Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Introduction The main aim of this study is to present a complex review comprising etiological factors, diagnostic options and therapeutic methods related to globus pharyngeus, a persistent or intermittent sensation of a lump or foreign body in the throat. The second purpose is to investigate the reciprocal relationship between motor control with musculoskeletal system and pressure changes in the esophagus, especially in the upper esophageal sphincter. Methods 37 patients participated in the study. 24 of them suffered globus pharyngeus and 13 were patients with GERD but without the symptoms of globus pharyngeus. Because of the complex physiology of esophageal function and the inability of conventional manometry to fully describe this complexity, we found High-Resolution Manometry as a useful device for accomlishing the referred task. Patients were examined in four different postural situations which had to be modified when the attitude wasn't tolerated. The examination was followed by manual physiotherapy and exercises targeted to influence postural alignment. 10 patients with globus pharyngeus who agreed with a control manometry examination were familiarized with the results as a form of biofeedback. Results On the basis of the results of this research, it can be concluded that a high pressure...

Die optimale Versorgung von Hiatushernien wird zurzeit viel diskutiert. Vor diesem Hintergrund sollten die Ergebnisse der operativen Versorgung von Patienten mit großen Hiatushernien an der chirurgischen Universitätsklinik Würzburg analysiert werden. Von Januar 2001 bis September 2007 wurden 141 Patienten an einer Hiatushernie operiert, die die Einschlusskriterien erfüllten (axiale Hiatushernie von mind. 5 cm, paraösophageale Hernie, Upside - Down - Magen, gemischte Hernie, Rezidiv einer Hernie bzw. von Refluxbeschwerden nach einer Hiatushernienoperation). Diese Patienen erhielen einen Fragebogen, der unter anderem neben der subjektiven Zufriedenheit gezielt gastroösophageale Beschwerden erfragt. Zudem erhielten die Patienten den Fragebogen zur Erfassung des Gastrointestinalen Lebensqualitätsindexes nach Eypasch und es wurde ihnen die Möglichkeit geboten, im gastrointestinalen Funktionslabor der Uniklinik Würzburg vorstellig zu werden. Es erschienen 25 Patienten zu einer objektiven Nachuntersuchung, wobei 10 Rezive (7,1 %) diagnostiziert wurden. Die Erstoperierten erzielten im gegensatz zu den Reoperierten deutlich bessere Werte für Zufriedenheit, aktuelles Befinden, Symptome sowie den GLQI. Bei den Rezidiven fand sich jedoch keine signifikante Häufigkeitsverteilung. Die OP-Techniken (360° - Nissen Fundoplicatio, 270° - Toupet Fundoplicatio) unterscheiden sich weder im subjektiven noch im objektiven Outcome und sind somit in unserem Kollektiv als gleichwertig anzusehen. Unter den Patienten, die eine Netzhiatoplastik erhielten, wurde ein Rezidiv (7,1%) diatnostiziert. Zu dem trat signifikant häufiger Dysphagie auf, als bei Patienten, die kein Netz im Rahmen der Hiatoplastik erhielten. Ansonsten zeigten sich keine Unterschiede in dieser Vergleichsgruppe. Somit ist davon auszugehen, dass das Netz in unserem Kollektiv keinen Vorteil bringt, und dessen restriktiver Gebrauch gerechtfertigt ist. / The proper surgical treatement of hiatal hernias is discussed a lot at present. So the aim of our study was to evaluate the results of the surgical treatement of patients suffering of a big hiatal hernia at the university hospital of Würzburg. From january 2001 to september 2007 there have been 141 patients operated on a hiatal hernia, who fulfilled one of the including criterias (axial hiatalhernia bigger than 5 cm, paraesophageal hernia, upside-down-stomach, mixed hernia, recurrence of hernia or reflux after a previous operation on hiatal hernia). Those patients received two questionnaires, one to evaluate their state of health and satisfaction, and the other to evaluate their quality of life (Eypasch). Moreover we offered the opportunity of a check-up examination at our hospital. There were 25 patients who took part of the check-up. Ten recurrent hernias (7,1%) were diagnosed among them. In comparison of the reoperated patients those, who underwent primary surgery, were more satisfied, had less symptoms and a higher grade of quality of life. But with regard to recurrences, there was no statistical differece. Concerning the various operation techniques (360° Nissen-fundoplication, 270° Toupet-fundoplication) there was no differece neither for subjective nor for objektive outcome. Sot they seem to be equal in our studies. One recurrent hiatal hernia has been diagnosed among the patients with mesh-hiatoplasty. In addition to that, a higher inzidence of dysphagia was seen in comparison to those who received a hiatoplasty with primary sutures. There were no further differences, so in our studies a mesh-hiatoplasty seems not to have any more advantages and its restricted usage is acceptable.

The UK has experienced an increase in the incidence of oesophageal adenocarcinoma (OAC) in recent years. The prognosis for patients with OAC remains poor with currently available treatments prompting a search for alternative ‘chemopreventive’ treatments that inhibit oesophageal carcinogenesis. Both non-steroidal anti-inflammatory drugs (NSAIDS) and flavonoids are associated with a significant risk reduction for developing OAC in epidemiological studies. The aim of this study was to validate Levrat’s surgical model of OAC in the rat, and assess the chemopreventive effects of the NSAID aspirin, and the flavonoid quercetin on the development of OAC in the validated rat model. METHODS: Levrat’s model was validated in a time course experiment. Morphological and molecular events occurring in the distal oesophagus during disease progression were determined and compared to human disease. The effect of aspirin and quercetin on disease initiation and progression was determined by commencing treatment either before the onset of reflux, or 4-weeks afterwards. The incidence of Barrett’s oesophagus (BO) and OAC within each group was determined, along with methylation levels of the ESR-1, p16 and HPP1 gene promoter regions. RESULTS: The morphological and molecular changes in the distal oesophagus of the rat model are broadly consistent with those reported in human disease. The incidence of OAC was significantly lower in aspirin treated rats. A non-significant reduction in incidence of OAC was observed with quercetin treatment. Timing of treatment with regard to onset of reflux had no significant effect on OAC development in either treatment group. Neither treatment significantly effected methylation levels within the gene promoters examined. CONCLUSION: Use of Levrat’s model as a model of human OAC seems justified. Aspirin inhibits development of oesophageal adenocarcinoma induced by reflux in this rat model. No additional reduction in cancer incidence is observed if treatment is commenced prior to inception of reflux disease.

Background: 20 to 30% of patients with GORD respond inadequately to conventional therapy. Most of these patients belong to the non-­‐erosive reflux disease group. Despite not having oesophagitis, in these patients oesophageal mucosal integrity appears to be impaired. Aims: To study the dynamic in vitro and in vivo properties of oesophageal mucosal integrity in patients with non-­‐erosive reflux disease, and to test the feasibility of a topical mucosal protectant therapy. Methods: In vitro studies of mucosal integrity were done on human oesophageal biopsies using Ussing chambers. Change in transepithelial electrical resistance (TER) on exposure to acidic solutions was measured. Integrity was assessed in vivo by measuring impedance change and subsequent recovery after oesophageal acid perfusion in symptomatic patients. Proximal and distal oesophageal mucosal integrity was assessed in vitro and in vivo. The effect of in vitro topical application of an alginate-­‐based solution on acid-­‐induced changes in mucosal integrity was tested. Results: In vitro exposure of biopsies to acidic and weakly acidic solutions caused a greater impairment of integrity in symptomatic patients than in controls. In vivo oesophageal acid perfusion causes a profound drop in distal oesophageal impedance that is slow to recover. Recovery is slower in patients with non-­‐erosive reClux disease than in patients with functional heartburn, and a low baseline impedance is associated with painful perception of acid. Proximal oesophageal sensitivity appears unrelated to impaired mucosal integrity, but rather to a distinct sensory afferent nerve distribution. Topical pre-­‐treatment with an alginate solution is able to prevent acid-­‐induced changes in integrity in vitro. Conclusion: Patients with non-­‐erosive reClux disease have a distinct mucosal vulnerability to acidic and weakly acidic solutions that may underlie persistent symptoms. A topical therapeutic approach may be a feasible add-­‐on strategy to treat GORD in the future.

by Wu Che-yuen Justin. / "September 2000 (amendment)." / Thesis (M.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 237-267). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Bibliography: leaves 205-258. / vii, 258 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The studies described in this thesis examine the mechanical function of the barostat. The barostat is then used to assess proximal gastric function in patients with gastro-oesophageal reflux disease, and the effects of hyperglycaemia on proximal gastric sensory and motor function in normal individuals. To detect the low pressures that may be important in determining gastric outflow, a high accuracy manometric recording system is developed ; patterns of intragastric pressure are then examined during gastric emptying of saline. Finally, a new barostat is designed and tested. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1997

ABSTRACT Background Oesophageal cancer has a high mortality; it is the 6th most common cause of death due to cancer worldwide. Of the common subtypes of oesophageal cancer, it is the adenocarcinomas that have been rising rapidly in incidence throughout the western world. The incidence of adenocarcinomas now exceeds the previously common squamous cell carcinoma. These recent changes in the incidence patterns of oesophageal cancer suggests that the environmental risk factors associated with these subtypes differ, and that changes in the prevalence of these exposures over time are the most likely explanation for the observed shifts in the incidence. However, due to its low incidence until a few decades ago, the adenocarcinoma subtype has been less studied compared to squamous cell carcinoma, and the environmental factors associated with this cancer have not been so clearly defined. Smoking and alcohol have been the strongest environmental risk factors reported for oesophageal squamous cell carcinoma (OSCC) whereas for oesophageal adenocarcinoma (OAC), the effect of smoking appears to be weaker, and the evidence for an effect of alcohol is scant and inconsistent. However, epidemiologic studies consistently identify people with frequent symptoms of gastro-oesophageal reflux (GOR) as having the highest risk of OAC, but the effect of GOR on OSCC has been negligible. Furthermore, it has been argued that adenocarcinoma occurring at the gastro-oesophageal junction (GOJAC) may have different aetiology again. Together, these reports suggest the three subtypes of oesophageal cancers (OAC, GOJAC and OSCC) may arise through different mechanisms with different strengths in the impact of risk factors. This thesis investigated the independent associations of smoking, alcohol and gastro-oesophageal reflux on cancers of the oesophagus by considering the possibility of variation in the risks due to differences in the dose effect patterns of various measures such as smoking, alcohol and GOR. Method Data from a population-based case-control study of oesophageal and ovarian cancers in Australia were used. Study participants comprised histologically confirmed cases of OSCC (n=308), OAC (n=367) and GOJAC (n=426) who were frequency matched to 1580 controls from the general population. Exposure history for both cases and controls were derived from health and lifestyle questionnaires. Unconditional multivariate logistic regression was used to calculate the odds ratios and 95% confidence intervals for the risk factors analysed. In addition, generalised additive model with a logit link was also used to explore and present the non-linearity in the dose effect pattern for continuous exposures adjusting for other confounding factors. The effects of two exposures combined on these cancers were assessed by obtaining synergy index. Results Smokers were at significantly higher risk of all three subtypes of oesophageal cancer with the risk greatest for OSCC. The effect of smoking was greater for adenocarcinoma occurring at the gastro-oesophageal junction compared to that of the oesophagus. Of the various measures of smoking, duration was significantly associated with all three subtypes of cancer whereas intensity was associated with only OSCC and GOJAC and the dose effect was non-linear. Time since quitting was associated with a steady decline in risk of all three cancers emphasising the health benefits of quitting among smokers. Alcohol was not associated with OAC or GOJAC but was significantly associated with OSCC among those drinking in excess of 170g/week. The association between alcohol and OSCC was modified by smoking; the association with alcohol was significantly greater among current smokers with effect. Low to moderate wine consumption was associated with significant risk reduction for all three cancers compared to non-drinkers. Increased frequency of GOR symptoms was associated with increased risks of OAC and GOJAC, although the risk of OSCC was constrained to frequent GOR symptoms only. The effect of GOR symptoms were exacerbated by smoking whereas it was weakened by regular NSAID use. Lastly, the sensitivity analysis that assessed the effect of non-participation among controls in the estimated effect of smoking and BMI (the two risk factors most likely to be affected by non-participation) showed a slight overestimation of effect of smoking assuming higher exposure rate among non-participants but not BMI while the effect remained strong and statistically significant. Conclusion Smoking, alcohol and GOR symptoms were the environmental factors strongly associated with all subtypes of oesophageal cancers. However, the dose effect patterns of these exposures varied by cancer subtypes. Smoking and alcohol were the larger contributing factors for OSCC whereas smoking and GOR symptoms had greater impact on OAC and GOJAC. Low to moderate wine consumption and regular NSAID use reduced the risk of all three subtypes significantly. While selection bias may have led to mildly inflated risks for smoking, the effects persisted even when modelled under extreme scenarios of biased participation amongst controls, and there was no evidence that selection bias materially affected the other associations.

ABSTRACT Background Oesophageal cancer has a high mortality; it is the 6th most common cause of death due to cancer worldwide. Of the common subtypes of oesophageal cancer, it is the adenocarcinomas that have been rising rapidly in incidence throughout the western world. The incidence of adenocarcinomas now exceeds the previously common squamous cell carcinoma. These recent changes in the incidence patterns of oesophageal cancer suggests that the environmental risk factors associated with these subtypes differ, and that changes in the prevalence of these exposures over time are the most likely explanation for the observed shifts in the incidence. However, due to its low incidence until a few decades ago, the adenocarcinoma subtype has been less studied compared to squamous cell carcinoma, and the environmental factors associated with this cancer have not been so clearly defined. Smoking and alcohol have been the strongest environmental risk factors reported for oesophageal squamous cell carcinoma (OSCC) whereas for oesophageal adenocarcinoma (OAC), the effect of smoking appears to be weaker, and the evidence for an effect of alcohol is scant and inconsistent. However, epidemiologic studies consistently identify people with frequent symptoms of gastro-oesophageal reflux (GOR) as having the highest risk of OAC, but the effect of GOR on OSCC has been negligible. Furthermore, it has been argued that adenocarcinoma occurring at the gastro-oesophageal junction (GOJAC) may have different aetiology again. Together, these reports suggest the three subtypes of oesophageal cancers (OAC, GOJAC and OSCC) may arise through different mechanisms with different strengths in the impact of risk factors. This thesis investigated the independent associations of smoking, alcohol and gastro-oesophageal reflux on cancers of the oesophagus by considering the possibility of variation in the risks due to differences in the dose effect patterns of various measures such as smoking, alcohol and GOR. Method Data from a population-based case-control study of oesophageal and ovarian cancers in Australia were used. Study participants comprised histologically confirmed cases of OSCC (n=308), OAC (n=367) and GOJAC (n=426) who were frequency matched to 1580 controls from the general population. Exposure history for both cases and controls were derived from health and lifestyle questionnaires. Unconditional multivariate logistic regression was used to calculate the odds ratios and 95% confidence intervals for the risk factors analysed. In addition, generalised additive model with a logit link was also used to explore and present the non-linearity in the dose effect pattern for continuous exposures adjusting for other confounding factors. The effects of two exposures combined on these cancers were assessed by obtaining synergy index. Results Smokers were at significantly higher risk of all three subtypes of oesophageal cancer with the risk greatest for OSCC. The effect of smoking was greater for adenocarcinoma occurring at the gastro-oesophageal junction compared to that of the oesophagus. Of the various measures of smoking, duration was significantly associated with all three subtypes of cancer whereas intensity was associated with only OSCC and GOJAC and the dose effect was non-linear. Time since quitting was associated with a steady decline in risk of all three cancers emphasising the health benefits of quitting among smokers. Alcohol was not associated with OAC or GOJAC but was significantly associated with OSCC among those drinking in excess of 170g/week. The association between alcohol and OSCC was modified by smoking; the association with alcohol was significantly greater among current smokers with effect. Low to moderate wine consumption was associated with significant risk reduction for all three cancers compared to non-drinkers. Increased frequency of GOR symptoms was associated with increased risks of OAC and GOJAC, although the risk of OSCC was constrained to frequent GOR symptoms only. The effect of GOR symptoms were exacerbated by smoking whereas it was weakened by regular NSAID use. Lastly, the sensitivity analysis that assessed the effect of non-participation among controls in the estimated effect of smoking and BMI (the two risk factors most likely to be affected by non-participation) showed a slight overestimation of effect of smoking assuming higher exposure rate among non-participants but not BMI while the effect remained strong and statistically significant. Conclusion Smoking, alcohol and GOR symptoms were the environmental factors strongly associated with all subtypes of oesophageal cancers. However, the dose effect patterns of these exposures varied by cancer subtypes. Smoking and alcohol were the larger contributing factors for OSCC whereas smoking and GOR symptoms had greater impact on OAC and GOJAC. Low to moderate wine consumption and regular NSAID use reduced the risk of all three subtypes significantly. While selection bias may have led to mildly inflated risks for smoking, the effects persisted even when modelled under extreme scenarios of biased participation amongst controls, and there was no evidence that selection bias materially affected the other associations.

ABSTRACT Background Oesophageal cancer has a high mortality; it is the 6th most common cause of death due to cancer worldwide. Of the common subtypes of oesophageal cancer, it is the adenocarcinomas that have been rising rapidly in incidence throughout the western world. The incidence of adenocarcinomas now exceeds the previously common squamous cell carcinoma. These recent changes in the incidence patterns of oesophageal cancer suggests that the environmental risk factors associated with these subtypes differ, and that changes in the prevalence of these exposures over time are the most likely explanation for the observed shifts in the incidence. However, due to its low incidence until a few decades ago, the adenocarcinoma subtype has been less studied compared to squamous cell carcinoma, and the environmental factors associated with this cancer have not been so clearly defined. Smoking and alcohol have been the strongest environmental risk factors reported for oesophageal squamous cell carcinoma (OSCC) whereas for oesophageal adenocarcinoma (OAC), the effect of smoking appears to be weaker, and the evidence for an effect of alcohol is scant and inconsistent. However, epidemiologic studies consistently identify people with frequent symptoms of gastro-oesophageal reflux (GOR) as having the highest risk of OAC, but the effect of GOR on OSCC has been negligible. Furthermore, it has been argued that adenocarcinoma occurring at the gastro-oesophageal junction (GOJAC) may have different aetiology again. Together, these reports suggest the three subtypes of oesophageal cancers (OAC, GOJAC and OSCC) may arise through different mechanisms with different strengths in the impact of risk factors. This thesis investigated the independent associations of smoking, alcohol and gastro-oesophageal reflux on cancers of the oesophagus by considering the possibility of variation in the risks due to differences in the dose effect patterns of various measures such as smoking, alcohol and GOR. Method Data from a population-based case-control study of oesophageal and ovarian cancers in Australia were used. Study participants comprised histologically confirmed cases of OSCC (n=308), OAC (n=367) and GOJAC (n=426) who were frequency matched to 1580 controls from the general population. Exposure history for both cases and controls were derived from health and lifestyle questionnaires. Unconditional multivariate logistic regression was used to calculate the odds ratios and 95% confidence intervals for the risk factors analysed. In addition, generalised additive model with a logit link was also used to explore and present the non-linearity in the dose effect pattern for continuous exposures adjusting for other confounding factors. The effects of two exposures combined on these cancers were assessed by obtaining synergy index. Results Smokers were at significantly higher risk of all three subtypes of oesophageal cancer with the risk greatest for OSCC. The effect of smoking was greater for adenocarcinoma occurring at the gastro-oesophageal junction compared to that of the oesophagus. Of the various measures of smoking, duration was significantly associated with all three subtypes of cancer whereas intensity was associated with only OSCC and GOJAC and the dose effect was non-linear. Time since quitting was associated with a steady decline in risk of all three cancers emphasising the health benefits of quitting among smokers. Alcohol was not associated with OAC or GOJAC but was significantly associated with OSCC among those drinking in excess of 170g/week. The association between alcohol and OSCC was modified by smoking; the association with alcohol was significantly greater among current smokers with effect. Low to moderate wine consumption was associated with significant risk reduction for all three cancers compared to non-drinkers. Increased frequency of GOR symptoms was associated with increased risks of OAC and GOJAC, although the risk of OSCC was constrained to frequent GOR symptoms only. The effect of GOR symptoms were exacerbated by smoking whereas it was weakened by regular NSAID use. Lastly, the sensitivity analysis that assessed the effect of non-participation among controls in the estimated effect of smoking and BMI (the two risk factors most likely to be affected by non-participation) showed a slight overestimation of effect of smoking assuming higher exposure rate among non-participants but not BMI while the effect remained strong and statistically significant. Conclusion Smoking, alcohol and GOR symptoms were the environmental factors strongly associated with all subtypes of oesophageal cancers. However, the dose effect patterns of these exposures varied by cancer subtypes. Smoking and alcohol were the larger contributing factors for OSCC whereas smoking and GOR symptoms had greater impact on OAC and GOJAC. Low to moderate wine consumption and regular NSAID use reduced the risk of all three subtypes significantly. While selection bias may have led to mildly inflated risks for smoking, the effects persisted even when modelled under extreme scenarios of biased participation amongst controls, and there was no evidence that selection bias materially affected the other associations.