published_or_final_version / abstract / toc / Medicine / Doctoral / Doctor of Philosophy

Thesis (M.Med.Sc.)--University of Hong Kong, 2003. / Also available in print.

Introdução: Os inibidores de bomba de prótons (IBP) são medicamentos muito usados e estão indicados no tratamento de doenças pépticas. São drogas consideradas seguras, com pouca incidência de efeitos adversos. Entretanto há relatos recentes de séries de caso associando uso de IBP e deficiência de magnésio. O magnésio é um cátion de grande importância em diversos processos bioquímicos e a sua homeostase é regulada pela absorção intestinal, metabolismo ósseo e excreção renal. Objetivos: Devido ao pouco conhecimento atual em relação à associação entre hipomagnesemia e o uso crônico de IBP, o objetivo deste trabalho foi determinar a prevalência deste distúrbio eletrolítico e seus fatores associados em pacientes internados em duas equipes de Medicina Interna do Hospital de Clínicas de Porto Alegre (HCPA). Métodos: O estudo consistiu em um corte-transversal. Amostras de sangue e urina foram coletadas no período da manhã, após pelo menos 4 horas de jejum. Dados, tais como, idade, sexo, uso de IBP, hora e indicação de uso de IBP, o uso de outras medicações, e co-morbidades foram obtidos dos prontuários médicos. Pacientes com diarréia ou vômito, uso crônico de álcool, diabetes mellitus descompensado foram excluídos. Pacientes com uso crônico de laxantes, diuréticos e outras drogas relacionadas com a deficiência de magnésio, tais como a anfotericina B, aminoglicosídeos, e ciclosporina, também foram excluídos.Resultados: De setembro de 2010 a Junho de 2011 cerca de 800 pacientes foram admitidos na ala de emergência da medicina interna. Destes, 635 pacientes tinham critérios de exclusão, 14 pacientes se recusaram a participar, então 151 pacientes foram incluídos no estudo. Todos os pacientes tinham níveis normais de magnésio no soro. Não houve diferença entre a média dos níveis séricos de magnésio homens e mulheres. Não houve correlação entre a idade, níveis séricos de fósforo e potássio, com níveis séricos de magnésio. Albumina, creatinina, e cálcio foram positivamente correlacionados com níveis séricos de magnésio. Após a regressão linear múltipla, apenas os níveis séricos de albumina e creatinina foram independentemente associados com níveis séricos de magnésio. Quando a fração excrecional de Mg (FEMg) foi calculada após a exclusão dos pacientes que tinham níveis de creatinina sérica maiores que 1.3mg/dl, a média FEMg foi maior em usuários do PPI quando comparado com os outros pacientes apesar de magnésio no soro significa níveis foram semelhantes entre os grupos. Conclusão: A prevalência de hipomagnesemia foi menor do que a observada anteriormente. Isto pode ser devido aos critérios de exclusão deste estudo, que retirou pacientes com comorbidades, ou uso de drogas, comumente associados a hipomagnesemia. Os dados deste estudo mostraram que a associação entre uso IBP e hipomagnesemia é incomum, podendo ser devido a defeitos congênitos no metabolismo de magnésio, que em situações normais podem ser superados pelo organismo, mas na presença do IBP se torna evidente. Os mecanismos através dos quais esse efeito ocorre permanecem obscuros. As limitações deste estudo incluem a falta de um instrumento para medir a adesão ao uso do IBP e o tamanho da amostra. Nenhum paciente apresentou níveis baixos de magnésio, sugerindo que, para permitir o cálculo da prevalência desse efeito adverso, faz-se necessária uma amostra maior. / Background: Proton pump inhibitors (PPIs) are widely used and are indicated in the treatment of peptic diseases. They are considered safe, with low incidence of adverse effects. However there are recent reports of case series involving the use of PPI and magnesium deficiency. Magnesium is a cation of great importance in many biochemical processes and its homeostasis is regulated by intestinal absorption, bone metabolism and renal excretion. Objectives: Due to the limited knowledge regarding the association between hypomagnesemia and chronic use of PPIs, the objective of this study was to determine the prevalence of electrolyte disturbances and associated factors among hospitalized patients in two teams of Internal Medicine, Hospital de Clinicas de Porto Alegre (HCPA). Methods: A cross-sectional study was designed. Blood and urine samples were collected in the morning, after at least 4 hours of fasting. Data such as age, sex, use of PPIs, time and indication for use of PPIs, the use of other medications, and comorbidities were obtained from medical records. Patients with diarrhea or vomiting, chronic alcohol use, uncompensated diabetes mellitus were excluded. Patients with chronic use of laxatives, diuretics and other drugs related to magnesium deficiency, such as amphotericin B, aminoglycosides, and cyclosporine, were also excluded.Resultados: From September 2010 to June 2011 about 800 patients were admitted to the emergency ward of internal medicine. Of these, 635 patients had exclusion criteria, 14 patients refused to participate, so 151 patients were included in the study. All patients had normal levels of serum magnesium. There was no difference between the mean serum magnesium levels of men and women. There was no correlation between age, serum phosphorus and potassium levels with serum magnesium levels. Albumin, creatinine, and calcium were positively correlated with serum magnesium. After multiple linear regression analysis, only serum albumin and creatinine were independently associated with serum magnesium. When the fractional excretion of Mg (FEMg) was calculated after exclusion of patients who had serum creatinine greater than 1.3mg/dl, mean FEMg was higher in the PPI users compared with the non-users, although mean serum magnesium levels were similar between groups. Conclusion: The prevalence of hypomagnesemia was lower than that observed previously. This may be due to the exclusion criteria of this study that withdrew patients with comorbidities, or use of drugs, often associated with hypomagnesemia. Data from this study showed that the association between PPI use and hypomagnesemia is uncommon and may be due to defects in the metabolism of magnesium, which in normal situations can be overcome by the body but in the presence of IBP becomes evident. The mechanisms by which this effect occurs remain unclear. Limitations of this study include the lack of an instrument to measure adherence to the use of PPI and the sample size. No patient had low levels of magnesium, suggesting that, to allow the calculation of the prevalence of this adverse effect, it is necessary a larger sample.

Para avaliar o efeito do uso oral de omeprazol em ruminantes adultos saudáveis, foram utilizados cinco ovinos machos, com dois anos de idade, hígidos e providos de cânula abomasal, que ou não receberam nada (grupo controle) ou receberam omeprazol oral em pasta, na dose de 4 mg/kg de peso vivo a cada 24 horas, durante 7 dias, em delineamento experimental de cross-over, com período de 'wash-out' de 7 dias. Diariamente os animais foram avaliados clinicamente e foram realizados o hemograma, a hemogasometria venosa; a mensuração dos eletrólitos, o perfil bioquímico, a concentração de pepsinogênio e o pH abomasal, urinário e fecal. Foi realizada, no último dia do período experimental a curva de 24 horas, com intervalo de duas horas, para o pH abomasal e o pepsinogênio sérico. Não houve efeito de tratamento para as variáveis analisadas, que permaneceram dentro do intervalo fisiológico para a espécie ovina. O uso do omeprazol na dose de 4 mg/kg de peso corporal durante sete dias, apesar de não aumentar o pH abomasal, diminuiu as concentrações de cálcio iônico e de cloro séricas / To evaluate the effect of oral omeprazole in healthy adult ruminants, five male sheep, two years old, healthy and provided with abomasal cannula, were used. Either received nothing (control group) or received oral omeprazole paste in dose of 4 mg /kg body weight every 24 hours for 7 days in experimental design of cross-over, with period of 'wash-out' of 7 days. Every day the animals were evaluated clinically and were performed the blood test, venous blood gas analysis; the measurement of electrolytes, biochemical profile, the concentration of pepsinogen and abomasal pH, urinary and fecal. It was held in last day trial period to 24 hours curve with an interval of two hours for the abomasal pH and serum pepsinogen. There was no treatment effect for the variables that remained within the physiological range for the sheep. The use of omeprazole at 4 mg / kg body weight for seven days, while not increasing the pH abomasal decreased the calcium ion concentration and serum chlorine

Introdução: Os inibidores de bomba de prótons (IBP) são medicamentos muito usados e estão indicados no tratamento de doenças pépticas. São drogas consideradas seguras, com pouca incidência de efeitos adversos. Entretanto há relatos recentes de séries de caso associando uso de IBP e deficiência de magnésio. O magnésio é um cátion de grande importância em diversos processos bioquímicos e a sua homeostase é regulada pela absorção intestinal, metabolismo ósseo e excreção renal. Objetivos: Devido ao pouco conhecimento atual em relação à associação entre hipomagnesemia e o uso crônico de IBP, o objetivo deste trabalho foi determinar a prevalência deste distúrbio eletrolítico e seus fatores associados em pacientes internados em duas equipes de Medicina Interna do Hospital de Clínicas de Porto Alegre (HCPA). Métodos: O estudo consistiu em um corte-transversal. Amostras de sangue e urina foram coletadas no período da manhã, após pelo menos 4 horas de jejum. Dados, tais como, idade, sexo, uso de IBP, hora e indicação de uso de IBP, o uso de outras medicações, e co-morbidades foram obtidos dos prontuários médicos. Pacientes com diarréia ou vômito, uso crônico de álcool, diabetes mellitus descompensado foram excluídos. Pacientes com uso crônico de laxantes, diuréticos e outras drogas relacionadas com a deficiência de magnésio, tais como a anfotericina B, aminoglicosídeos, e ciclosporina, também foram excluídos.Resultados: De setembro de 2010 a Junho de 2011 cerca de 800 pacientes foram admitidos na ala de emergência da medicina interna. Destes, 635 pacientes tinham critérios de exclusão, 14 pacientes se recusaram a participar, então 151 pacientes foram incluídos no estudo. Todos os pacientes tinham níveis normais de magnésio no soro. Não houve diferença entre a média dos níveis séricos de magnésio homens e mulheres. Não houve correlação entre a idade, níveis séricos de fósforo e potássio, com níveis séricos de magnésio. Albumina, creatinina, e cálcio foram positivamente correlacionados com níveis séricos de magnésio. Após a regressão linear múltipla, apenas os níveis séricos de albumina e creatinina foram independentemente associados com níveis séricos de magnésio. Quando a fração excrecional de Mg (FEMg) foi calculada após a exclusão dos pacientes que tinham níveis de creatinina sérica maiores que 1.3mg/dl, a média FEMg foi maior em usuários do PPI quando comparado com os outros pacientes apesar de magnésio no soro significa níveis foram semelhantes entre os grupos. Conclusão: A prevalência de hipomagnesemia foi menor do que a observada anteriormente. Isto pode ser devido aos critérios de exclusão deste estudo, que retirou pacientes com comorbidades, ou uso de drogas, comumente associados a hipomagnesemia. Os dados deste estudo mostraram que a associação entre uso IBP e hipomagnesemia é incomum, podendo ser devido a defeitos congênitos no metabolismo de magnésio, que em situações normais podem ser superados pelo organismo, mas na presença do IBP se torna evidente. Os mecanismos através dos quais esse efeito ocorre permanecem obscuros. As limitações deste estudo incluem a falta de um instrumento para medir a adesão ao uso do IBP e o tamanho da amostra. Nenhum paciente apresentou níveis baixos de magnésio, sugerindo que, para permitir o cálculo da prevalência desse efeito adverso, faz-se necessária uma amostra maior. / Background: Proton pump inhibitors (PPIs) are widely used and are indicated in the treatment of peptic diseases. They are considered safe, with low incidence of adverse effects. However there are recent reports of case series involving the use of PPI and magnesium deficiency. Magnesium is a cation of great importance in many biochemical processes and its homeostasis is regulated by intestinal absorption, bone metabolism and renal excretion. Objectives: Due to the limited knowledge regarding the association between hypomagnesemia and chronic use of PPIs, the objective of this study was to determine the prevalence of electrolyte disturbances and associated factors among hospitalized patients in two teams of Internal Medicine, Hospital de Clinicas de Porto Alegre (HCPA). Methods: A cross-sectional study was designed. Blood and urine samples were collected in the morning, after at least 4 hours of fasting. Data such as age, sex, use of PPIs, time and indication for use of PPIs, the use of other medications, and comorbidities were obtained from medical records. Patients with diarrhea or vomiting, chronic alcohol use, uncompensated diabetes mellitus were excluded. Patients with chronic use of laxatives, diuretics and other drugs related to magnesium deficiency, such as amphotericin B, aminoglycosides, and cyclosporine, were also excluded.Resultados: From September 2010 to June 2011 about 800 patients were admitted to the emergency ward of internal medicine. Of these, 635 patients had exclusion criteria, 14 patients refused to participate, so 151 patients were included in the study. All patients had normal levels of serum magnesium. There was no difference between the mean serum magnesium levels of men and women. There was no correlation between age, serum phosphorus and potassium levels with serum magnesium levels. Albumin, creatinine, and calcium were positively correlated with serum magnesium. After multiple linear regression analysis, only serum albumin and creatinine were independently associated with serum magnesium. When the fractional excretion of Mg (FEMg) was calculated after exclusion of patients who had serum creatinine greater than 1.3mg/dl, mean FEMg was higher in the PPI users compared with the non-users, although mean serum magnesium levels were similar between groups. Conclusion: The prevalence of hypomagnesemia was lower than that observed previously. This may be due to the exclusion criteria of this study that withdrew patients with comorbidities, or use of drugs, often associated with hypomagnesemia. Data from this study showed that the association between PPI use and hypomagnesemia is uncommon and may be due to defects in the metabolism of magnesium, which in normal situations can be overcome by the body but in the presence of IBP becomes evident. The mechanisms by which this effect occurs remain unclear. Limitations of this study include the lack of an instrument to measure adherence to the use of PPI and the sample size. No patient had low levels of magnesium, suggesting that, to allow the calculation of the prevalence of this adverse effect, it is necessary a larger sample.

Introdução: Os inibidores de bomba de prótons (IBP) são medicamentos muito usados e estão indicados no tratamento de doenças pépticas. São drogas consideradas seguras, com pouca incidência de efeitos adversos. Entretanto há relatos recentes de séries de caso associando uso de IBP e deficiência de magnésio. O magnésio é um cátion de grande importância em diversos processos bioquímicos e a sua homeostase é regulada pela absorção intestinal, metabolismo ósseo e excreção renal. Objetivos: Devido ao pouco conhecimento atual em relação à associação entre hipomagnesemia e o uso crônico de IBP, o objetivo deste trabalho foi determinar a prevalência deste distúrbio eletrolítico e seus fatores associados em pacientes internados em duas equipes de Medicina Interna do Hospital de Clínicas de Porto Alegre (HCPA). Métodos: O estudo consistiu em um corte-transversal. Amostras de sangue e urina foram coletadas no período da manhã, após pelo menos 4 horas de jejum. Dados, tais como, idade, sexo, uso de IBP, hora e indicação de uso de IBP, o uso de outras medicações, e co-morbidades foram obtidos dos prontuários médicos. Pacientes com diarréia ou vômito, uso crônico de álcool, diabetes mellitus descompensado foram excluídos. Pacientes com uso crônico de laxantes, diuréticos e outras drogas relacionadas com a deficiência de magnésio, tais como a anfotericina B, aminoglicosídeos, e ciclosporina, também foram excluídos.Resultados: De setembro de 2010 a Junho de 2011 cerca de 800 pacientes foram admitidos na ala de emergência da medicina interna. Destes, 635 pacientes tinham critérios de exclusão, 14 pacientes se recusaram a participar, então 151 pacientes foram incluídos no estudo. Todos os pacientes tinham níveis normais de magnésio no soro. Não houve diferença entre a média dos níveis séricos de magnésio homens e mulheres. Não houve correlação entre a idade, níveis séricos de fósforo e potássio, com níveis séricos de magnésio. Albumina, creatinina, e cálcio foram positivamente correlacionados com níveis séricos de magnésio. Após a regressão linear múltipla, apenas os níveis séricos de albumina e creatinina foram independentemente associados com níveis séricos de magnésio. Quando a fração excrecional de Mg (FEMg) foi calculada após a exclusão dos pacientes que tinham níveis de creatinina sérica maiores que 1.3mg/dl, a média FEMg foi maior em usuários do PPI quando comparado com os outros pacientes apesar de magnésio no soro significa níveis foram semelhantes entre os grupos. Conclusão: A prevalência de hipomagnesemia foi menor do que a observada anteriormente. Isto pode ser devido aos critérios de exclusão deste estudo, que retirou pacientes com comorbidades, ou uso de drogas, comumente associados a hipomagnesemia. Os dados deste estudo mostraram que a associação entre uso IBP e hipomagnesemia é incomum, podendo ser devido a defeitos congênitos no metabolismo de magnésio, que em situações normais podem ser superados pelo organismo, mas na presença do IBP se torna evidente. Os mecanismos através dos quais esse efeito ocorre permanecem obscuros. As limitações deste estudo incluem a falta de um instrumento para medir a adesão ao uso do IBP e o tamanho da amostra. Nenhum paciente apresentou níveis baixos de magnésio, sugerindo que, para permitir o cálculo da prevalência desse efeito adverso, faz-se necessária uma amostra maior. / Background: Proton pump inhibitors (PPIs) are widely used and are indicated in the treatment of peptic diseases. They are considered safe, with low incidence of adverse effects. However there are recent reports of case series involving the use of PPI and magnesium deficiency. Magnesium is a cation of great importance in many biochemical processes and its homeostasis is regulated by intestinal absorption, bone metabolism and renal excretion. Objectives: Due to the limited knowledge regarding the association between hypomagnesemia and chronic use of PPIs, the objective of this study was to determine the prevalence of electrolyte disturbances and associated factors among hospitalized patients in two teams of Internal Medicine, Hospital de Clinicas de Porto Alegre (HCPA). Methods: A cross-sectional study was designed. Blood and urine samples were collected in the morning, after at least 4 hours of fasting. Data such as age, sex, use of PPIs, time and indication for use of PPIs, the use of other medications, and comorbidities were obtained from medical records. Patients with diarrhea or vomiting, chronic alcohol use, uncompensated diabetes mellitus were excluded. Patients with chronic use of laxatives, diuretics and other drugs related to magnesium deficiency, such as amphotericin B, aminoglycosides, and cyclosporine, were also excluded.Resultados: From September 2010 to June 2011 about 800 patients were admitted to the emergency ward of internal medicine. Of these, 635 patients had exclusion criteria, 14 patients refused to participate, so 151 patients were included in the study. All patients had normal levels of serum magnesium. There was no difference between the mean serum magnesium levels of men and women. There was no correlation between age, serum phosphorus and potassium levels with serum magnesium levels. Albumin, creatinine, and calcium were positively correlated with serum magnesium. After multiple linear regression analysis, only serum albumin and creatinine were independently associated with serum magnesium. When the fractional excretion of Mg (FEMg) was calculated after exclusion of patients who had serum creatinine greater than 1.3mg/dl, mean FEMg was higher in the PPI users compared with the non-users, although mean serum magnesium levels were similar between groups. Conclusion: The prevalence of hypomagnesemia was lower than that observed previously. This may be due to the exclusion criteria of this study that withdrew patients with comorbidities, or use of drugs, often associated with hypomagnesemia. Data from this study showed that the association between PPI use and hypomagnesemia is uncommon and may be due to defects in the metabolism of magnesium, which in normal situations can be overcome by the body but in the presence of IBP becomes evident. The mechanisms by which this effect occurs remain unclear. Limitations of this study include the lack of an instrument to measure adherence to the use of PPI and the sample size. No patient had low levels of magnesium, suggesting that, to allow the calculation of the prevalence of this adverse effect, it is necessary a larger sample.

Study Objective: To compare the rates and severity of hospital-acquired Clostridium difficile infection (CDI) among patients taking proton pump inhibitors (PPIs) versus those not taking PPIs. Design: Retrospective, single-center, cohort study. Setting: Tertiary community hospital with a teaching service. Patients: A total of 41,663 patients with CDI who were hospitalized between January 2013 and May 2014; of those, 17,471 patients (41.9%) had received at least one dose of a PPI (PPI group), and 24,192 patients (58.1%) had no PPI exposure (control group). Measurements and Main Results: A total of 348 patients had CDI during the study period, with 269 cases present on admission. Hospital-acquired CDI was defined as CDI diagnosis occurring on or after the third calendar day of admission. After excluding those patients with CDI on admission, 65 (0.38%) of 17,302 patients later developed CDI in the hospital in the PPI group compared with only 14 (0.058%) of 24,092 patients in the control group. Of these patients, 36 patients (0.21%) in the PPI group met the definition of severe CDI compared with 8 (0.03%) in the control group. This demonstrated an unadjusted relative risk (RR) of 6.46 (95% confidence interval [CI] 3.63–11.51, p<0.0001) of developing hospital-acquired CDI and an unadjusted RR of 6.27 (95% CI 2.91–13.48, p<0.0001) of developing severe CDI while taking a PPI. When evaluating only patients who developed severe-complicated CDI, there were 22 cases in the PPI group and 2 cases in the control group, demonstrating an unadjusted RR of 15.3 (95% CI 3.6–65.13, p=0.0002) of developing severe-complicated CDI. Confounding variables were similar between groups. Conclusion: PPI use was associated with an increase in both the rate and severity of hospital-acquired CDI.

Over half of patients with gastroesophageal reflux disease (GERD) report nocturnal symptoms. Proton pump inhibitors (PPIs) are the main medications used to treat GERD. Multichannel intraluminal impedance with pH (MII-pH) monitoring is the most sensitive method for detection and characterization of GERD. The aim of this study was to assess and compare reflux frequency in patients with refractory GERD symptoms on and off PPI therapy during the nocturnal recumbent period, as assessed by MII-pH testing. We analyzed 24-hour MII-pH studies performed in 200 patients monitored either on twice-daily (n=100) or off (n=100) PPI therapy. Demographic analysis of the on-therapy group revealed a mean age of 52 years (24-78 years) with 37% males, and the off-therapy group revealed a mean age of 49 years (18-84 years) with 40% males. All studies were interpreted to assess and characterize the number of acid and nonacid reflux episodes in the nocturnal recumbent period identified by each patient on an overnight recorder (Zephyr, Sandhill Scientific, Inc., Highlands Ranch, CO, USA). The nocturnal recumbent period was the period documented by patients during which they lie in the recumbent period at night to sleep with average periods lasting 456 and 453 minutes for patients on and off PPI therapy. There were more mean recumbent reflux episodes in the on-therapy group in comparison with the off-therapy group (3.76 mean reflux episodes [mre] per patient in the recumbent vs. 2.82 mre); the difference was not statistically significant (P=0.187). When the reflux events are classified into acid and non-acid reflux episodes, the relative occurrence of acid reflux events is less in the on-therapy group (P=0.047), while the off-therapy group have fewer nonacid reflux episodes (P=0.003). PPIs decrease the acidity of esophageal refluxate but do not decrease the relative frequency of reflux episodes in the recumbent position in patients with refractory GERD despite twice-a-day treatment with PPI therapy. The explanation for the finding of numerically increased, although not statistically significant, amount of reflux episodes in the PPI treatment group in this study, and previous studies is unclear and warrants further evaluation.

IUPUI / Fatty acid synthase (FASN) over-expression has been associated with poor prognosis and recurrence in cancer patients. In addition, it has also been found that overexpression of FASN causes resistance to DNA-damaging treatments by up-regulating the non-homologous end joining (NHEJ) repair of DNA double-strand break. Proton pump inhibitors (PPIs), were originally designed to decrease gastric acid production by binding irreversibly with gastric hydrogen potassium ATPase. PPIs have recently been reported to reduce drug resistance in cancer cells when used in combination with other chemotherapeutics, although the mechanism of resistance reduction is uncertain. In our lab, previous investigation showed that PPIs decreased FASN thioesterase (TE) domain activity and cancer cell proliferation in a dose-dependent manner. In this study, I tested the hypothesis that PPIs sensitize breast cancer cells to doxorubicin and ionizing radiation (IR) treatments by inhibiting FASN. When administered to breast cancer cells as single-agent, lansoprazole exhibited the highest potency in inhibiting both FASN activity and breast cancer cell proliferation, among four PPIs tested. In addition, treatment of breast cancer cells with lansoprazole decreased the mRNA and protein levels of poly (ADP-ribose) polymerase-1 (PARP-1) and NHEJ activity, accompanied by elevated γ-H2AX expression. Following a 3-day treatment with lansoprazole, a dose-dependent disruption in cell cycle disruption and increased apoptosis were also detected. Combination of lansoprazole with either doxorubicin or IR caused profoundly higher levels of DNA damage accumulation than doxorubicin or IR treatment alone, suggesting synergistic effects. Taken together, our observations suggest that PPIs synergistically suppress breast cancer cells in combination with DNA damaging treatments by inhibiting FASN. These findings may provide a potential route to overcome resistance to DNA-damaging chemo/radiation treatments in refractory breast cancers.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第19277号 / 社医博第68号 / 新制||社医||9(附属図書館) / 32279 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 松原 和夫, 教授 今中 雄一, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM