: fonction et statut clinique des manifestations épileptiformes chez des sujets présentant une épilepsie et/ou des troubles pseudo-épileptiques d'origine non organique". Doctoral thesis, Universite Libre de Bruxelles, 2001. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211516.

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27

Nutt, David, Christer Allgulander, Yves Lecrubier, T. Peters y Hans-Ulrich Wittchen. "Establishing non-inferiority in treatment trials in psychiatry - guidelines from an Expert Consensus Meeting". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-106816.

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Comparing the efficacy of different treatments in psychiatry is difficult for many reasons, even when they are investigated in `head-to-head' studies. A consensus meeting was, therefore, held to produce best practice guidelines for such studies. This article presents the conclusions of this consensus and illustrates it using published data in the field of antidepressant treatment of generalized anxiety disorder.

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28

Gruntman, Alisha. "A Translational Pathway for Recombinant Adeno-Associated Virus Human Gene Therapy: From Target Identification and Animal Modeling of the Disease to Non-Human Primate and Human Studies". eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/882.

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Many steps go into developing a clinical viral gene therapy. The course starts with appropriate disease selection and moves through the many hurdles of in-vitro testing, animal model validation and proof-of-concept studies, all the way through pre-clinical large animal studies. In this thesis, I propose to outline the process of developing a translation pathway for a gene therapy using recombinant adeno-associated virus (rAAV). I will expand on this outline using data that I have generated during the course of my Ph.D. that ranges from animal model validation all the way through pre-clinical vector stability studies. Two disease models will be discussed throughout this thesis, Cockayne Syndrome (CS) and Alpha-1 Antitrypsin Deficiency (AATD). Cockayne Syndrome is a rare autosomal recessive genetic disorder involving mutations in either the CSA or CSB gene, leading to defects in DNA repair. Clinically this presents as progressive degeneration of the central nervous system, retina, cardiovascular system, and cochlea, which leads to mental retardation, post-natal growth defects, ocular abnormalities, and shortened life expectancy. Alpha-1 antitrypsin is a serine protease inhibitor largely produced in the liver that mainly functions to inhibit neutrophil elastase within the lung. AATD leads to an increased risk of emphysema, with shortened life expectancy, and also results in accumulations of mutant AAT polymers in the liver, sometimes leading to liver failure. Using these two disease models I will outline the upstream and downstream pre-clinical work as well as the transition to clinical trials of a rAAV based gene therapy.

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29

Gruntman, Alisha. "A Translational Pathway for Recombinant Adeno-Associated Virus Human Gene Therapy: From Target Identification and Animal Modeling of the Disease to Non-Human Primate and Human Studies". eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/882.

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Many steps go into developing a clinical viral gene therapy. The course starts with appropriate disease selection and moves through the many hurdles of in-vitro testing, animal model validation and proof-of-concept studies, all the way through pre-clinical large animal studies. In this thesis, I propose to outline the process of developing a translation pathway for a gene therapy using recombinant adeno-associated virus (rAAV). I will expand on this outline using data that I have generated during the course of my Ph.D. that ranges from animal model validation all the way through pre-clinical vector stability studies. Two disease models will be discussed throughout this thesis, Cockayne Syndrome (CS) and Alpha-1 Antitrypsin Deficiency (AATD). Cockayne Syndrome is a rare autosomal recessive genetic disorder involving mutations in either the CSA or CSB gene, leading to defects in DNA repair. Clinically this presents as progressive degeneration of the central nervous system, retina, cardiovascular system, and cochlea, which leads to mental retardation, post-natal growth defects, ocular abnormalities, and shortened life expectancy. Alpha-1 antitrypsin is a serine protease inhibitor largely produced in the liver that mainly functions to inhibit neutrophil elastase within the lung. AATD leads to an increased risk of emphysema, with shortened life expectancy, and also results in accumulations of mutant AAT polymers in the liver, sometimes leading to liver failure. Using these two disease models I will outline the upstream and downstream pre-clinical work as well as the transition to clinical trials of a rAAV based gene therapy.

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30

Nutt, David, Christer Allgulander, Yves Lecrubier, T. Peters y Hans-Ulrich Wittchen. "Establishing non-inferiority in treatment trials in psychiatry - guidelines from an Expert Consensus Meeting". Technische Universität Dresden, 2008. https://tud.qucosa.de/id/qucosa%3A26701.

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Comparing the efficacy of different treatments in psychiatry is difficult for many reasons, even when they are investigated in `head-to-head' studies. A consensus meeting was, therefore, held to produce best practice guidelines for such studies. This article presents the conclusions of this consensus and illustrates it using published data in the field of antidepressant treatment of generalized anxiety disorder.

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31

Zschaeck, Sebastian, Monique Simon, Steffen Löck, Esther G. C. Troost, Kristin Stützer, Patrick Wohlfahrt, Steffen Appold et al. "PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-219714.

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Background Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects. Methods/design This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week. Discussion The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects. Trial registration Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.

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32

Zschaeck, Sebastian, Monique Simon, Steffen Löck, Esther G. C. Troost, Kristin Stützer, Patrick Wohlfahrt, Steffen Appold et al. "PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial". BioMed Central, 2016. https://tud.qucosa.de/id/qucosa%3A30184.

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Background Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects. Methods/design This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week. Discussion The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects. Trial registration Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.

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33

Wang, Lin-Ti y 王麟弟. "Clinical and laboratory studies of non-alcoholic fatty liver disease in Taiwan". Thesis, 2005. http://ndltd.ncl.edu.tw/handle/80617015563711969961.

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碩士
國立臺灣大學
臨床醫學研究所
93
論文英文簡述 Background: Nonalcoholic fatty liver disease (NAFLD) is not an uncommon disease in developed countries. NAFLD is frequently associated with type II DM, obesity, dyslipidemia, but some patients with NAFLD still have normal glucose tolerance or normal body weight. In the literatures, NAFLD may be a common cause of cryptogenic hepatitis or even cirrhosis and the relationship between NAFLD and HFE gene mutations (C282Y and H63D) remains controversial. Adiponectin has antilipogenic effects that may protect nonadipocytes tissues such as liver against lipid accumulation. In addition, the conditions most associated with the development of NAFLD, namely, obesity, insulin resistance, type 2 diabeties and dyslipidemia, all have reduced adiponectin levels. Aims: (1) To determine the clinical and laboratory characteristics in Taiwanese patients with NAFLD and the correlation between NAFLD and HFE gene mutation. (2) To compare the plasma adiponectin levels between NAFLD patients, normal controls and HBV carriers. Materials and Methods: From January to October 2004, 57 consecutive subjects were collected and into 3 groups. Group I (healthy control): 11 males and 4 females with mean age of 33.5±7.8 years. Group II (HBV carriers): 16 males and 4 females with mean age of 36.1±8.7 years. Group III (NAFLD): 19 males and 3 females with mean age of 34.3±11.3 years and serum ALT, AST at least 1.5 X the upper limit of normal. Viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, Wilson’s disease, hemochromatosis and alcohol abuse were excluded. Clinical and biochemical characteristics such as gender, age, body mass index (BMI), AST, ALT, γGT, ALP, total cholesterol, triglyceride, HDL, LDL, uric acid, fasting glucose, fasting insulin, insulin resistance, iron, total iron binding capacity, ferritin, total and direct bilirubin and adiponectin were measured. HFE gene (C282Y and H63D) mutations were detected by PCR- restriction fragment length polymorphisms (RFLP). Results: There were significant differences between Group I and III in terms of BW, BH, BMI, TIBC, ferritin, Total cholesterol, TG, HDL, LDL, AST, ALT, ALP, insulin and insulin resistance (P＜0.05). There were also significant differences between group III and II with respect to BH, BMI, Total cholesterol, AST, ALT, γGT and fasting sugar (P＜0.05). Borderline significance of fasting sugar (p=0.05) and DM (p=0.06) were noted between group III and group I. Borderline significance (p=0.05) of LDL, insulin resistance and insulin were noted between group III and group II. All 57 patients received PCR-RFLP analysis and only one has HFE (H63D) mutation was detected. Plasma adiponectin level was significantly lower in group III compared to group I or II. Conclusions: In Taiwan, NAFLD is correlated with metabolic syndrome (obesity, dyslipidemia, DM, insulin resistance) and low adiponectin. The frequency of HFE gene mutations in NAFLD patients is comparable to that in healthy adults or HBV carriers, suggesting a minimal role of HFE gene mutations in the pathogenesis of NAFLD.

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34

Aldrich, Carrie Lynn. "Clinical and molecular evolutionary studies of the non-classical human leukocyte antigen HLA-G /". 2001. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3006469.

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35

Foley, Christine Marie. "Comparison And Application Of Methods To Address Confounding By Indication In Non-Randomized Clinical Studies". 2013. https://scholarworks.umass.edu/theses/1121.

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Objective: The project aimed to compare marginal structural models, and propensity score adjusted models with Cox Proportional Hazards models to address confounding by indication due to time-dependent confounders. These methods were applied to data from approximately 120,000 women in the Women’s Health Initiative to evaluate the causal effect of antidepressant medication with respect to diabetes risk. Methods: Four approaches were compared. Three Cox Models were used. The first used baseline covariates. The second used time-varying antidepressant medication use, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates. The third used time-varying antidepressant medication use, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates and propensity to taking antidepressants at baseline. Our fourth method used a Marginal Structural Cox Model with Inverse Probability of Treatment Weighting that included time-varying antidepressant medication, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates. Results: All approaches showed an increase in diabetes risk for those taking antidepressants. Diabetes risk increased with adjustment for time-dependent confounding and results for these three approaches were similar. All models were statistically significant. Ninety-five percent confidence intervals overlapped for all approaches showing they were not different from one another. Conclusions: Our analyses did not find a difference between Cox Proportional Hazards Models and Marginal Structural Cox Models in the WHI cohorts. Estimates of the Inverse Probability of Treatment Weights were very close to 1 which explains why we observed similar results.

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36

(8086361), Yuhao Peng. "Communication Features Associated with Clinical Performance and Non-technical Skills in Healthcare Settings". Thesis, 2019.

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Effective teamwork and communication are critical to patient outcomes, and subjective assessment tools have been developed for measuring team performance using both technical and non-technical skills. However, inherent biases remain with using subjective assessment tools.

In this study, 3rd-year medical students participated in the Acute Care Trauma Simulation (ACTS). The student performed the role of clinician in a team that included a nurse and a simulated patient. Participants conducted post-operative patient management, patient care diagnoses, and treatment. Audio from all team members was recorded, and speech variables (e.g., speech duration, frequency of interaction, etc.) from student’s audio were extracted.

The models for Research Question I showed that increasing frequency of checkbacks between student and nurse (p<0.05) and speech duration from student to patient (p=0.001) significantly increased student’s clinical performance score. In Research Question II, a positive association (ρ=0.456, p<0.001) between speech duration from student to patient and overall NTS scores was observed, and this correlation was the strongest amongst all other vocal features with overall NTS score.

Both studies showed significant positive relationships between key vocal features (e.g., speech duration), frequency of communication with respect to performance. Metrics and vocal features derived from audio recordings can be measured in predicting clinical performance and NTS, moreover, it can further contribute to the understanding of communication in the healthcare setting. Most importantly, the potential of providing an objective approach for simulation-based trauma care training.

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37

Serralheiro, Ana Isabel Azevedo. "Intranasal Delivery of Antiepileptic Drugs: Non-clinical Evaluation of Pharmacokinetics and Brain Biodistribution". Doctoral thesis, 2016. http://hdl.handle.net/10316/29482.

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Tese de doutoramento em Ciências Farmacêuticas, na especialidade de Farmacologia e Farmacoterapia, apresentada à Faculdade de Farmácia da Universidade de Coimbra
Even though remarkable advances in the treatment of epilepsy have been made over the last years, the currently available anticonvulsant pharmacotherapy is unsatisfactory as it provides only the management of epileptic seizures, is not effective in a significant percentage of patients, and is often associated to several adverse effects. Therefore, the development of novel and alternative therapeutic approaches towards a safer and more effective seizure control is urgently needed. The search for an ideal antiepileptic drug (AED) that will be capable of preventing, delaying or modifying epilepsy is still ongoing. However, since the process of discovery and development of new chemical entities is very expensive and commonly accompanied by reduced rates of success, the use of already existing AEDs by improving some of their formulation properties, delivery systems or routes of administration aiming at allowing their efficient and prompt delivery to the brain could also be an attractive strategy. Owing to the unique anatomical connection between the nasal cavity and the central nervous system, a great deal of interest has recently been focused on the exploitation of the intranasal (IN) route for the delivery of therapeutics directly to the brain by circumventing the blood-brain barrier (BBB). Indeed, the olfactory region is the only site in the human body where the nervous system is in direct contact with the surrounding environment, providing a great opportunity for drugs intranasally administered to gain a quick and easy access to the brain, minimising their systemic exposure. The purpose of the present thesis was to assess and compare the pharmacokinetic behaviour of phenytoin (PHT), carbamazepine (CBZ), oxcarbazepine (OXC) and lamotrigine (LTG) administered via the IN and intravenous (IV) routes to mice and to investigate whether a direct transport of the referred compounds from nose to brain could be involved. This project started with the development and validation of appropriate and reliable bioanalytical techniques to support the execution of the intended pharmacokinetic and brain biodistribution studies. In essence, two high performance liquid chromatographic methods coupled with ultraviolet detection were properly validated for the quantification of drugs and some of their respective main metabolites in mouse plasma, brain (whole brain, olfactory bulb and frontal cortex) and liver matrices. An additional technique developed in human plasma has also shown to be a useful tool to be applied in clinical practice. Due to unexpected difficulties encountered during the definition and optimisation of the in vivo experimental setup, two of the four initially proposed test molecules were excluded from further investigation, which was performed only with CBZ and LTG. The fairly comparable concentration-time profiles of both of these drugs obtained in plasma, brain and liver following IN and IV administrations to mice, together with a high IN absolute bioavailability, underscored the fact that a substantial absorption of the drugs from the nasal vasculature into the systemic circulation has occurred. Conversely, the uneven biodistribution profile after IN delivery of either CBZ or LTG, with the highest drug concentration levels attained in the olfactory bulb contrasted with the homogeneous biodistribution pattern typically observed following IV injection, strongly suggesting the involvement of a pathway to directly transport these drugs from nose-to-brain, bypassing the BBB. According to our results, it seems that the IN route can be assumed as a suitable and a valuable drug delivery strategy for the chronic treatment of epilepsy and, in the specific case of CBZ, it gathers favourable conditions to be also applied in acute convulsive emergencies. Considering all its inherent potential and indisputable advantages, the IN administration may likewise emerge as a promising and a non-invasive alternative approach for a prospective management of pharmacoresistance.
Apesar de, ao longo dos últimos anos, terem sido alcançados avanços notáveis no que ao tratamento da epilepsia diz respeito, a terapêutica farmacológica anticonvulsivante atualmente disponível não é satisfatória, uma vez que possibilita apenas o controlo das crises epiléticas, não é eficaz numa percentagem muito significativa de doentes e é frequentemente associada a vários efeitos adversos. Deste modo, afigura-se urgente o desenvolvimento de abordagens terapêuticas novas e alternativas com vista a um controlo mais seguro e eficaz das crises. A procura pelo fármaco antiepilético (AED) ideal que permita prevenir, retardar ou modificar a doença ainda permanece uma realidade. Porém, tendo em conta que o processo de descoberta e desenvolvimento de novas entidades químicas é geralmente muito dispendioso e acompanhado de uma reduzida taxa de sucesso, a otimização das propriedades de formulação, sistemas de entrega ou vias de administração de AEDs já estabelecidos e disponíveis na clínica também poderá constituir uma estratégia muito atrativa. A ligação anatómica ímpar entre a cavidade nasal e o sistema nervoso central tem recentemente suscitado um interesse particular na exploração da via intranasal (IN) para a entrega de agentes terapêuticos diretamente para o cérebro, circunscrevendo a barreira hemato-encefálica (BBB). De facto, a região olfativa representa o único local do corpo humano onde o sistema nervoso se encontra em contacto direto com o meio ambiente, oferecendo assim uma grande oportunidade aos fármacos administrados por via IN de atingirem o cérebro de uma forma rápida e facilitada, minimizando a sua exposição sistémica. Com o trabalho de investigação subjacente à presente dissertação pretendeu-se avaliar e comparar o comportamento farmacocinético da fenitoína (PHT), carbamazepina (CBZ), oxcarbazepina (OXC) e lamotrigina (LTG) administrados por via IN e intravenosa (IV) a murganhos, e investigar o eventual envolvimento de um transporte direto para estas moléculas desde a cavidade nasal até ao cérebro. Este projeto iniciou-se com o desenvolvimento e validação de técnicas bioanalíticas adequadas e confiáveis para suportar a execução dos estudos farmacocinéticos e de biodistribuição cerebral pretendidos. Para tal, foram validados dois métodos de cromatografia líquida de alta eficiência acoplada a deteção ultravioleta para a quantificação dos referidos fármacos e alguns dos seus principais metabolitos em matrizes de plasma, cérebro (cérebro total, bolbo olfativo e córtex frontal) e fígado de murganho. Uma técnica adicional em plasma humano foi ainda desenvolvida demonstrando aplicabilidade na prática clínica. Face a dificuldades inesperadamente encontradas durante a definição e otimização do protocolo experimental in vivo, apenas a CBZ e a LTG, de entre as quatro moléculas teste inicialmente propostas, foram amplamente avaliadas neste trabalho. A semelhança observada entre os perfis de concentração-tempo em plasma, cérebro e fígado após a administração IN e IV a murganhos, juntamente com a elevada biodisponibilidade absoluta IN indicaram a ocorrência de uma absorção substancial de ambos os fármacos a partir da vasculatura nasal para a circulação sanguínea. Por outro lado, em oposição a um padrão de biodistribuição cerebral homogéneo tipicamente observado mediante administração IV, após administração IN foi obtido um perfil muito heterogéneo com níveis de concentração de CBZ e LTG mais elevados no bolbo olfativo, sugerindo assim o provável envolvimento de uma via de transporte direto desde a cavidade nasal até ao cérebro contornando a BBB. De acordo com os nossos resultados, pressupõe-se que a via IN seja assumida como uma estratégia válida e apropriada para a administração continuada de ambos os fármacos visando o tratamento crónico da epilepsia, reunindo no caso específico da CBZ condições favoráveis para ser aplicada também em situações de emergência convulsiva. Considerando todas as suas vantagens e potencial inerente, a administração IN poderá igualmente representar uma abordagem alternativa, não-invasiva e promissora para um controlo prospetivo da epilepsia farmacorresistente.
FCT - SFRH/BD/64895/2009

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38

Yen, Meng Hsiu y 顏盟修. "Intravenous immunoglobulin and lactoferrin: evaluation of the possible non-specific antiviral measurements for pediatric non-polio enterovirus infections, from clinical to bench studies". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/51938092964146339627.

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博士
長庚大學
臨床醫學研究所
101
Non-polio enterovirus infections are common infectious diseases of children worldwide including Taiwan. Although most enterovirus infections are self-limited, the severe infections including meningoencephalitis resulted from EV71 infections and hepatitis with coagulopathy in neonatal patients are potentially fatal and may accompany by sequel. The treatment of severe enterovirus infections is mainly supportive due to the lack of licensed specific anti-viral agent. This underlines the importance of developing or evaluating the potentially effective agents currently available for the treatment or prevention of enterovirus infections. In 2005 increased coxsackievirus B3 (CVB3) activity was noted in Taiwan. During this endemic of CVB3 infections we revealed the role of viral load in disease severity of infants with CVB3 infection. In addition, we noticed a rapid decline of viral load after IVIG use in the 2 patients received viral load determination before IVIG therapy. In addition in the 4 patients who suffered severe infections and received IVIG therapy within 3 days of illness, the use of IVIG was accompanied by an improvement in AST level and clinical condition. We further conducted a retrospective study to evaluate the influence of IVIG therapy on outcome with timing of IVIG therapy taken into consideration. A total of 67 neonates (52 survived and 15 died) with severe enterovirus infection were collected during a period of 16 years. Firstly the prognostic role of AST level in the first 3 days of illness was noted. A total of 41 patients received IVIG therapy, and for patients received early IVIG therapy (receiving IVIG within 3 days of illness) the timing of IVIG therapy and peak AST level were highly correlated. In addition, among all patients enrolled the patients received early IVIG therapy had a probability of survival 15 times higher than that of those patients who did not. These findings suggest that timing of IVIG therapy is likely crucial in its effectiveness and timely IVIG therapy is probably life saving for severely infected neonates. These finings also highlight the importance of timing of therapy for future studies addressing the benefit of IVIG therapy in severe neonatal enterovirus infections. Lactoferrin is a mammalian milk glycoprotein which is also present in tears, saliva, and neutrophil granules. In addition to iron binding ability, it possesses several biological functions including inhibiting several bacteria and viruses. Bovine lactoferrin now could be industrially mass produced and incorporated into several nutritional supplements including yogurt and infant formula. Its anti-rotavirus effect had been reported before. In 2002 we identified its anti-enterovirus activity towards EV71 and coxsackievirus A16. We then executed a clinical trial to evaluate the effect of oral supplement of lactoferrin in preventing enterovirus or rotavirus infection in health children aged 2 to 6 years old in 2002 and 2003. However a beneficial effect of oral supplement of lactoferrin could not be shown in this trial. There are several possible explanations for this result. Firstly, the dose of lactoferrin supplemented (70 mg/day) probably was not high enough to establish a local intestinal concentration to prevent disease. Second, enteroviruses are contagious not only by fecal-oral route but also respiratory route, through which route the viral infection could not benefit from oral supplement of LF-containing nutrients. In addition, disease burden of EV71 and rotavirus infection during the study period was low, and the school carried out a strict hygiene policy. These results and suggestions could be helpful in the design of future studies. All lactoferrin are glycosylated by 3 to 5 N-glycan chains, but the information about functions of the glycans are limited. We perform basic research focusing on the role of lactoferrin’s N-glycans in recognition and binding by ELLSA (Enzyme-linked lectinosorbent assay) with panels of applied lectins. Results show that both human and bovine lactoferrin interact strongly with several categories of lectins. The results suggest several active glycotopes of lactoferrin including oligo-mannose chain (bovine lactoferrin only), a tri-mannose core structure, an (II beta 1->2)2M structure, LFuc and sialic acid residues. These findings advance the understanding of the recognition role of glycans of lactoferrin, are probably useful in interpreting and predicting the biological functions of lactoferrin, and are probably applicable in the design of future studies. The differential anti-EV71 activities of lactoferrin peptides including the 6 polypeptides (N1 to N3, C1 to C3) tailored by structure domains was evaluated. The data showed that the anti-EV71 activity of lactoferrin is not significantly influenced by the absence of its N-glycans. Of the polypeptides tested C1 peptide (87 a.a) is sufficient to inhibit EV71 infection while lactoferricin is not. In the time of addition assay by using C1 peptide, the inhibiting EV71 activity remained when C1 peptide was added within 10 hours after viral adsorption, which suggested that the anti-EV71 activity of C1 peptide may not limited in viral adsorption stage. Enterovirus infections have been a major health problem of children in Taiwan, and vaccine or specific antiviral agents are still under evaluation or development. Before further advance is achieved, clinical or basic research of other safe, potentially effective, commercially available agents would possibly of great value in disease treatment or prevention. Hope that our findings would be an aid in clinical practice or future studies of the same scope of interest.

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39

Chang, Gee-Chen y 張基晟. "The Molecular mechanisms of ZD1839 and Gemcitabine on non-small cell lung cancer from clinical to basic studies". Thesis, 2005. http://ndltd.ncl.edu.tw/handle/57086510420698621060.

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博士
中山醫學大學
醫學分子毒理學研究所
93
Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85%, while SCLC accounts for the rest 15%. In spite of new treatments, the overall five-year survival rate remains about 14% and most patients present with advanced disease. Novel therapeutic strategies to improve efficacy in accord with safety are urgently needed. Epithelial growth factor receptor (EGFR) has been proposed as a target for anticancer therapy. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is under clinical use in cancer patients. We retrospectively evaluated the efficacy and tolerability of ZD1839 in patients with advanced NSCLC and very poor performance status (PS) in Taiwan. Tumor response rate was 25.0% (13/52). The median overall survival was 2.5 months (response group 9.1 months, stable disease 3.1 months, and progressive group 0.8 month, p < 0.001). Clinically, ZD1839 has good antitumor activity and tolerability in Taiwan patients with advanced NSCLC and very poor performance status. Taiwan patients have a higher response rate to ZD1839 than that had been seen in Europe or in European heritage Americans. Chemonaive patients responded better than patients with prior chemotherapy. We also found the unique side effects of ZD1839, inducing paronychia and skin hyperpigmentation in some of our patients. The molecular mechanisms involved in ZD1839-mediated anticancer effects were characterized using human lung adenocarcinoma A549 cells in this study,exposure of A549 cells to ZD1839 caused G1 arrest, and subsequently induced apoptosis. The results indicate that downregulation of the expression and function of CDK2, CDK4, CDK6, cyclin-D1 and cyclin-D3, as well as upregulation of p27KIP1 and pRb2/p130, both are strong candidates for the cell cycle regulator that arrests ZD1839-treated A549 cells at G1 phase. Furthermore, upregulation of Fas and inactivation of ERK appear to play a major role in the initiation of ZD1839-induced apoptosis, activation of caspase-8/caspase-3 cascade is involved in the execution phase of this death program. Gemcitabine is currently the effective chemotherapeutic drug available for patients with lung cancer, but it has minimally effective against this aggressive disease in combination with ZD1839. To understand their mode of action, we designed the treatments involving gemcitabine either alone or in combination with ZD1839. We found that ERK activation and AKT inactivation contributed to gemcitabine-induced apoptosis in NSCLC. When ZD1839 and gemcitabine were given in combination or sequence, gemctibine followed by ZD1839 induced the greatest induction of apoptosis. However, the sequential treatment ZD1839 followed by gemcitabine caused an antagonistic interaction. Our findings suggest that the interaction of ZD1839 and gemcitabine is highly schedule dependent.

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40

Chou, Chung-Wei y 周中偉. "The studies on immune response of Pneumocystis jirovecii pneumonia and its clinical relevance in non-acquired immunodeficiency syndrome patients". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/53037494974431029362.

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博士
國立陽明大學
臨床醫學研究所
103
Pneumocystis jirovecii pneumonia (PJP) is a common and potentially lethal infectious disease in immunocompromised patients with or without acquired immunodeficiency syndrome (AIDS). AIDS and other immunocompromised patients presented two distinct clinical patterns of PJP. Compared with AIDS patients, the PJP in non-AIDS immunocompromised patients shows a more acute and aggressive clinical course, and is associated with higher mortality. Some lines of evidence suggests that the major factor contributing to morbidity and mortality of PJP patients appears to be the host immunoinflammatory response to infectious organism rather than the organism itself. Compared with non-AIDS PJP patients, significantly greater pathogens and fewer neutrophils or inflammatory cells associated with less severe lung inflammation were reported in bronchoalveolar lavage fluid (BALF) of PJP patients with AIDS. The studies on cytokine profiles in BALF of PJP patients with or without AIDS are limited and most studies focus mainly on the pro-inflammatory cytokines including interleukin-1 (IL-1), IL-6, IL-8 and tumor necrosis factor-α (TNF-α). In the following studies, we would like to explore the clinical relevance of immune response of PJP in non-AIDS immunocompromised patients and the studies were performed as follows: (1) the importance of pro-inflammatory and anti-inflammatory cytokines in PJP; (2) the impact of concurrent pulmonary infection on immune dysregulation in PJP of non-AIDS patients; (3) the clinical usefulness of HRCT in assessing the severity of PJP: (A cross-sectional study). We hope the results of the studies could be of value in elucidating the immune response of the PJP as evidenced by BALF in non-AIDS immunocompromised patients and its clinical relevance and in exploring the clinical usefulness of thoracic high resolution of computed tomography (HRCT) in assessing the severity of PJP. The results of the first study showed that compared with control group, PJP patients had significantly higher BALF levels of IL-1β, TNF-α, IL-6, IL-8 and MCP-1 and significantly higher blood levels of IL-10, TGF-β1, IL-8, IL-6 and MCP-1. For PJP patients, BALF levels of IL-8, IL-8/IL-10 ratio and IL-8/TGF-β1 ratio and blood levels of IL-8 and IL-8/IL-10 ratio were significantly higher in the patients with PaO2/FiO2 < 200 mmHg than in those with PaO2/FiO2> 200 mmHg. Similarly, significantly higher BALF levels of IL-8, IL-8/IL-10 ratio, IL-1β/IL-10 ratio, IL-1β/TGF-β1 ratio, MCP-1/TGF-β1 ratio and IL-8/TGF-β1 ratio were found in the patients requiring mechanical ventilation and in non-survivors. The results of the second study demonstrated that compared with pure PJP group, mixed PJP (PJP associated with concurrent pulmonary infection with other pathogens) group had significantly higher BALF levels of IL-1β, TNF-α and IL-8 and significantly higher blood levels of IL-8. The data of the ratios of TNF-α/IL-10, IL-8/IL-10, IL-1β/IL-10, TNF-α/TGF-β1, IL-8/TGF-β1, IL-1β/TGF-β1 and IL-1β/IL-1RA in BALF were significantly higher in mixed than in pure PJP patients. There was no significant difference in clinical features and outcome between pure and mixed PJP groups, including inflammatory biomarkers and the fungal burden. In pure PJP patients, significantly higher BALF levels of IL-8 and the ratios of IL-8/IL-10, IL-1β/TGF-β1, MCP-1/TGF-β1, MCP-1/IL1RA and IL-8/TGF-β1 were found in the patients requiring mechanical ventilation and in non-survivors. The results of the third study showed that mean lung attenuation (MLA) highly correlated with extent of increased attenuation (EIA) of PJP lesions (ρ = 0.906, p<0.001). MLA and EIA of PJP lesions were significantly correlated with PaO2/FiO2 (ρ = -0.481 and -0.370 respectively, p= 0.007 and 0.044, respectively). When the time period between intensive care unit (ICU) admission and HRCT performed were within two days, MLA and EIA of PJP lesions were significantly correlated with APACHE II score (ρ = 0.791 and 0.670 respectively, p= 0.001 and 0.009, respectively). There were significant differences in the values of MLA and EIA of PJP lesions between patients with and without assisted mechanical ventilator (MLA, median and (IQR, 25%;75%) -516.44(-572.10;-375.34) vs. -649.27(-715.62;-594.01), P <0.001 and EIA, median and (IQR, 25%;75%) 0.75(0.66;0.82) vs. 0.53(0.45;0.68), P = 0.003, respectively). However, the MLA and EIA of PJP lesions had limited value in predicting the mortality of PJP in non-AIDS immunocompromised patients. In summary, an imbalance of pro-inflammatory and anti-inflammatory cytokines in BALF was found in PJP of non-AIDS immunocompromised patients. BALF levels of IL-8, IL-8/IL-10 ratio, IL-1β /IL-10 ratio, IL-1β /TGF- β1 ratio, MCP-1/TGF-β1 ratio and IL-8/TGF-β1 ratio might be of value in assessing the severity of PJP and in predicting the outcome of the patients. Concurrent pulmonary infection with other pathogens might enhance immune dysregulation of PJP in non-AIDS immunocompromised patients, but did not affect the outcome as evidenced by morbidity and mortality. Because of limited number of cases studied, further studies with larger populations are needed to verify these issues. The MLA and EIA values of PJP lesions measured on thoracic HRCT might be valuable in assessing the severity of PJP in non-AIDS immunocompromised patients but might have limited value in predicting the mortality of the patients.

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41

Gonçalves, Daniela de Oliveira. "Non-clinical Evaluation of the Pharmacokinetics and Pharmacodynamics of Opicapone, a Novel Catechol-O-methyltransferase Inhibitor". Doctoral thesis, 2017. http://hdl.handle.net/10316/79620.

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Tese de doutoramento em Ciências Farmacêuticas, na especialidade de Farmacologia e Farmacoterapia, apresentada à Faculdade de Farmácia da Universidade de Coimbra
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder with an increasing worldwide incidence. Despite the progress in understanding the pathogenesis of the disease and in its therapy over the last years, no treatments are currently available to cure or modify the neurodegenerative process. Therefore, PD treatment remains symptomatic. Curiously, almost 50 years after the clinical introduction of levodopa, this drug continues to be considered the most effective therapy for the management of motor symptoms of PD and, when patients develop motor fluctuations, a catechol-O-methyltransferase (COMT) inhibitor is widely recommended to be associated with the levodopa/aromatic L-amino acid decarboxylase (AADC) inhibitor therapy. However, the well-known COMT inhibitors (tolcapone and entacapone) exhibit relevant drawbacks that have restricted their clinical success, demanding the development of new COMT inhibitors with better therapeutic profiles. In this context, opicapone has emerged as an attempt to fulfil this unmet therapeutic need. At the onset of the project underlying the present PhD thesis, opicapone was in clinical development and little information was available in literature about this new and promising COMT inhibitor. Thus, in order to deepen the non-clinical pharmacological knowledge about opicapone and complement the data generated during its clinical development program, the present work was focused on providing non-clinical information on systemic and tissue pharmacokinetics of opicapone and its active metabolite (BIA 9-1079), as well as their effect on erythrocyte, liver and kidney COMT activity after single and multiple (once-daily for seven consecutive days) oral administrations of opicapone to Wistar rats. Owing to the lack of an available analytical technique to support the execution of the planned pharmacokinetic studies, the present project began with the development and full validation of a suitable and reliable bioanalytical method. Hence, a high performance liquid chromatography method coupled with a diode array detector was adequately validated for the quantification of opicapone and BIA 9-1079 in rat plasma, liver and kidney matrices. In addition, a similar method developed in human plasma revealed to be an appropriate bioanalytical tool to support future clinical pharmacokinetic studies involving opicapone. The obtained results suggest that the gastrointestinal absorption of opicapone was relatively rapid as well as its elimination from systemic circulation following both single- and multiple-dose administrations. BIA 9-1079 was also quickly eliminated and represented a high relative percentage of the systemic exposure of opicapone, suggesting that this active metabolite may contribute to the pharmacological activity of opicapone in rats. Interestingly, although opicapone apparently exhibited an approximately dose-proportional increase in its extent of systemic exposure following a single oral administration in the tested dose range (30–90 mg/kg), the systemic exposure to BIA 9-1079 was similar after the administration of 60 and 90 mg/kg of opicapone, suggesting a saturation of this metabolic pathway at the higher tested doses. The systemic accumulation of opicapone and BIA 9-1079 seems to be negligible or, perhaps, non-existent at the evaluated multiple-dose regimen (30 mg/kg once-daily for seven consecutive days), with no hepatic or renal accumulation of both compounds, except for BIA 9-1079 in liver. In addition, the tissue-systemic exposure relationships to opicapone indicated a low exposure of the liver and kidneys to the drug. Following the single and multiple oral administration of 30 mg/kg opicapone, the COMT inhibition profiles were reasonably comparable in all the assessed biological matrices (erythrocytes, liver and kidneys). Furthermore, in spite of its poor exposure in tissues and rapid elimination, opicapone showed a strong and long-lasting pharmacological effect independently of the dosage regimen. Nevertheless, a slightly higher extent of COMT inhibition was observed after repeated administrations. In conclusion, the experimental work herein described contributed to enhance the current non-clinical pharmacological knowledge of a new drug recently approved by European Medicines Agency to be used as adjunct to levodopa/AADC inhibitor therapy in PD patients with motor fluctuations. Moreover, according to our results, it seems that no pharmacokinetic or pharmacodynamic concerns related to the physiological restoration of COMT activity are expected when opicapone is administered once-daily.
A doença de Parkinson (DP) é uma doença neurodegenerativa crónica e progressiva com uma incidência crescente a nível mundial. Apesar do progresso observado nos últimos anos na compreensão da patogénese da doença e na sua terapêutica, nenhum tratamento parece ser capaz de curar ou modificar o processo neurodegenerativo. Desta forma, o tratamento da DP permanece sintomático. Curiosamente, quase 50 anos após a introdução clínica da levodopa, esta continua a ser considerada a terapia mais eficaz no controlo dos sintomas motores da DP, sendo amplamente recomendado adicionar-se um inibidor da catecol-O-metiltransferase (COMT) à terapia combinada levodopa/inibidor da descarboxilase dos L-aminoácidos aromáticos (DCAA) em doentes que desenvolvem flutuações motoras. Contudo, os inibidores da COMT de referência (tolcapone e entacapone) apresentam inconvenientes clinicamente relevantes que têm vindo a limitar o seu sucesso, permanecendo assim a necessidade de desenvolver novos inibidores com um melhor perfil terapêutico. Neste contexto, o opicapone surgiu como uma tentativa de colmatar esta necessidade terapêutica. No início dos trabalhos de investigação subjacentes ao desenvolvimento da presente tese de doutoramento, o opicapone encontrava-se em fase de desenvolvimento clínico e pouca informação estava disponível na literatura sobre este novo e promissor inibidor da COMT. Assim, a fim de aprofundar o conhecimento farmacológico não-clínico sobre o opicapone e complementar os dados gerados durante o seu desenvolvimento clínico, o trabalho aqui apresentado visou obter informações não-clínicas sobre a farmacocinética sistémica e tecidular do opicapone e do seu metabolito ativo (BIA 9-1079), bem como sobre o seu efeito na atividade da COMT eritrocitária, hepática e renal após administrações orais em dose única e múltipla (uma vez por dia durante sete dias consecutivos) do opicapone a ratos Wistar. Devido à não existência de uma técnica analítica disponível para suportar a execução dos estudos farmacocinéticos planeados, o início deste projeto foi dedicado ao desenvolvimento e validação completa de um método bioanalítico adequado e fiável. Assim, foi adequadamente validado um método de cromatografia líquida de alta pressão acoplada a um detetor de fotodíodos para a quantificação do opicapone e do BIA 9-1079 em matrizes de plasma, fígado e rim de rato. Em adição, um método similar foi desenvolvido em plasma humano e revelou ser uma ferramenta bioanalítica apropriada para suportar futuros estudos de farmacocinética clínica que envolvam o opicapone. Os resultados obtidos sugerem que a absorção gastrointestinal do opicapone foi relativamente rápida, bem como a sua eliminação da circulação sistémica após cada um dos regimes posológicos instituídos (dose única e dose múltipla). O BIA 9-1079 foi também rapidamente eliminado e representou uma elevada percentagem relativa da exposição sistémica ao opicapone, sugerindo que este metabolito ativo pode contribuir para a atividade farmacológica do opicapone no rato. Curiosamente, embora o opicapone aparentemente tenha exibido um aumento na sua extensão de exposição sistémica aproximadamente proporcional à dose após a administração oral de uma dose única na gama testada (30–90 mg/kg), a exposição sistémica ao BIA 9-1079 foi similar após a administração de 60 e 90 mg/kg de opicapone, apontando para uma saturação desta via metabólica nas doses mais elevadas. A acumulação sistémica do opicapone e do BIA 9-1079 parece ser negligenciável, ou mesmo inexistente, no regime de dose múltipla avaliado (30 mg/kg uma vez por dia durante sete dias consecutivos), não tendo sido detetada acumulação hepática ou renal para os compostos, exceto para o BIA 9-1079 no fígado. Além disso, as relações de exposição tecido-plasma ao opicapone indicaram uma baixa exposição do fígado e dos rins ao fármaco. Após a administração oral única e múltipla de 30 mg/kg de opicapone, os perfis de inibição da COMT foram razoavelmente comparáveis entre as matrizes biológicas avaliadas (eritrócitos, fígado e rins). Ademais, apesar da sua fraca exposição tecidular e rápida eliminação, o opicapone exibiu um efeito farmacológico forte e duradouro independentemente do regime de administração considerado. No entanto, observou-se uma extensão de inibição da COMT ligeiramente superior após a administração repetida. Em conclusão, o trabalho experimental aqui descrito contribui para pormenorizar o conhecimento farmacológico não-clínico atual de um novo fármaco que foi recentemente aprovado pela Agência Europeia de Medicamentos para ser utilizado como adjuvante da terapia combinada levodopa/inibidor da DCAA em doentes de Parkinson com flutuações motoras. Mais ainda, de acordo com os nossos resultados, não são esperadas preocupações do ponto de vista farmacocinético ou farmacodinâmico relacionadas com a restauração fisiológica da atividade da COMT quando o opicapone é administrado uma vez por dia.

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Ball, David L. (David Lee). "Clinical studies of the effect of radiotherapy dose and fractionation on survival in patients with limited non-small cell lung cancer". 2001. http://web4.library.adelaide.edu.au/theses/09MD/09MDB187.pdf.

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Bibliography: leaves 180-204. A thesis which examines the proposition that higher doses of radiotherapy might be associated with longer survival in patients with non-metastatic non-small cell lung cancer by analysing the survival outcomes for patients treated with a variety of radiotherapy doses according to a standardised policy, and using modern treatment planning and delivery techniques.

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Ball, David Lee. "Clinical studies of the effect of radiotherapy dose and fractionation on survival in patients with limited non-small cell lung cancer / by David L. Ball". Thesis, 2001. http://hdl.handle.net/2440/38238.

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Bibliography: leaves 180-204
A thesis which examines the proposition that higher doses of radiotherapy might be associated with longer survival in patients with non-metastatic non-small cell lung cancer by analysing the survival outcomes for patients treated with a variety of radiotherapy doses according to a standardised policy, and using modern treatment planning and delivery techniques.
Thesis (M.D.) -- University of Adelaide, Dept. of Medicine, 2001

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Fylan, Beth, Hanif Ismail, S. Hartley, C. P. Gale, A. J. Farrin, Peter H. Gardner, Jonathan Silcock y D. P. Alldred. "A non-randomised feasibility study of an intervention to optimise medicines at transitions of care for patients with heart failure". 2021. http://hdl.handle.net/10454/18551.

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Yes
Heart failure affects 26 million people globally, and the optimal management of medicines is crucial for patients, particularly when their care is transferred between hospital and the community. Optimising clinical outcomes requires well-calibrated cross-organisational processes with staff and patients responding and adapting to medicines changes. The aim of this study was to assess the feasibility of implementing a complex intervention (the Medicines at Transitions Intervention; MaTI) co-designed by patients and healthcare staff. The purpose of the intervention was to optimise medicines management across the gaps between secondary and primary care when hospitals handover care. The study objectives were to (1) assess feasibility through meeting specified progression criteria to proceed to the trial, (2) assess if the intervention was acceptable to staff and patients, and (3) determine whether amendment or refinement would be needed to enhance the MaTI. The feasibility of the MaTI was tested in three healthcare areas in the North of England between July and October 2017. Feasibility was measured and assessed through four agreed progression to trial criteria: (1) patient recruitment, (2) patient receipt of a medicines toolkit, (3) transfer of discharge information to community pharmacy, and (4) offer of a community pharmacy medicines review/discussion or medicines reconciliation. From the cardiology wards at each of the three NHS Acute Trusts (sites), 10 patients (aged ≥ 18 years) were recruited and introduced to the 'My Medicines Toolkit' (MMT). Patients were asked to identify their usual community pharmacy or nominate a pharmacy. Discharge information was transferred to the community pharmacy; pharmacists were asked to reconcile medicines and invited patients for a medicines use review (MUR) or discussion. At 1 month following discharge, all patients were sent three questionnaire sets: quality-of-life, healthcare utilisation, and a patient experience survey. In a purposive sample, 20 patients were invited to participate in a semi-structured interview about their experiences of the MaTI. Staff from hospital and primary care settings involved in patients' care were invited to participate in a semi-structured interview. Patient and staff interviews were analysed using Framework Analysis. Questionnaire completion rates were recorded and data were descriptively analysed. Thirty-one patients were recruited across three sites. Eighteen staff and 18 patients took part in interviews, and 19 patients returned questionnaire sets. All four progression to trial criteria were met. We identified barriers to patient engagement with the intervention in hospital, which were compounded by patients' focus on returning home. Some patients described not engaging in discussions with staff about medicines and lacking motivation to do so because they were preoccupied with returning home. Some patients were unable or unwilling to attend a community pharmacy in person for a medicines review. Roles and responsibilities for delivering the MaTI were different in the three sites, and staff reported variations in time spent on MaTI activities. Staff reported some work pressures and staff absences that limited the time they could spend talking to patients about their medicines. Clinical teams reported that recording a target dose for heart failure medicines in patient-held documentation was difficult as they did not always know the ideal or tolerable dose. The majority of patients reported receiving the patient-held documentation. More than two-thirds reported being offered a MUR by their community pharmacists. Delivery of the Medicines at Transitions Intervention (MaTI) was feasible at all three sites, and progression to trial criteria were met. Refinements were found to be necessary to overcome identified barriers and strengthen delivery of all steps of the intervention. Necessary changes to the MaTI were identified along with amendments to the implementation plan for the subsequent trial. Future implementation needs to take into account the complexity of medicines management and adaptation to local context.
This study is funded by the National Institute for Health Research (NIHR) (Programme Grants for Applied Research (Grant Reference Number RP-PG-0514-20009)). The study is also supported by the NIHR Yorkshire and Humber Patient Safety Translational Research Centre.

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45

Světlík, Svatopluk. "Variabilita farmakokinetiky a možnost jejího sledování". Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-415775.

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Backgroun and aims: Pharmacokinetic variability is of paramount importance for sucessfull pharmacotherapy. The main purpose of this work was to study variability of pharmacokinetics in clinical and non-clinical setting with the aim to predict variability in target population. Specifically, three drugs were chosen, sufentanil, with relativelly narrow therapeutic index, and nabumeton and abirateron, both with known high variability. Methods: The study of pharmacokinetic variability of sufentanil was based on clinical samples taken from patients undergoing surgical cardiac procedure, where the sufentanil was used as a part of the drug coctail used during the procedure. New analytical method was necessary to prepare and validate to measure sufentanil concentrations and obtain pharmacokinetic parameters. These were compared between determined genotype groups of MDR1 and OPRM1. Similarly, clinical study was executed with nabumetone, in which nabumetone was administered in a group of 24 subjects on two separate occassions. Plazma samples were obtained and concentrations of nabumetone and its active metabolite, 6-methoxynaphtylacetic acid (6-MNA), were determined. Obtained pharmacokinetic profiles were compared between female and male volunteers, and genotypes for MDR1 and CYP2D6. Finaly for abiraterone,...

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46

Forkel, Walter. "Closed-World Semantics for Query Answering in Temporal Description Logics". 2020. https://tud.qucosa.de/id/qucosa%3A73773.

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Ontology-mediated query answering is a popular paradigm for enriching answers to user queries with background knowledge. For querying the absence of information, however, there exist only few ontology-based approaches. Moreover, these proposals conflate the closed-domain and closed-world assumption, and therefore are not suited to deal with the anonymous objects that are common in ontological reasoning. Many real-world applications, like processing electronic health records (EHRs), also contain a temporal dimension, and require efficient reasoning algorithms. Moreover, since medical data is not recorded on a regular basis, reasoners must deal with sparse data with potentially large temporal gaps. Our contribution consists of three main parts: Firstly, we introduce a new closed-world semantics for answering conjunctive queries with negation over ontologies formulated in the description logic ELH⊥, which is based on the minimal universal model. We propose a rewriting strategy for dealing with negated query atoms, which shows that query answering is possible in polynomial time in data complexity. Secondly, we introduce a new temporal variant of ELH⊥ that features a convexity operator. We extend this minimal-world semantics for answering metric temporal conjunctive queries with negation over the logic and obtain similar rewritability and complexity results. Thirdly, apart from the theoretical results, we evaluate minimal-world semantics in practice by selecting patients, based their EHRs, that match given criteria.

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Mielke, Matthias. "Maximum Likelihood Theory for Retention of Effect Non-Inferiority Trials". Doctoral thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-B3D4-3.

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Kombrink, Karola. "Ein semiparametrisches Verfahren zur Planung und Auswertung von Nichtunterlegenheitsstudien im Cox-Modell". Doctoral thesis, 2011. http://hdl.handle.net/11858/00-1735-0000-0006-B3F6-8.

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VRZALOVÁ, Monika. "Role sestry ve screeningu deprese u seniorů". Master's thesis, 2016. http://www.nusl.cz/ntk/nusl-260905.

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The diploma thesis deals with problems of depression in older people. Mainly the work is focused on identifying and analyzing the role of nurses in screening for depression in older people in primary care, acute care, long-term care and home care. This thesis was focused on theoretical direction and was used the method of design and demonstration. In this thesis was set one main goals with five research questions. The main goal was to identify and analyze the role of nurses in screening for depression in the elderly. RQ 1: What is the role of the nurse in screening for depression in the elderly? RQ 2: What is the role of the nurse in the primary care in screening for depression in the elderly? RQ 3: What is the role of the nurse in screening for depression in hospitalized patients in acute care? RQ 4: What is the role of the nurse in screening for depression in seniors in long-term and home care? RQ 5: What rating scales and methods are used in screening for depression in the elderly? The thesis introduce the concept of depression. The following are specified the causes of and the important factors that affect depression in the elderly. It also deals the differences in the clinical symptomatology of depression in old age. It explains possibilities and various barriers in the diagnosis of depression. Another chapter introduces complete geriatric examination, diagnostic classification systems, possible screening methods and scales for detection of depression in the elderly population. It also deals methods of pharmacological and non-pharmacological treatment and its possible complications associated with older age. By reason of increased suicide rate caused by depressive disorder the issue of suicidal behavior in the elderly is introduced. The next chapter deals with the nursing process, which is used by nurses in practice. It consists of the evaluation of the patient's health condition, making nursing diagnosis, creating nursing plan and subsequent implementation and evaluation. The nursing process is also needy for providing quality care. The nursing process in the stage of nursing diagnosis, introduces possible nursing diagnosis for a patient suffering from depression, which are based on the latest classification. Finally is described the role of nurses in screening for depression in the elderly in different health facilities and their contribution to the timely evaluation of depression in the elderly. This chapter introduces the role of nurses, nursing screening and collaboration with a physician. The role of nurses in screening for depression in different medical facilities is based on the first phase of the nursing process of assessment. On the basis of objective and subjective information, the nurse will assess the overall health and mental condition of the patient. Primarily, it was investigated what is the role of the nurse in screening for depression. On the basis of content analysis and synthesis it was necessary to used and processed domestic and foreign literature. A number of relevant sources are the results of various studies and Meta-analyzes, mostly from abroad, but also from the Czech Republic. The thesis can serve as a basis for nurses. The result of this thesis is to create e-learning material available for students in the Faculty of Health and Social Sciences of South Bohemia in Ceske Budejovice in the tutorial called Moodle.

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