Introdução: A acromegalia é uma doença crônica geralmente causada por adenoma hipofisário produtor de hormônio do crescimento (GH). Os pacientes com acromegalia são expostos a altos níveis de GH e do fator de crescimento semelhante à insulina 1 (IGF-1) e têm risco aumentado de doenças cardiovasculares. Os distúrbios respiratórios do sono, caracterizados por apneia obstrutiva do sono (AOS) e apneia central (AC), são comuns nos pacientes com acromegalia. Os distúrbios respiratórios do sono causam hipóxia intermitente e sono fragmentado e são fatores de risco para pior prognóstico cardiovascular. No entanto, não está claro se os distúrbios respiratórios do sono contribuem para pior desfecho cardiovascular entre pacientes com acromegalia. Objetivo: Elucidar a contribuição dos distúrbios respiratórios do sono na gênese de doenças cardiovasculares em pacientes com acromegalia. Neste contexto foram realizados dois estudos, um estudo transversal (Estudo I) e um estudo de intervenção (Estudo II) que serão descritos a seguir. Método: Estudo I: Foram avaliados pacientes consecutivos com diagnóstico confirmado de acromegalia e acompanhados no ambulatório da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram submetidos à avaliação clínica, questionário de sonolência de Epworth (ESE, escore variando entre 0 - 24), índice de qualidade de sono de Pittsburgh (PSQI, escore variando entre 0 - 21), questionário de qualidade de vida SF-36 (escore variando entre 0 - 100), polissonografia (PSG), monitorização ambulatorial da pressão arterial (MAPA), velocidade de onda de pulso (VOP), e ecocardiograma. Estudo II: Pacientes com acromegalia e AOS moderada a grave (índice de apneias hipopneias (IAH) 15 eventos/h) foram tratados por 3 meses em sequência aleatória com CPAP ou adesivo nasal. Os pacientes foram submetidos à avaliação clínica, questionários de ESE, PSQI, SF-36, questionário de satisfação do tratamento (0 - 10), MAPA, VOP, diâmetro e distensibilidade de carótida e PSG ao entrar no estudo, 3 meses e 6 meses. Resultados: Estudo I: Foram avaliados 48 pacientes (sexo masculino = 31%; idade = 52 ± 11 anos; índice de massa corpórea = 32,0 ± 5,5 Kg/m2). Vinte e nove pacientes (60,4%) apresentaram distúrbios respiratórios do sono moderado a grave (IAH 15 eventos/h) distribuídos em 23 (88%) com AOS e 6 (12%) com AC. Os pacientes com distúrbios respiratórios do sono eram mais velhos (56 ± 9 vs. 48 ± 12 anos, p= 0,018), mais obesos (33,3 ± 5,9 vs. 29,4 ± 4,0 Kg/m2, p = 0,014), apresentaram maior pressão arterial sistólica (131 ± 17 vs. 122 ± 11 mm Hg; p = 0,02) e diastólica (88 ± 14 vs. 81 ± 6 mm Hg, p = 0,02), maior diâmetro da carótida (7244 (6646 - 7685) vs. 6795 (6072 - 7341) m, p = 0,03), menor distensibilidade carotídea (5,01 ± 1,80 vs. 6,32 ± 2,16 m, p = 0,04) e pior qualidade de sono (9 (6 - 14) vs. 6 (5 - 8), p = 0,005) do que pacientes sem distúrbios respiratórios do sono. A presença de distúrbios respiratórios do sono se associou de forma independente com maior idade (p = 0,01), maior pressão arterial diastólica (p = 0,04) e menor distensibilidade carotídea (p = 0,04). Estudo II: Dezessete pacientes com acromegalia e AOS moderada a grave (masculino/feminino = 9/8, idade = 54 ± 10 anos, índice de massa corpórea = 34,0 ± 5,7 Kg/m2, IAH = 49,8 ± 23,7 eventos/h, ESE = 12 ± 6, PSQI = 12 (7- 14) completaram o estudo. A média da pressão do CPAP foi de 11 ± 2 cm H2O. O CPAP foi usado em média 6 ± 2 h/noite. O uso do adesivo nasal foi utilizado em 80% das noites. O IAH diminuiu significativamente com CPAP, mas não mudou com dilatador nasal (8,1 ± 5,2 vs. 47,4 ± 25,4 eventos/h, respectivamente, p = 0,0001). Todos os sintomas subjetivos melhoraram com ambos os tratamentos, no entanto significativamente mais com CPAP do que com dilatador nasal (ESE = 5 ± 4 vs. 9 ± 7, p = 0,002; PSQI = 3 (1- 5) vs. 5 (4-10), p <0,0001; satisfação do tratamento = 9 ± 1 vs. 6 ± 3, p = 0,001, respectivamente). O tratamento da AOS com CPAP comparado com adesivo nasal não resultou em melhora significativa nos níveis de pressão arterial no período da vigília (pressão arterial sistólica = 127 ±11 vs. 129 ± 10, p = 0,23; pressão arterial diastólica = 79 ± 11 vs. 80 ± 10, p = 0,46, respectivamente) e no período do sono (pressão arterial sistólica = 120 ± 14 vs. 124 ± 15, p = 0,66; pressão arterial diastólica = 71 (66 - 82) vs. 54 (52 - 63), p = 0,54, respectivamente) avaliado pela MAPA e rigidez da arterial (VOP = 9,0 ± 1,2 vs. 9,6 ± 1,5 m/s, p = 0,69 respectivamente). Conclusão: Os distúrbios respiratórios do sono são comuns entre os pacientes com acromegalia e estão associados de forma independente com maior pressão arterial diastólica, menor distensibilidade da carótida e pior qualidade do sono. O tratamento da AOS com CPAP em pacientes com acromegalia melhora a qualidade do sono. No entanto, não existe evidência até o momento de melhora em parâmetros cardiovasculares / Introduction: Acromegaly is a chronic disease usually caused by pituitary adenoma producing growth hormone (GH). Patients with acromegaly are exposed to high levels of GH and insulin-like growth factor 1 (IGF-1) and have increased risk of cardiovascular disease. Sleep-disordered breathing, characterized by obstructive sleep apnea (OSA) and central sleep apnea (AC), are common in patients with acromegaly. Sleep-disordered breathing cause intermittent hypoxia and fragmented sleep and are risk factors for poor cardiovascular outcome among patients with acromegaly. However, it is unclear whether sleep-disordered breathing are simply a result of acromegaly contribute to worse cardiovascular outcomes in patients with acromegaly. Objective: To elucidate the contribution of sleep-disordered breathing in the genesis of cardiovascular disease in patients with acromegaly. Two studies were conducted a cross sectional study (Study I) and a interventional study (Study II). Method: Study I: We evaluated consecutive patients with a confirmed diagnosis of acromegaly of a dedicated outpatient clinic of tertiary University Hospital (Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo). Patients underwent clinical assessment questionnaire for evaluation of daytime somnolence (Epworth sleepiness - ESS score, ranging from 0 - 24), index of Pittsburgh sleep quality (PSQI score, ranging from 0 - 21), quality of life questionnaire SF-36 (score ranging from 0 - 100), polysomnography (PSG), ambulatory blood pressure (ABMP), pulse wave velocity (PWV), diameter and distensibility carotid and echocardiography. Study II: Patients with acromegaly and moderate to severe OSA (apnea index - hypopnea index (AHI) 15 events / h) were treated for 3 months in random sequence with nasal CPAP or nasal dilator strips. The patients underwent clinical evaluation, questionnaires ESS, PSQI, SF-36, treatment satisfaction questionnaire (0-10), ABMP and PWV, diameter and distensibility carotid and PSG at study entry, 3 months and 6 months. Results: Study I: We evaluated 48 patients (male = 31%, age = 52 ± 11 years, body mass index = 32.0 ± 5.5 kg/m2). Twenty-nine patients (60.4%) had moderate to severe sleep-disordered breathing (AHI 15 events / h) distributed n = 23 (88%) OSA and n = 6 (12%) CA. Patients with sleep-disordered breathing were older (56 ± 9 vs. 48 ± 12 years, p = 0.018), more obese (33.3 ± 5.9 vs. 29.4 ± 4.0 kg/m2, p = 0.014), had higher systolic blood pressure (131 ± 17 vs. 122 ± 11 mm Hg, p = 0.02) and diastolic (88 ± 14 vs. 81 ± 6 mm Hg, p = 0.02), larger Carotid diameter (7244 (6646 - 7685) vs. 6795 (6072 - 7341) m, p = 0.03), lower carotid distensibility (5.01 ± 1.80 vs. 6.32 ± 2.16 mm, p = 0.04) and worse sleep quality (9 (6 -14) vs. 6 (5 - 8) score, p = 0.005) than patients without sleep-disordered breathing. The presence of sleep-disordered breathing was independently associated with older age (p = 0.01), higher diastolic blood pressure (p = 0.04) and lower carotid distensibility (p = 0.04). Study II: Seventeen patients with acromegaly and moderate to severe OSA (male / female = 9/8, age = 54 ± 10 years, body mass index = 34.0 ± 5.7 kg/m2, AHI = 49.8 ± 23.7 events / h, SE = 12 ± 6 score, PSQI = 12 (7 - 14) score) completed the study. The average CPAP pressure was 11 ± 2 cm H2O. CPAP was used on average 6 ± 2 h / night. The use of the nasal dilator strips was used in 80% of nights. The AHI decreased significantly with CPAP, but did not change with nasal dilator (8.1 ± 5.2 vs. 47.4 ± 25.4 events / h, respectively, p = 0.0001). All subjective symptoms improved with both treatments, but significantly more than with CPAP than nasal dilator strips (ESE = 5 ± 4 vs. 9 ± 7, p = 0.002; PSQI = 3 (1 - 5) vs. 5 (4 - 10), p <0.0001; treatment satisfaction = 9 ± 1 vs. 6 ± 3, p = 0.001, respectively). Treatment of OSA with CPAP compared with nasal dilator strips did result in significant improvements in ABMP during wakefulness (systolic blood pressure = 127 ± 11 vs. 129 ± 10, p = 0.23, diastolic blood pressure = 79 ± 11 vs. 80 ± 10, p = 0.46, respectively) and during sleep (systolic blood pressure = 120 ± 14 vs. 124 ± 15, p = 0.66; diastolic blood pressure = 71 (66 - 82) vs. 54 (52 - 63), p = 0.54, respectively) measured by ABMP and arterial stiffness (PWV = 9.0 ± 1.2 vs. 9.6 ± 1.5 m / s, p = 0,69 respectively). Conclusion: Sleep-disordered breathing is independently associated with higher diastolic blood pressure and lower carotid distensibility. However, there is no evidence that treatment of OSA with CPAP in patients with acromegaly results in significant improvement in blood pressure and carotid artery distensibility.

INTRODUÇÃO: A rinite alérgica é uma condição clínica comum que apresenta sintomas diversos num significante número de pacientes, deteriorando a qualidade de vida daqueles refratários aos tratamentos usuais (anti-histamínicos e corticosteróides nasais tópicos). Apresentando princípios curativos similares, a imunoterapia sublingual e a homeopatia podem reduzir os sintomas e a necessidade de medicamentos na rinite alérgica, embora a eficácia e a efetividade de ambas terapêuticas não sejam ainda suficientemente conhecidas. OBJETIVOS: O objetivo deste estudo foi avaliar a efetividade clínica do tratamento homeopático individualizado prolongado, comparativamente ao placebo, em adultos portadores de rinite alérgica perene. MÉTODOS: Um total de 41 pacientes com rinite alérgica perene foi alocado numa primeira fase duplo-cego e placebo-controlada durante seis meses, sendo tratada com doses sublinguais semanais de medicamentos homeopáticos individualizados ou placebo. Após esta fase inicial fechada, todos os pacientes foram convidados a participar de uma segunda fase controlada aberta, em que receberiam tratamento homeopático pelo período máximo de 36 meses, e os resultados foram comparados com a melhora da fase inicial. O escore dos sinais e sintomas, a necessidade de medicamentos de resgate e a qualidade de vida foram mensurados por questionários e avaliações clínicas pessoais, aplicadas por um mesmo avaliador independente, antes e após cada fase. As doses dos medicamentos homeopáticos e de resgate utilizados, assim como os efeitos colaterais, foram documentados num diário pessoal. Os desfechos clínicos primário e secundários foram, respectivamente, os escores dos sinais e sintomas alérgicos específicos e gerais. Títulos da IgE total foram mensurados antes e após cada fase. RESULTADOS: Após os seis meses da fase placebo-controlada inicial, na análise por protocolo de todos os pacientes incluídos no estudo, não foram observadas diferenças significativas entre os grupos ativo e placebo nos escores clínicos, na utilização de drogas de resgate, na qualidade de vida e nos títulos da IgE total. Entretanto, as análises dos subgrupos da segunda fase mostraram uma crescente e significativa melhora nos desfechos clínicos primário e secundários após 12 meses de tratamento homeopático individualizado, comparativamente à variação de melhora dos mesmos pacientes na fase inicial fechada. Diferença significativa na qualidade de vida foi observada apenas após o segundo ano de tratamento homeopático. CONCLUSÃO: Neste estudo, o tratamento homeopático foi acompanhado de um significante efeito placebo. A efetividade da homeopatia pôde ser observada após 12 meses da terapêutica, apresentando efeito preventivo de longa duração após 36 meses de tratamento homeopático individualizado. / INTRODUCTION: Allergic rhinitis is a common clinical condition which presented several symptoms in a significant number of patients, deteriorating the quality of life in those resistant to the usual treatments (antihistamines and topical nasal corticosteroids). Presenting similar curative principles, sublingual immunotherapy and homeopathy can reduce symptoms and medication requirements in allergic rhinitis, although the efficacy and effectiveness of both therapeutics are not still sufficiently known. OBJECTIVES: The objective of this study was to evaluate clinical effectiveness of prolonged individualized homeopathic treatment, compared with placebo, in adults with perennial allergic rhinitis. METHODS: A total of 41 adults with perennial allergic rhinitis were enrolled in a first double-blind placebo-controlled phase for six months, and treated on a weekly basis with sublingual doses of single individualized homeopathic medicines or placebo. After this closed initial phase, all patients were invited to participate in an open label controlled phase, in that they would receive homeopathic treatment for the maximum period of 36 months, and the results were compared with the improvement of the initial phase. Signs and symptoms scores, rescue medication requirements and quality of life were assessed by questionnaires and personal clinical evaluation by a same independent researcher, before and after each phase. Applied homeopathic and rescue drugs dosage, and side effects were documented by diary cards. Primary and secondary clinical outcome were, respectively, specific and general allergic signs and symptoms scores. Total IgE titles were performed before and after each phase. RESULTS: After six months of placebo-controlled phase, analyzing all patients included in the study per protocol, we observed no significant difference between treatment and placebo groups in primary and secondary clinical outcomes, use of rescue drugs, quality of life and total IgE. However, second phase subgroups analysis showed a significant and growing improvement of clinical symptoms after 12 months of individualized homeopathic treatment, comparatively to the same patients\' variation in closed initial phase. Significant difference in quality of life score were observed only after second homeopathic treatment year. CONCLUSION: In this study, homeopathic treatment was accompanied by a significant placebo effect. Effectiveness of homeopathy could be seen after 12 months of therapy, presenting preventive effect of long duration after 36 months of individualized homeopathic treatment.

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Vilken arbetsmiljö möter vi som konstnärer? Vad får våra kroppar hantera? I mitt konstnärliga utforskande har jag intresserat mig för de risker vi utsätter oss för i vår arbetsmiljö på Konstfack. Vardagen i verkstäderna för med sig många exempel på de utmaningar våra kroppar ställs inför.  Vi testar gärna nya tekniker, nya material, plaster och kemikalier med främmande egenskaper att förhålla sig till. Kroppen, materialet och arbetsmiljön har varit centralt närvarande i min process, men kanske framför allt frågan om varför vi så gärna bortser från de risker vi utsätter oss för. Hur hanterar vi vetskapen om hoten på ett psykologiskt plan?  Genom skulptur, hantverkstekniker och materialval har jag undersökt det luftburna hotet, ett ämne som lämnar utrymme för subjektivitet. Det är idén av ett hot, något abstrakt och osynligt, ibland förnimbart, ibland inte. Vad vi väljer att tro på kan i vissa fall ha större effekt än den faktiska materiella inverkan på våra kroppar. Något som länge ansetts vara helande kan plötsligt ses som skadligt – en dualitet som jag gett uttryck för i min gestaltning. Den mångbottnade upplevelsen av dessa hot har en förmåga att påverka varje del av våra liv. För att ge en upplevelse av kontroll och avdramatisera kroppens sårbarhet skapar vi undermedvetet nya beteendemönster, eller förändrar hela vår verklighetsuppfattning. Men vad händer om vi förlikar oss med det som rör sig i det undermedvetna? Kan vi internalisera vetskapen om kroppens sårbarhet? / What work environment do we encounter as artists? What can our bodies handle? In my artistic exploration, I have taken an interest in the risks we expose ourselves to in our work environment at Konstfack. Everyday life in the workshops brings many examples of the challenges our bodies face. We like to test new technologies, new materials, plastics, and chemicals with strange new properties to deal with. The body, the material, and the work environment have been central in my process, but perhaps above all the question of why we are so happy to ignore the risks we expose ourselves to. How do we deal with the knowledge of these threats on a psychological level? Through sculptural techniques and choice of materials, I have explored the airborne threat, a subject that leaves room for subjectivity. It is the idea of a threat, something abstract and invisible, sometimes tangible, sometimes not. What we choose to believe in can in some cases have a more significant effect than the actual material impact on our bodies. Something that has long been considered healing can suddenly be seen as harmful – a duality that I have expressed in my artistic exploration. The multifaceted experience of these threats has the ability to affect every part of our lives. To give an experience of control, and downplay the subconscious presence of the body's vulnerability we create new behavior patterns or change our entire perception of reality. But what happens if we come to terms with what moves in the subconscious? Can we internalize the knowledge of the body's vulnerability?

Placebo response, an apparent improvement in the clinical condition of patients randomly assigned to the placebo treatment, is a major issue in clinical trials on psychiatric and pain disorders. Properly addressing the placebo response is critical to an accurate assessment of the efficacy of a therapeutic agent. The Sequential Parallel Comparison Design (SPCD) is one approach for addressing the placebo response. A SPCD trial runs in two stages, re-randomizing placebo patients in the second stage. Analysis pools the data from both stages. In this thesis, we propose a Bayesian approach for analyzing SPCD data. Our primary proposed model overcomes some of the limitations of existing methods and offers greater flexibility in performing the analysis. We find that our model is either on par or, under certain conditions, better, in preserving the type I error and minimizing mean square error than existing methods. We further develop our model in two ways. First, through prior specification we provide three approaches to model the relationship between the treatment effects from the two stages, as opposed to arbitrarily specifying the relationship as was done in previous studies. Under proper specification these approaches have greater statistical power than the initial analysis and give accurate estimates of this relationship. Second, we revise the model to treat the placebo response as a continuous rather than a binary characteristic. The binary classification, which groups patients into “placebo-responders” or “placebo non-responders”, can lead to misclassification, which can adversely impact the estimate of the treatment effect. As an alternative, we propose to view the placebo response in each patient as an unknown continuous characteristic. This characteristic is estimated and then used to measure the contribution (or the weight) of each patient to the treatment effect. Building upon this idea, we propose two different models which weight the contribution of placebo patients to the estimated second stage treatment effect. We show that this method is more robust against the potential misclassification of responders than previous methods. We demonstrate our methodology using data from the ADAPT-A SPCD trial.

Orientador: Thais Borges Cesar / Banca: Camila Cremonezi Japur / Banca: Caroline Dário Capitani / Banca: Thábata Koester Weber / Banca: Katia Sivieri / Resumo: Objetivo: Foi avaliar os efeitos da suplementação de flavonoides cítricos nos parâmetros bioquímicos, inflamatórios e metabólicos de indivíduos pré-diabéticos durante 12 semanas. Métodos: 103 indivíduos pré-diabéticos (49 ± 10 anos) foram divididos aleatoriamente em quatro grupos paralelos: (1) Placebo: 25 indivíduos receberam dose diária de 400 mg de placebo; (2) Eriomin 200 mg: 26 indivíduos receberam dose diária de 200 mg de Eriomin; (3) Eriomin 400 mg: 27 indivíduos receberam dose diária de 400 mg de Eriomin; (4) Eriomin 800 mg: 25 indivíduos receberam dose diária de 800 mg de Eriomin. Eriomin® é um bioflavonoide cítrico, composto por principalmente por eriocitrina, hesperidina, naringenina e didimina. A avaliação da composição corporal, dos marcadores bioquímicos, inflamatórios, metabólicos, renais, hepáticos e do consumo alimentar foram analisados ao longo de 12 semanas. Resultados: O tratamento após 12 semanas com todas as doses de Eriomin (200, 400, 800 mg) mostrou redução similar nos níveis de glicemia (-5%, p ≤ 0,001), HbA1c (-2%, p < 0,05), HOMA-IR (-7%, p < 0,05), glicemia 2 horas (-7%, p < 0,05), glucagon (-6.5%, p < 0,001), peptídeo C (-5%, p < 0,001), PCRus (-12%, p <0,05), IL-6 (-13%, p = 0,03), TNF-α (-11%, p = 0,04), peroxidação lipídica (-17%, p < 0,01) e pressão arterial sistólica (-8%, p < 0,05), e aumento nos níveis de GLP-1 (+15%, p< 0.001), adiponectina (+19%, p < 0,05) e capacidade antioxidante (6%, p = 0,03). Conclusão: A suplementação com Eriomin po... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objective: To evaluate the effects of citrus flavonoid supplementation on the biochemical, inflammatory and metabolic parameters of pre-diabetic subjects for 12 weeks. Methods: 103 pre-diabetic subjects (49 ± 10 years) were randomly divided into four parallel groups: (1) Placebo: 25 subjects received a daily dose of 400 mg placebo; (2) Eriomin 200 mg: 26 subjects received 200 mg daily dose of Eriomin; (3) Eriomin 400 mg: 27 subjects received 400 mg daily dose of Eriomin; (4) Eriomin 800 mg: 25 subjects received a daily dose of 800 mg Eriomin. Eriomin® is a citric bioflavonoid composed of eriocitrin, hesperidin, naringenin and didymin. Evaluation of body composition, biochemical, inflammatory, metabolic, renal, hepatic and food markers were analyzed during 12 weeks of intervention. Results: Treatment with all doses of Eriomin (200, 400, 800 mg) after 12 weeks showed similar reduction in glycemia levels (-5%, p ≤ 0.001), HbA1c (-2%, p <0.05) (-7%, p <0.05), glycemia 2 hours (-7%, p <0.05), glucagon (-6.5%, p <0.001), peptide C (-5%, p (-12%, p <0.05), IL-6 (-13%, p = 0.03), TNF-α (-11%, p = 0.04), lipid peroxidation (P <0.01), and systolic blood pressure (-8%, p <0.05), and increased GLP-1 (+ 15%, p <0.001), adiponectin (+ p <0.05) and antioxidant capacity (6%, p = 0.03). Conclusion: Supplementation with Eriomin for 12 weeks in pre-diabetic individuals improved the biochemical, inflammatory and metabolic parameters that constitute the risk factors for the development of type 2 ... (Complete abstract click electronic access below) / Doutor

Medicine has been called a science, as well as an art or a craft, among other terms that express aspects of its practical nature. Medicine is not the abstract pursuit of knowledge. Medical researchers and clinical practitioners aim primarily to help people. As a first approximation then, given its practical focus on the person, the most important question in medicine is: what works? To answer that question, however, we need to understand how we know what works. What are the standards, methods and limits of medical knowledge? That is the central focus and subject of this inquiry: how we know what works in medicine. To explore medical knowledge and its limits, this thesis examines the common notion that laughter is the best medicine. Focusing on laughter provides a robust case study of how we know what works in medicine; it also, in part, reveals the thin, perhaps even non-existent, distinction in medicine between empirically-grounded knowledge and intuition. As there is no single academic discipline devoted to laughter in medicine, the first chapter situates and charts the course of this unusual project and explains why inquiry into laughter in medicine matters. In the following chapters, we encounter claims from distinguished sources that laughter and humor are the best medicine. These claims are examined from a variety of perspectives including not only the orthodox view of evidence-based medicine, but also from narrative, evolutionary and complexity views of medicine. The rarely explored serious negative side of laughter is also examined. No view provides a firm foundation for belief in laughter medicine. A general conclusion from this inquiry is that none of the approaches effectively tame the complexity of medical phenomena; indeed each starkly reveals a greater complexity than found at first glance. A narrower conclusion is that providing a basis for claims about laughter in medicine poses its own specific challenges. A third conclusion is that, as things stand, none of the existing approaches seems up to the task of determining whether something such as laughter is the best medicine.

Medicine has been called a science, as well as an art or a craft, among other terms that express aspects of its practical nature. Medicine is not the abstract pursuit of knowledge. Medical researchers and clinical practitioners aim primarily to help people. As a first approximation then, given its practical focus on the person, the most important question in medicine is: what works? To answer that question, however, we need to understand how we know what works. What are the standards, methods and limits of medical knowledge? That is the central focus and subject of this inquiry: how we know what works in medicine. To explore medical knowledge and its limits, this thesis examines the common notion that laughter is the best medicine. Focusing on laughter provides a robust case study of how we know what works in medicine; it also, in part, reveals the thin, perhaps even non-existent, distinction in medicine between empirically-grounded knowledge and intuition. As there is no single academic discipline devoted to laughter in medicine, the first chapter situates and charts the course of this unusual project and explains why inquiry into laughter in medicine matters. In the following chapters, we encounter claims from distinguished sources that laughter and humor are the best medicine. These claims are examined from a variety of perspectives including not only the orthodox view of evidence-based medicine, but also from narrative, evolutionary and complexity views of medicine. The rarely explored serious negative side of laughter is also examined. No view provides a firm foundation for belief in laughter medicine. A general conclusion from this inquiry is that none of the approaches effectively tame the complexity of medical phenomena; indeed each starkly reveals a greater complexity than found at first glance. A narrower conclusion is that providing a basis for claims about laughter in medicine poses its own specific challenges. A third conclusion is that, as things stand, none of the existing approaches seems up to the task of determining whether something such as laughter is the best medicine.

Introduction: Several studies have used sham acupuncture methods in recent years as a way of masking to test the real effect of real acupuncture, however the placebo method selection has not followed methodological criteria to create a consensus on what the best option to use. This study aimed to evaluate the effectiveness of three placebo acupuncture methods for masking applied in healthy subjects and observe the effect of the types of placebo and real acupuncture in the skin and deep sensitivity threshold. Methods: 321 healthy volunteers were randomly divided into seven groups using the ST25 point (abdominal) to puncture, and seven groups using the BL52 point (lumbar), real acupuncture was applied and three different methods of placebo acupuncture, It was also mixed real acupuncture and sham acupuncture in the same person, totaling fourteen groups, evaluations of skin and deep sensitivity and the questionnaire were performed before and immediately after applying the technique by the investigator who was unaware of the technique had been applied. Results: The question that asked if the volunteer believed received real acupuncture or placebo showed no significant result, the percentage of subjects who reported believe that having received real acupuncture in the ST25 point was 69.56% in real group, 86.95% group Park Sham, 82.60% needle + foam, 91.30% insertion and removal, 78.26% real + Park Sham, 86.36% + real needle and foam and 86.95% + real insertion and removal and at the point BL52 was 86.36% in real group, 86.95% group Park Sham, 69.56% needle + foam, 72% insertion and removal, 86.95% real + Park Sham, 81.81% real and needle + foam and 78.26% real + insertion and removal. The skin sensitivity threshold showed no statistical difference in the intragroup analysis and in the comparison between groups, the pressure pain threshold showed a decrease in the value after the technique of application only at the real group BL52 (p = 0.044) and insert and removal BL52 (p = 0.037) for intragroup analysis and showed a statistical difference between groups real group ST25 compared with Park Sham BL52 (p <0.05) and Real in BL52 compared with insertion and removal at the point BL52 (p <0.05). Conclusion: placebo acupuncture groups used are effective in masking acupuncture research, and none of the placebo methods demonstrated have greater advantage for use in clinical trials. The skin sensitivity threshold remains unchanged after applying acupuncture or placebo, but these techniques influence the pressure pain threshold. / Introdução: Diversos estudos têm utilizado métodos de acupuntura placebo nos últimos anos como forma de mascaramento para testar o efeito terapêutico da acupuntura real, entretanto a seleção do dispositivo placebo não tem seguido critérios metodologicos a ponto de se criar um consenso de qual seria o melhor método para se utilizar. O presente estudo objetivou averiguar se técnicas de acupuntura placebo são indistinguíveis entre si e da acupuntura real. Métodos: Foram incluídos 321 voluntários saudáveis, os quais foram divididos aleatoriamente em sete grupos que utilizaram o ponto E25 (abdominal) e sete grupos que utilizaram o ponto B52 (lombar) para puntura. Foi aplicado acupuntura real, três métodos diferentes de acupuntura placebo além da mescla entre acupuntura real e placebo em um mesmo individuo, totalizando 14 grupos. As avaliações da sensibilidade cutânea e profunda assim como a aplicação do questionário foram realizadas antes e imediatamente após a aplicação da técnica por investigador cego quanto a técnica que tinha sido aplicada. Resultados: A maioria dos sujeitos referiram que tinham recebido acupuntura real em todos os grupos, porém não houve diferença significativa quanto à percepção de que estavam recebendo acupuntura real ou placebo entre os grupos. O percentual de sujeitos que informaram acreditar ter recebido acupuntura real no ponto E25 foi de 69,56% no grupo real, 86,95% no grupo Park Sham, 82,60% no agulha + espuma, 91,30% na inserção e retirada, 78,26% no grupo real + Park Sham, 86,36% no real + agulha e espuma e 86,95% no real + inserção e retirada, no ponto B52 foi de 86,36% no grupo real, 86,95% no grupo Park Sham, 69,56% no agulha + espuma, 72% na inserção e retirada, 86,95% no real + Park Sham, 81,81% no grupo real + agulha e espuma e 78,26% no real + inserção e retirada. O limiar de sensibilidade cutânea não apresentou diferença estatística na análise intragrupo e também na comparação entre os grupos estudados, o limiar de dor por pressão apresentou uma diminuição dos valores após a aplicação da técnica apenas no grupo Real B52 (p = 0,044) e inserção e retirada (p = 0,037) para análise intragrupo e na comparação entre os grupos houve diferença estatística para o redução do limiar de dor entre o grupo Real E25 comparado com Park Sham B52 (p < 0,05) e Real no B52 comparado com inserção e retirada no ponto B52 (p < 0,05). Conclusão: Todos os métodos de acupuntura placebo utilizados são igualmente eficazes para mascaramento dos sujeitos de pesquisa que são punturados em distintos pontos corporais, e nenhum dos métodos placebo apresentou vantagem em relação aos demais para utilização em futuros ensaios clínicos. O limiar de sensibilidade cutânea não sofre alteração após a aplicação de acupuntura ou placebo, porém as técnicas Real E25 e Real B52 podem favorecer alteração do limiar de dor por pressão.

Many dieters and compulsive overeaters report that sugar and chocolate are the most commonly craved foods. Further, many individuals have proclaimed themselves to be "addicted" to sugar or chocolate. It remains unclear, however, what factors lead to report of specific food addictions. A number of researchers have suggested that highly repetitive consumption of sugar and chocolate may result from various physiological processes (e.g., neurochemical imbalances, glucose/insulin malfunctioning). However, there is also considerable evidence that psychosocial factors (i.e., expectancies, classical, and operant conditioning) play the major role in the development and maintenance of excessive sugar,chocolate intake. Empirical studies examining factors that underlie this behavior are almost nonexistent. Therefore, it is useful for researchers to explore perspectives about the causes of addictive or compulsive behavior. This study addressed the question, "Are adverse eating symptoms/outcomes for women who believe they are addicted to sugar or chocolate explained primarily by learning factors or by the key chemical constituents in these foods?" This study involved procedures that influenced subjects' perceptions and expectations about the sugar/chocolate content of a beverage (i.e., real chocolate, sugar versus synthetic substitute [placebo]) in a laboratory taste test situation. In an ABAB experimental design, self-avowed addict and control subjects were tested on four consecutive days receiving two chocolate/sugar (A) and two placebo (B) beverages. Changes in mood and food cravings were measured, as was an index of perceived eating dyscontrol following the consumption of beverages. In addition to establishing a baseline measure each day, subjects' mood and cravings were assessed immediately after consumption of chocolate or placebo as well as 45 minutes later. The responses (mood, food cravings, food intake) that occurred after exposure to drinks containing placebo or sugar/chocolate suggested that subjects do not always respond in the manner they purport to (e.g., increased cravings, mood improvement, subsequent overeating of treats). Other factors such as learning and conditioning may play a key role in accounting for their report of excessive behavior. Specifically, individuals who believe they are addicted to sugar or chocolate evidence similar responses and symptoms irrespective of wether they consumed a placebo versus sugar or chocolate.