Jan Wallentin. Vägar till samadhi : en granskning av Robert K. C. Formans begrepp ”Pure Consciousness Event” (Roads to Samadhi : An Examination of Robert K. C. Forman’s Concept of ”Pure Consciousness Event”). Umeå University: Department of Historical, Philosophical and Religious studies. Bachelor thesis. June 2021.Is Robert K. C. Forman’s concept of ”pure consciousness event” an example of a universal,mystical core experience? Is it possible to establish the neural correlates of this proposedexperience, and to induce it experimentally? These are the main questions of this study,which is a literature review drawing on recent scientific research from three fields: religious studies, philosophy of consciousness and neuroscience.The major findings are:The concept of ”pure consciousness event” (PCE) does seem like a tenable way ofgetting around the constructivist critique regarding universal, mystical core experiences.However, Forman’s original definition of PCE seems too strict. Forman defines PCE as ”a wakeful though contentless (non-intentional) consciousness”, but in the conventional wisdom of contemporary philosophy it is deemed impossible to be conscious without beingconscious about something. A conceivable solution would be to replace the term ”PCE” withThomas Metzinger’s less strict term ”Minimal Phenomenal Experience” (MPE), whichallows for some, though minimal, mental content during these kind of experiences.Regarding neural correlates, several recent studies suggest that a high level of activityin the brain’s default mode network (DMN) is correlated with a heightened sense of self-awareness. A low level of activity in the DMN is, vice versa, correlated with a sense of self-forgetting, as in the flow-experience. However, the activity-level of the DMN does not seem to fully explain the proposed existence of pure consciousness events, even in a less strict definition of this term.Methods used to induce experiences reminiscent of PCE include the white dreams ofTibetan dream yoga (yoga nidrā), states of deep meditation, and the intake of psychoactive substances, like psilocybin, DMT and LSD.Keyterms: Robert K. C. Forman, pure consciousness event, mysticism, samadhi, philosophy of consciousness,Thomas Metzinger, minimal phenomenal experience, drug induced ego dissolution.

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Introdução: A correta localização do sítio de obstrução nas vias aéreas superiores (VAS) possibilita melhores resultados de tratamento para os pacientes com Síndrome da Apneia Obstrutiva do Sono (SAOS). A endoscopia com sono induzido (DISE) com propofol permite esta avaliação, mas o sono induzido pelo propofol altera a arquitetura do sono, abolindo a presença do sono REM (rapid eye movement). Objetivos: Avaliar as alterações promovidas pelo propofol nos principais parâmetros respiratórios por meio do exame de polissonografia (PSG) nos pacientes portadores de SAOS com predomínio no sono REM (SAOS-R). Descrever os achados da DISE nesses pacientes, comparando-os aos achados da manobra de Müller e às descrições na literatura. Casuística e Métodos: Foram estudados 12 indivíduos não obesos com SAOS-R (confirmado por PSG noturna diagnóstica recente), submetidos a dois exames polissonográficos diurnos, com e sem indução do sono com propofol. O propofol foi utilizado via endovenosa em infusão contínua e controlada por bomba de infusão alvocontrolada (Diprifusor®). Os parâmetros comparados entre os exames foram: IAH (índice de apneia e hipopneia), IA (índice de apneia), IH (índice de hipopneia) e saturação de oxi-hemoglobina (SaO2) mínima e média. Além desses parâmetros, os sítios de obstrução das VAS encontrados na DISE foram comparados com os observados na avaliação ambulatorial com os indivíduos em estado de vigília. Resultados: Não foi evidenciado sono REM em nenhum exame realizado com propofol. O IAH, IA e IH do exame com propofol não apresentaram diferença estatística quando comparados com os exames diurnos sem indução e PSG noturna. A SaO2 média apresentou diferença estatística entre os três exames, sendo menor nas PSGs com indução do sono utilizando propofol, tanto em relação ao exame sem sedação (p<0,0001) quanto ao noturno (p=0,004). A SaO2 mínima foi semelhante entre as PSGs com sedação e noturnas, mas foi significativamente menor nos exames com sedação em relação aos sem sedação diurnos (p=0,011). Quando houve diferença significativa, esta ocorreu em torno de 2 a 3%. A análise de concordância para a classificação de VOTE (velum, oropharynx, tongue base and epiglottis) na avaliação ambulatorial e na DISE não demonstrou nenhuma concordância para todas as estruturas avaliadas (Kappa = - 0,029 em palato, 0,1 em orofaringe, 0,16 em base da língua e 0,0 em epiglote). Os resultados demonstraram que, apesar de o propofol influenciar a arquitetura do sono, abolindo o sono REM, os principais parâmetros utilizados na avaliação dos pacientes com SAOS-R, permaneceram inalterados, ou foram clinicamente irrelevantes. Conclusão: Assim, quando utilizado por infusão contínua, o propofol demonstrou ser uma droga segura na avaliação endoscópica dos indivíduos com SAOS-R para a determinação dos sítios de obstrução, acrescentando informações importantes para o correto tratamento. Ainda, a PSG sob sono induzido com propofol manteve os principais parâmetros ventilatórios em comparação à PSG sob sono espontâneo. / Introduction: The correct localization of upper airway obstruction induces the patients with obstructive sleep apnea syndrome (OSAS) to present better treatment results. Drug induced sleep endoscopy (DISE) with propofol allows this evaluation, but changes the sleep architecture, abolishing the presence of REM sleep. Objecives: To evaluate the changes promoted by propofol on the main respiratory parameters of polysomnography (PSG) in patients with REM-related OSAS (REM-OSAS). To describe the endoscopic findings in these patients, and to compare them to the outpatient Müller\'s maneuver and to the findings described in literature. Casuistic and Methods: In this study, 12 non-obese subjects with REM-OSAS (confirmed by recent nocturnal PSG) underwent two polysomnographic examinations during the day, with and without sleep induction with propofol. Propofol was used intravenously in continuous infusion controlled by target-controlled infusion pump (Diprifusor®). The parameters compared between the examinations were: AHI (apnea-hypopnea index), AI (apnea index), HI (hypopnea index) and both minimal and mean oxihemoglobin saturation (SaO2). Besides these parameters the sites of upper airway obstruction found in DISE were compared with those found in awake outpatient evaluation. Results: REM sleep was not achieved in any moment, in any patient, when propofol was infused. The AHI, AI and HI during infusion with propofol showed no statistical difference when compared with both diurnal test without propofol and diagnostic nocturnal PSG. Mean SaO2 showed statistical difference between the 3 tests, being lower in PSG with sleep induction with propofol, both for the exam without sedation (p<0.0001) as for and the diagnostic PSG (p=0.004). Minimum SaO2 was similar between examinations with sedation and diagnostic nocturnal PSG, but it was significantly lower in tests with propofol infusion compared with the diurnal exam without sedation (p=0,011). Mean difference, when significant, was about 2 to 3%. The analysis of agreement for the VOTE classification by patient evaluation and DISE showed no agreement in any measured structure (kappa = -0.029 for velum, 0,1 for oropharynx, 0,16 for tongue base and 0,0 for epiglottis). The results demonstrate that although propofol influences sleep architecture, abolishing REM sleep, the main respiratory parameters remained unchanged in patients with REMOSAS. Conclusions: Thus, target-controlled infusion of propofol is a safe method for endoscopic evaluation of patients with REM-OSAS, in order to determine the sites of obstruction, and it adds important information for proper treatment. Yet, PSG during DISE with propofol was related to manteinance of the most important ventilatory parameters when compared with PSG under spontaneous sleep.

Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes. The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions. In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Introdução: A correta localização do sítio de obstrução nas vias aéreas superiores (VAS) possibilita melhores resultados de tratamento para os pacientes com Síndrome da Apneia Obstrutiva do Sono (SAOS). A endoscopia com sono induzido (DISE) com propofol permite esta avaliação, mas o sono induzido pelo propofol altera a arquitetura do sono, abolindo a presença do sono REM (rapid eye movement). Objetivos: Avaliar as alterações promovidas pelo propofol nos principais parâmetros respiratórios por meio do exame de polissonografia (PSG) nos pacientes portadores de SAOS com predomínio no sono REM (SAOS-R). Descrever os achados da DISE nesses pacientes, comparando-os aos achados da manobra de Müller e às descrições na literatura. Casuística e Métodos: Foram estudados 12 indivíduos não obesos com SAOS-R (confirmado por PSG noturna diagnóstica recente), submetidos a dois exames polissonográficos diurnos, com e sem indução do sono com propofol. O propofol foi utilizado via endovenosa em infusão contínua e controlada por bomba de infusão alvocontrolada (Diprifusor®). Os parâmetros comparados entre os exames foram: IAH (índice de apneia e hipopneia), IA (índice de apneia), IH (índice de hipopneia) e saturação de oxi-hemoglobina (SaO2) mínima e média. Além desses parâmetros, os sítios de obstrução das VAS encontrados na DISE foram comparados com os observados na avaliação ambulatorial com os indivíduos em estado de vigília. Resultados: Não foi evidenciado sono REM em nenhum exame realizado com propofol. O IAH, IA e IH do exame com propofol não apresentaram diferença estatística quando comparados com os exames diurnos sem indução e PSG noturna. A SaO2 média apresentou diferença estatística entre os três exames, sendo menor nas PSGs com indução do sono utilizando propofol, tanto em relação ao exame sem sedação (p<0,0001) quanto ao noturno (p=0,004). A SaO2 mínima foi semelhante entre as PSGs com sedação e noturnas, mas foi significativamente menor nos exames com sedação em relação aos sem sedação diurnos (p=0,011). Quando houve diferença significativa, esta ocorreu em torno de 2 a 3%. A análise de concordância para a classificação de VOTE (velum, oropharynx, tongue base and epiglottis) na avaliação ambulatorial e na DISE não demonstrou nenhuma concordância para todas as estruturas avaliadas (Kappa = - 0,029 em palato, 0,1 em orofaringe, 0,16 em base da língua e 0,0 em epiglote). Os resultados demonstraram que, apesar de o propofol influenciar a arquitetura do sono, abolindo o sono REM, os principais parâmetros utilizados na avaliação dos pacientes com SAOS-R, permaneceram inalterados, ou foram clinicamente irrelevantes. Conclusão: Assim, quando utilizado por infusão contínua, o propofol demonstrou ser uma droga segura na avaliação endoscópica dos indivíduos com SAOS-R para a determinação dos sítios de obstrução, acrescentando informações importantes para o correto tratamento. Ainda, a PSG sob sono induzido com propofol manteve os principais parâmetros ventilatórios em comparação à PSG sob sono espontâneo. / Introduction: The correct localization of upper airway obstruction induces the patients with obstructive sleep apnea syndrome (OSAS) to present better treatment results. Drug induced sleep endoscopy (DISE) with propofol allows this evaluation, but changes the sleep architecture, abolishing the presence of REM sleep. Objecives: To evaluate the changes promoted by propofol on the main respiratory parameters of polysomnography (PSG) in patients with REM-related OSAS (REM-OSAS). To describe the endoscopic findings in these patients, and to compare them to the outpatient Müller\'s maneuver and to the findings described in literature. Casuistic and Methods: In this study, 12 non-obese subjects with REM-OSAS (confirmed by recent nocturnal PSG) underwent two polysomnographic examinations during the day, with and without sleep induction with propofol. Propofol was used intravenously in continuous infusion controlled by target-controlled infusion pump (Diprifusor®). The parameters compared between the examinations were: AHI (apnea-hypopnea index), AI (apnea index), HI (hypopnea index) and both minimal and mean oxihemoglobin saturation (SaO2). Besides these parameters the sites of upper airway obstruction found in DISE were compared with those found in awake outpatient evaluation. Results: REM sleep was not achieved in any moment, in any patient, when propofol was infused. The AHI, AI and HI during infusion with propofol showed no statistical difference when compared with both diurnal test without propofol and diagnostic nocturnal PSG. Mean SaO2 showed statistical difference between the 3 tests, being lower in PSG with sleep induction with propofol, both for the exam without sedation (p<0.0001) as for and the diagnostic PSG (p=0.004). Minimum SaO2 was similar between examinations with sedation and diagnostic nocturnal PSG, but it was significantly lower in tests with propofol infusion compared with the diurnal exam without sedation (p=0,011). Mean difference, when significant, was about 2 to 3%. The analysis of agreement for the VOTE classification by patient evaluation and DISE showed no agreement in any measured structure (kappa = -0.029 for velum, 0,1 for oropharynx, 0,16 for tongue base and 0,0 for epiglottis). The results demonstrate that although propofol influences sleep architecture, abolishing REM sleep, the main respiratory parameters remained unchanged in patients with REMOSAS. Conclusions: Thus, target-controlled infusion of propofol is a safe method for endoscopic evaluation of patients with REM-OSAS, in order to determine the sites of obstruction, and it adds important information for proper treatment. Yet, PSG during DISE with propofol was related to manteinance of the most important ventilatory parameters when compared with PSG under spontaneous sleep.

La pancréatite, qui désigne l’inflammation du pancréas, est une condition grave qui survient lorsque les enzymes pancréatiques, servant normalement à la digestion des aliments, digèrent le pancréas. Les causes les plus fréquentes sont la consommation excessive d’alcool et la migration de lithiases vésiculaires dans les voies biliaires. On reconnait également des formes moins fréquentes qui contribuent au fardeau de la maladie et la pancréatite induite par un médicament est l’une d’entre elles. En cours d’hospitalisation et lors du suivi, cette étiologie cause des difficultés aux médecins et aux pharmaciens qui doivent travailler de concert pour d’abord la diagnostiquer, mais également identifier le médicament déclencheur afin d’éviter la récurrence. Néanmoins, cette identification se voit complexifiée, dû à un manque de données probantes fiables et récentes concernant d’une part l’épidémiologie, mais aussi l’étiologie de cette condition. L’objectif principal de ce projet est d’étudier les cas de pancréatites aiguës médicamenteuses hospitalisés au Centre intégré universitaire de santé et services sociaux du Saguenay–Lac-Saint-Jean afin d'obtenir un portrait réel de cette étiologie en plus d’ajouter de nouvelles preuves à la littérature. La méthodologie repose sur la révision des dossiers médicaux des cas hospitalisés pour au moins une pancréatite médicamenteuse dans les six hôpitaux du Saguenay–Lac-Saint-Jean entre 2006 et 2014. Les données recueillies et leurs analyses ont permis de documenter les médicaments ayant causé une pancréatite aiguë médicamenteuse au Saguenay–Lac-Saint-Jean en plus de participer à l’avancement des connaissances actuelles par l’identification de médicaments non associés à la pancréatite aiguë jusqu’à maintenant. / Pancreatitis, which refers to the inflammation of the pancreas, is a serious medical condition in which the pancreatic enzymes, that normally digest food, start to digest the pancreas. The most common causes are excessive alcohol consumption and gallstone migration into the bile ducts. Less common causes also contribute to the burden of the disease and drugs are one of them. Diagnosis of drug-induced pancreatitis and identification of the triggering drug in order to avoid recurrence is a challenge to both physicians and pharmacists. Moreover, identification of the causative drug is complex due to a lack of reliable and recent evidence concerning the epidemiology and the etiology of this condition. The main objective of this project is to study drug-induced acute pancreatitis cases hospitalized at the Centre intégré universitaire de santé et services sociaux of the Saguenay–Lac-Saint-Jean in order to obtain an accurate representation of this etiology in addition to adding new evidences to the literature. The methodology relies on the review of medical records of hospitalized cases for at least one drug-induced acute pancreatitis in the six hospitals of the Saguenay–Lac-Saint-Jean between 2006 and 2014. The data collected and their analyzes document drugs involved in acute pancreatitis in the Saguenay–Lac-Saint-Jean region in addition to participating in the advancement of our current knowledge by describing drugs that had not been associated with acute pancreatitis until now.

A young man receiving high dose cytosine arabinoside (3g/m2 every 12 hours) for promyelocytic leukemia developed rapidly increasing hyperbilirubinemia and hepatorenal syndrome. The patient had been treated previously with courses of standard dose cytosine arabinoside without hepatic or renal complications. His condition rapidly deteriorated, and he required hemodialysis. The total bilirubin increased to 45.4 mg/dL, but alkaline phosphatase remained normal. Twelve days after starting chemotherapy, the patient died of hepatorenal failure. Liver necropsy revealed mild bile stasis and microvesicular steatosis. We suspect high dose cytosine arabinoside played a major role in causing impairment of bilirubin transport within the hepatocyte in this patient.