O refluxo vésico-ureteral (RVU) é uma das condições urológicas comumente diagnosticada entre crianças. Altos graus dessa condição podem causar cicatrização renal, insuficiência renal e hipertensão arterial. A uretrocistografia miccional é o método mais comumente utilizado para o diagnóstico, no entanto, esse procedimento envolve sedação, cateterismo vesical e expõe a criança a uma quantidade significativa de radiação. A investigação metabolômica pode fornecer novos entendimentos sobre a doença e visa a descoberta de metabólitos específicos associados a ela. Assim, existe um potencial considerável para a implementação de perfil metabólico em análises clínicas. Dessa forma, buscou-se estabelecer uma alternativa não invasiva para identificar crianças com o RVU através da metabolômica. Para a investigação metabolômica alvo um método por eletroforese capilar acoplada ao espectrômetro de massas (CE-MS) com analisador to tipo ion trap foi desenvolvido e validado para a determinação de 27 aminoácidos em urina. Os parâmetros experimentais relacionados às configurações da interface CE-MS, eletrólito (BGE) e espectrômetro de de massas (MS) foram otimizados, proporcionando uma boa separação dos 27 aminoácidos, incluindo os isômeros L-leucina, L-isoleucina e L-alloisoleucina, em menos de 30 min. O líquido auxiliar (SHL) foi composto de 0,5% (v/v) ácido fórmico em 60% (v/v) água/metanol à uma vazão de 5 µL min-1. O BGE consistiu de 0,80 mol L-1 de ácido fórmico e 15% (v/v) de metanol. Um procedimento de stacking por pH foi implementado para aumentar a detectabilidade (uma solução de NH4OH a 12,5% (v/v) foi injetada a 0,5 psi/9 s antes das amostras). O método foi validado de acordo com os protocolos FDA e ICH, exibindo parâmetros aceitáveis. A quantificação bem sucedida dos aminoácidos em amostras de urina de um estudo piloto do RVU foi alcançada. A avaliação estatística dos resultados mostrou que alguns dos aminoácidos avaliados podem carregar informações que possibilitam discriminar as amostras de urina entre os grupos teste e controle. Para a análise metabolômica global urinária, métodos por RPLC-MS e HILIC-MS foram otimizados. Cinco colunas com diferentes propriedades foram investigadas para RPLC e quatro colunas para HILIC; adicionalmente, foram investigados a influência dos aditivos e pH da fase móvel. As condições ótimas foram determinadas avaliando o formato de pico, a relação sinal-ruído, o tempo de retenção, o número de molecular features detectados e sua distribuição durante o gradiente de eluição. A melhor condição obtida para RPLC utiliza a coluna CSH C18 e fase móvel composta por 0,1% (v/v) ácido fórmico em água (A) e 0,1% (v/v) ácido fórmico em acetonitrila (B). Para HILIC, o melhor desempenho foi obtido com a coluna zwitteriônica ZIC-HILIC e fase móvel composta por 10 mmol L-1 acetato de amônio pH 6,8 (B) e 95% (v/v) acetonitrila e 5% 200 mmol L-1 acetato de amônio pH 6,8 (A). As amostras de urina dos grupos controle e teste foram submetidas à análise metabolômica global por RPLC-MS usando o método otimizado e por CESI-MS. Os resultados indicaram que diversas rotas metabólicas podem ter sido alteradas pelo RVU. Alteração dos níveis de carnitinas e acilcarnitinas, aminoácidos e derivados, purinas e outros foi observada. Ainda, a presença de acilcarnitinas na urina podem indicar danos mitocondriais e a diminuição de triptofano e aumento do ácido quinurênico indicam uma alteração no metabolismo do triptofano. / Vesicoureteral reflux (VUR) is one of the most commonly urologic conditions diagnosed among children. A high degree of this condition can cause kidney scarring, kidney failure and high blood pressure. Voiding cystourethrography is the standard method for diagnosis; however, this procedure involves sedation, bladder catheterization and exposes the child to a significant amount of radiation. Metabolomics has provided new insights about the disease and aims to discover specific metabolites associated with it. Thus, there is a considerable potential for the implementation of metabolic profile in clinical analyses. Thus, we attempted to establish a noninvasive alternative to identify children with VUR through metabolomics approach. For target metabolomics, a CE-MS method was developed and validated for the separation and quantitative analysis of 27 amino acids in urine. Experimental parameters related to the CE-MS interface (based on co-axial sheath liquid, SHL), background electrolyte (BGE) and mass spectrometer (MS) settings were optimized providing a good separation of 27 amino acids, including the isomers L-leucine, L-isoleucine and L-alloisoleucine, in less than 30 min. The SHL was composed of 0.50% (v/v) formic acid in 60% (v/v) methanol-water delivered at a flow rate of 5 µL min-1. The BGE consisted of 0.80 mol L-1 formic acid and 15% (v/v) methanol. A pH stacking procedure was implemented to enhance sensitivity (a 12.5% (v/v) NH4OH solution was injected at 0.5 psi/9 s prior to samples). The proposed method was thoroughly validated according to FDA and ICH protocols exhibiting acceptable parameters. A successful quantification of amino acids in urine samples from the VUR cohort was achieved. The statistical evaluation of the results showed that some of the amino acids may carry information for the discrimination of the urine samples between the test and control groups. For untargeted metabolomics analysis, methods by RPLC-MS and HILIC-MS were optimized. Five columns with different properties were investigated for RPLC and four columns for HILIC; additionally, the influence of additives and pH of the mobile phase were investigated. The optimum conditions were determined assessing the peak shape, signal-to-noise ratio, retention time, number of molecular features detected and their distribution during the elution gradient. The best condition obtained for RPLC uses CSH C18 column and mobile phase composed by 0.1% (v/v) formic acid in water (A) and 0.1% (v/v) formic acid in acetonitrile (B). For HILIC, the best performance was obtained with the zwitterionic ZIC-HILIC column and mobile phase composed by 10 mmol L-1 ammonium acetate pH 6.8 (B) and 95% (v/v) acetonitrile and 5% (v/v) 200 mmol L-1 ammonium acetate pH 6.8 (A). Urine samples from the control and test groups were submitted to global metabolomics analysis by RPLC-MS using the optimized method and by CESI-MS. The results indicated that several metabolic pathways may have been altered by VUR. Changes of carnitine and acylcarnitine levels, amino acids and derivatives, purines and others was observed. Furthermore, the presence of acylcarnitines in the urine may indicate mitochondrial damage and the decrease of tryptophan and increase of the kynurenic acid indicate a change in the metabolism of tryptophan.

Uma avaliação da concentração dos aminoácidos primários em amostras de urina de crianças com refluxo vésico-ureteral (VUR) em busca de caminhos para o diagnóstico não invasivo desta doença. Dois métodos analíticos por eletroforese capilar com detecção UV/vis foram desenvolvidos para a quantificação dos analitos. No método 1 empregou-se a detecção UV/vis direta em 200 e 214 nm com as condições eletroforéticas eletrólito tampão fosfato 90 mmol L-1 pH 2,1; tensão de +15 kV; injeção de 7 s a 0,5 psi; capilar de 75 µm de diâmetro interno; 40,2 cm de comprimento total e 30,0 cm de comprimento efetivo. No método 2, fez-se uso da detecção indireta em 254 nm, com as condições eletroforéticas eletrólito tampão TEA 20 mmol L-1 e DNB 10 mmol L-1 pH 10,84; modificador de fluxo DDAB a 4 mmol L-1; tensão de -15 kV; injeção de 7 s a 0,5 psi; capilar de 75 µm de diâmetro interno; 50,2 cm de comprimento total e 40,0 cm de comprimento efetivo. O método 1 apresentou parâmetros de validação linearidade, precisão intra-dia e inter-dia, seletividade, robustez e recuperação satisfatórios. A quantificação de creatinina, fenilalanina (Phe), histidina (His), triptofano (Trp), tirosina (Tyr) nas amostras de urina foi possível pelo método 1, porém inviável para quantificação de arginina (Arg). O método 2 apresentou valores de robustez e recuperação satisfatórios para os aminoácidos alanina (Ala), aspartato (Asp), glutamato (Glu) e glicina (Gly) satisfatórios, mas a quantificação dos mesmos na maioria das amostras de urina diluída não foi possível por estarem em nível de concentração abaixo da detecção ou quantificação. Para avaliar a potencialidade dos resultados como ferramenta no diagnóstico do VUR, os aminoácidos His, Phe, Trp e Tyr, quantificados em todas as amostras, foram empregados como variáveis na classificação das amostras em dois grupos distintos (1) grupo de crianças saudáveis e (2) grupo de crianças diagnosticadas com VUR. A classificação realizada pelo método de análise de componente principal (PCA) apresentou valores estatísticos satisfatórios e poder de predição: R2 (capacidade de ajuste) e Q2 (capacidade de predição) foram 0.9993 e 0.65, respectivamente com os dois componentes principais (PC1 e PC2). A separação total com valor de Q2 desejável (acima de 0,8) poderia ser alcançada com uma quantidade maior de informação, sendo neste caso, número maior de aminoácidos quantificados. Assim, este trabalho abre caminho para estudos mais aprofundados na investigação da concentração dos aminoácidos primários em pacientes com VUR, objetivando o desenvolvimento de um potencial biomarcador para VUR. / An assessment of the concentration of primary amino acids in urine samples from children with vesicoureteral reflux (VUR) using capillary electrophoresis separation with UV/vis detection has been proposed to help establishing a means for non invasive diagnosis of the disease. Two analytical methods were developed. Method 1 used direct UV/vis detection at 200 and 214 nm, 90 mmol L-1 phosphate buffer at pH 2.1, high voltage separation at +15 kV, injection of 0.5 psi during 7 s, and a fused-silica capillary of 75 µm inner diameter, 40.2 cm total length, and 30.0 cm effective length. Method 2 used indirect UV/vis detection at 254 nm, TEA at 20 mmol L-1 and DNB at 10 mmol L-1 electrolyte at pH 10.84, 4 mmol L-1 DDAB as flow modifier, separation voltage at -15 kV, injection of 0,5 psi during 7 s, fused-silica capillary of 75 µm inner diameter, 50.2 cm total length, and 40,0 cm effective length. Method 1 presented satisfactory results for linearity, intra-day and inter-day precision, selectivity, robustness, and recovery. By method 1 it was possible to quantify creatinine, phenylalanine (Phe), histidine (His), tryptophan (Trp), tyrosine (Tyr) but not arginine (Arg) in the urine samples under investigation. Method 2 presented satisfactory robustness and recovery for alanine (Ala), aspartate (Asp), glutamate (Glu) and glycine (Gly), but the contents of these metabolites in the urine samples were not established because they lay below the limits of detection and quantitation. To assess the potentiality of the results as diagnostic tool for VUR condition, the concentrations of the amino acids His, Phe, Trp and Tyr, quantified in all samples, were used as variables in a classification procedure where samples were divided in two distinct groups: (a) a group of healthy children and (b) a group of children diagnosed with VUR. The classification by principal component analysis (PCA) showed a partial separation with good statistics and prediction power: R2 (goodness of fit) and Q2 (goodness of prediction) were 0.9993 and 0.65, respectively with two components analysis (PC1 and PC2). Values of Q2 greater than 0.8 are usually desired and it could be provided if more information was available, such as a greater number of amino acids being quantified. Thus, this research opens the way for further investigative studies of amino acids concentration in patients with primary VUR, aimed at developing a potential biomarker for VUR.

La rupture spontanee de l'oesophage (RSO), le syndrome Boerhaave - une<br />pathologie rare, mais avec une haute mortalite, et, selon les donnees des differents<br />auteurs, varie entre 21 % et 67 %.<br />Les tentatives de reproduire experimentalement le mecanisme de la rupture<br />de l'oesophage etaient entreprises par differents auteurs, mais a chaque fois les<br />conditions experimentales se distinguaient. Toutes les etudes n'etaient pas a notre<br />avis tout a fait correctes sur le plan du mecanisme d'influence sur la paroi de<br />l'oesophage. Premierement, la rupture de l'oesophage se provoque par<br />augmentation de la pression hydraulique, deuxiemement, il est necessaire de<br />prendre en consideration non seulement les particularites anatomiques de<br />l'oesophage et du hiatus oesophagien du diaphragme, mais aussi l'etat de la<br />muqueuse de l'oesophage chez les cadavres humains.<br />Malgre les succes atteints en chirurgie de l'oesophage, on constate toujours<br />un haut pourcentage de l'inconsistance des sutures chez les malades ayant une<br />RSO, 30-50 %. A notre avis cela est lie a l'absence de la prevention du reflux<br />gastro-oesophagien et de la prevention de la precarite des sutures de l'oesophage.<br />Cette these est consacree a la definition des facteurs du risque de la rupture<br />spontanee de l'oesophage et l'amelioration des resultats de son traitement.

Gastrointestinal symptoms have a prevalence of 20-40% in the general adult population in the Western world. These symptoms are generally considered to be poor predictors of organic findings [e.g. peptic ulcer disease (PUD) or malignancy]. Approximately 50% of patients seeking care for such symptoms have no organic explanation for these upon investigation. When other organic or other functional conditions are excluded [e.g. PUD, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)] the remaining patients are labelled as having functional dyspepsia (persistent or recurrent pain and/or discomfort centred in the upper abdomen). Management of functional dyspepsia remains a challenge, reflecting the heterogeneity of the patients and the uncertain role of drug treatment. Also, prognostic factors for treatment success are largely unknown. I have therefore performed a series of studies to shed light on these issues: The first study (Paper I) was performed in a randomly selected adult population (n=1,001) assessing upper and lower gastrointestinal symptoms at two occasions with 1 to 6 month intervals. The results show that gastrointestinal symptoms are common (57%) and fluctuate to some extent in the shorter term. Troublesome dyspeptic symptoms remain in two out of three individuals. This proportion was similar whether or not organic findings were present. In the second study (Paper II) 799 patients with dyspeptic symptoms were evaluated with regard to whether gastrointestinal symptoms, identified by self-administered questionnaires, correlate with endoscopic diagnoses and discriminate organic from non-organic (functional) dyspepsia. The impact of dyspeptic symptoms on health-related well-being was also evaluated. Approximately 50% of these dyspeptic patients were found to have functional dyspepsia at upper endoscopy. A difference was discovered in the symptom profile between patients with organic and functional dyspepsia. Predicting factors for functional dyspepsia were found. This study shows that use of self-administered symptom questionnaires may aid in clinical decision making for patient management, e.g. by reducing the number of endoscopies, although probabilities of risks for organic dyspepsia are difficult to transfer to management of the individual patient. The results also indicate that the health-related well-being in patients with functional and organic dyspepsia is impaired to the same extent, illustrating the need for effective treatment of patients with functional dyspepsia, a group not well served by currently available treatment modalities. The aim of the third study (Paper III) was to develop and evaluate a selfadministered questionnaire focusing on upper abdominal and reflux complaints to allow for identification of patients with heartburn and factors that might predict symptom relief with omeprazole both in GERD and functional dyspepsia patients. The diagnostic validity of the questionnaire was tested against endoscopy and 24-hour pH monitoring. The questionnaire had a sensitivity of 92%, but a low specificity of 19%. Symptom relief by omeprazole was best predicted by the presence of predominant heartburn described as ‘a burning feeling rising from the stomach or lower chest up towards the neck’ and ‘relief from antacids’. These results indicate that this questionnaire which used descriptive language, appeared to be useful in identifying heartburn and predicting responses to omeprazole in patients with upper gastrointestinal symptoms. The fourth study (Paper IV) was a pilot study investigating the symptom response to omeprazole 20 mg twice daily or placebo for a duration of 14 days in 197 patients with functional dyspepsia. We concluded that a subset of patients with functional dyspepsia, with or without heartburn, would respond to therapy with omeprazole. In the final study (Paper V) the aim was to identify prognostic factors for the treatment success to a 4-week course of omeprazole 10 or 20 mg once daily in 826 patients with functional dyspepsia. The most highly discriminating predictor of treatment success was the number of days without dyspeptic symptoms during the first week of treatment. Fewer days with symptoms during the first week indicated higher response rates at four weeks. In addition, positive predictors of treatment response to omeprazole were identified as age &gt;40 years, bothersome heartburn, low scores of bloating and diarrhoea, history of symptoms for &lt;3 months and low impairment of vitality at baseline. The results indicate that early response during the first week to treatment with a proton pump inhibitor seems to predict treatment success after four weeks in patients with functional dyspepsia. Conclusion: These studies have shown that a large proportion of adult individuals in society, both those who seek and those who do not seek medical care, suffer from symptoms located in the upper part of the abdomen regardless of whether an organic cause is present. A subset of patients without organic findings and other functional conditions, i.e. functional dyspepsia, respond to therapy with omeprazole irrespective of the presence or absence of heartburn . An excellent way to predict the response to a full course of omeprazole in functional dyspepsia is to assess the early response (first week) to treatment. These findings allow for better and faster targeting of acid inhibitory therapy in functional dyspepsia, which potentially can result in more effective clinical management of these patients and savings of health care resources.

ABSTRACT KINETIC STUDIES FOR THE PRODUCTION OF TERTIARY ETHERS USED AS GASOLINE ADDITIVES Boz, Nezahat Ph. D., Department of Chemical Engineering Supervisor: Prof. Dr. Timur Dogu Co-supervisor: Prof. Dr. G&uuml / lSen Dogu June 2004, 174 pages In the present study, the kinetics studies for etherification reactions were investigated in detail. In the first phase of present study, different acidic resin catalysts were prepared by the heat treatment of Amberlyst-15 catalysts at 220&deg / C at different durations of time and also by the synthesis of sulfonated styrene divinylbenzene cross-linked resins at different conditions. A linear dependence of reaction rate on hydrogen ion-exchange capacity was in 2M2B+ethanol reaction. However, in the case of 2M1B+ethanol reaction hydrogen ion-exchange capacities over 2.8 meq.H+/g did not cause further increase in reaction rate, which was concluded to be majorly due to significance of diffusional resistances. DRIFTS experiments carried out with alcohols, isobutylene, isoamylenes and TAME (tert-amyl-methyl-ether) in a temperature range of 333-353 K supported a Langmuir-Hinshelwood type reaction mechanism involving adsorbed isoolefins molecules forming a bridged structure between &ndash / SO3H sites of the catalyst and adsorbed alcohol molecules. A rate expression derived basing on the mechanism proposed from the DRIFTS results gave good agreement with the published data. Reaction rate was found to give a sharp maximum at ethanol activity of around 0.1. The third phase of this work included evaluation of effective diffusivities and adsorption equilibrium constants of methanol, ethanol and 2M2B, in Amberlyst-15 from moment analysis of batch adsorber dynamic results. Models proposed for monodisperse and bidisperse pore structures were used for the evaluation of effective diffusivities. It was shown that surface diffusion contribution was quite significant. In the last phase of the work, a batch Reflux-Recycle-Reactor (RRR) was proposed, modeled and constructed to achieve high yields and selectivities in equilibrium limited reactions. The batch reflux recycle reactor was modeled by assuming plug flow in the reactor section, perfect mixing in the reboiler and vapor-liquid equilibria between the liquid in the reboiler and reactor inlet stream. In this system conversion values of isoamylenes reaching to 0.91 were achieved at 82&deg / C with almost 100% selectivity. Such conversion values were shown to be much higher than the corresponding equilibrium values that could be obtained in vapor phase fixed bed reactors. The activation energies evaluated in this system were found to be much less than the activation energies evaluated in the fixed bed reactor studies. This was concluded to be majorly due to the significance of transport resistant in the batch Reflux-Recycle-Reactor in which catalyst particles are partially wet. As a result of catalyst development, characterization, kinetic and reactor development studies carried out in this study, it was concluded that tert-amyl-ethyl-ether (TAEE) could be effectively produced and used as a gasoline blending oxygenate.

Μελέτη της αναπνευστικής λειτουργίας με εργοσπιρομετρία σε ασθενείς με γαστροοισοφαγική παλινδρομική νόσο. Εισαγωγή: Η Γαστροοισοφαγική Παλινδρομική Νόσος (ΓΟΠΝ) έχει συσχετισθεί με πλειάδα πνευμονικών εκδηλώσεων αλλά είναι ασαφές εάν η γαστροοισοφαγική παλινδρόμηση προκαλεί οποιαδήποτε δυσλειτουργία στην πνευμονική λειτουργία. Η εργοσπιρομετρία είναι μια εξειδικευμένη μέθοδος η οποία χρησιμοποιείται για να διερευνήσει την αναπνευστική λειτουργία κατά την άσκηση. Σκοπός: Σκοπός της μελέτης ήταν να αποκαλυφθεί οποιαδήποτε ανωμαλία της πνευμονικής λειτουργίας σε ασθενείς με ΓΟΠΝ και αναπνευστικά συμπτώματα. Μέθοδος: Μελετήσαμε 34 ασθενείς με ΓΟΠΝ (ηλικίας 21-63, 24 άνδρες/10 γυναίκες) και εξωοισοφαγικά αναπνευστικά συμπτώματα (συριγμός ή/και βήχας) πριν και μετά από 12 εβδομάδες θεραπεία με διπλή δόση ομεπραζόλης. Κανείς ασθενής δεν παρουσίασε παθολογική σπιρομέτρηση. Εργομετρία διενεργήθηκε σε όλους του ασθενείς πριν την θεραπεία και μετά την θεραπεία. Γαστροσκόπηση διενεργήθηκε σε όλους τους ασθενείς πριν την θεραπεία και σε αυτούς με οισοφαγίτιδα επανελήφθη μετά την θεραπεία. Καταγραφήκαν οι ακόλουθες εργομετρικές παράμετροι: VO2rest, VO2max, VCO2rest, VCO2max, O2–puls rest, O2–puls max, HR (heart rate) rest, HRmax, PETCO2rest, PETCO2max, VE/VCO2 SLOPE πριν και μετά την θεραπεία. Αποτελέσματα: Είκοσι τέσσερις ασθενείς (70.6%) είχαν οισοφαγίτιδα (βαθμού Α-D), 16 ασθενείς είχαν διαφραγματοκήλη (47.1%), και σε 13 ασθενείς (38.23 %) ανιχνεύθηκε Helicobacter pylori.Οι εργομετρικές παράμετροι ήταν εντός φυσιολογικών ορίων σε όλους τους ασθενείς, κανείς ασθενής δεν παρουσίασε οποιαδήποτε ανωμαλία κατά την άσκηση. Είκοσι οκτώ ασθενείς επανελέγχθηκαν. Καμία βελτίωση σε οποιαδήποτε εργομετρική παράμετρο μετά την θεραπεία δεν παρατηρήθηκε παρά την ύφεση των οισοφαγικών και των εξωοισοφαγικών συμπτωμάτων σε όλους τους ασθενείς. Καμία στατιστικώς σημαντική διαφορά δεν παρατηρήθηκε πριν και μετά την θεραπεία μεταξύ ασθενών μεγαλύτερων των 40 ετών και νεότερων των 40 ετών, καπνιστών και μη καπνιστών, Hp(+) και Hp(-) ασθενών, όπως επίσης και μεταξύ ασθενών με και χωρίς οισοφαγίτιδα, και μεταξύ ασθενών με και χωρίς διαφραγματοκήλη. Συμπεράσματα: Ασθενείς με ΓΟΠΝ, αναπνευστικές εκδηλώσεις και φυσιολογική σπιρομέτρηση, δεν παρουσιάζουν διαταραχές κατά την εργομετρία (δοκιμασία άσκησης). Επίσης δεν παρατηρείται καμιά κλινικά αξιόλογη μεταβολή στις εργομετρικές τιμές μετά την θεραπεία ούτε διαφορά στις εργομετρικές τιμές σύμφωνα με την ηλικία, το κάπνισμα, την παρουσία H.pylori, οισοφαγίτιδας ή διαφραγματοκήλης. / Evaluation of respiratory function with cardiopulmonary exercise test in patients with gastroesophageal reflux disease. Introduction: Gastroesophageal reflux disease (GERD) has been associated with a variety of pulmonary manifestations but it is unclear if gastroesophageal reflux causes any abnormality in pulmonary function. Cardiopulmonary exercise test (CPET) is a specialized method which is used to evaluate respiratory function during exercise. Aim: The aim of this study was to reveal any abnormality of pulmonary function in patients with GERD and respiratory symptoms. Method: We evaluated 34 patients with GERD (age 21-63, 24 men) and extraesophageal respiratory symptoms (wheezing and/or cough) before therapy and after twelve weeks treatment with double dose omeprazole. No patient presented abnormal spirometry. CPET was performed in all patients at baseline and after completion of 12 week treatment. The following CPET parameters: VO2rest, VO2max, VCO2rest, VCO2max, O2–pulse rest, O2–pulse max, HR (heart rate) rest, HRmax, PETCO2rest, PETCO2max, VE/VCO2 slope were recorded pre-treatment and post-treatment. Results: Twenty four patients (70.6%) had esophagitis (grade I-IV), 16 patients had hiatal hernia (47.1%) and in 13 patients (38,2%) Helicobacter pylori was positive. All patients completed the CPET. No one presented shortness of breath or respiratory symptoms. CPET parameters were within normal limits in all patients. Twenty eight patients were reevaluated. No improvement in any CPET parameter post treatment was observed despite remission of esophageal and extraesophageal symptoms in all patients. No statistically significant difference was observed pre and post-treatment, between older and younger than 40 year old patients, smokers and non smokers, Hp(+) and Hp(-) patients and those with and without hiatal hernia and esophagitis. Conclusions: Patients with GERD and respiratory manifestations and normal spirometry present no pulmonary dysfunction during CPET. Also no alterations in CPET values post-treatment neither differences in CPET values according to age, smoking, Hp status, presence of oesophagitis or hiatal hernia were observed.

Introdução: A fisiopatologia da Doença do Refluxo Gastroesofágico (DRGE) é multifatorial, sendo a motilidade esofágica um dos fatores implicados na sua gênese. Todavia, ainda não há consenso sobre a existência de associação entre dismotilidade e Hérnia Hiatal (HH) em pacientes com DRGE. Esse estudo tem como objetivo estabelecer a prevalência de Dismotilidade Esofágica (DE) em pacientes com HH e avaliar se a herniação é fator relacionado à DE. Métodos: Foram estudados 356 pacientes com diagnóstico clínico de DRGE submetidos à Endoscopia Digestiva Alta e Manometria Esofágica. Hérnia Hiatal foi definida endoscopicamente por uma distância igual ou maior que 2 cm entre o pinçamento diafragmático e a junção escamo-colunar e Dismotilidade Esofágica quando a ME identificou amplitude das ondas peristálticas no esôfago distal < 30 mmHg e/ou menos de 80% de contrações efetivas. Foi feita a divisão dos pacientes para a análise estatística em 2 grupos, com e sem HH. Resultados: Pacientes com DRGE portadores de HH tiveram prevalência de DE igual a 14,8% e os sem HH, prevalência de 7,7% (p = 0,041). O grupo de pacientes com HH apresentou também maior frequência de esofagite erosiva (47,5% contra 24,2%, p <0,001), menor valor de pressão no EEI (10,4 versus 13,10; p < 0,001) e maior frequência de indivíduos com valores de pH-metria anormais (p < 0,001). A razão bruta de prevalências de DE, segundo a presença de HH, foi 1,92 (IC: 1,04 - 3,53; p = 0,037), porém essa associação não persistiu quando controlada por idade, esofagite, pH-metria alterada e EEI alterado (RP ajustada: 1,69; IC: 0,68 – 4,15; p = 0,257). Conclusão: Apesar da prevalência de DE no grupo HH ter sido maior do que no grupo sem HH, a associação entre HH e DE em indivíduos com DRGE desaparece ao se controlar por co-variáveis relevantes, levando a crer que neste tipo de paciente, HH não é fator de risco independente destas variáveis. / Introduction: The pathophysiology of gastroesophageal reflux disease is multifactorial, where esophageal motility is one of the factors implicated in its genesis. However, there is still no consensus on the existence of an association between esophageal dysmotility and hiatal hernia in patients with gastroesophageal reflux disease. The objective of this study was to establish the prevalence of esophageal dysmotility in patients with hiatal herina and to determine if herniation is a factor related to esophageal dysmotility. Methods: The study included 356 patients with a clinical diagnosis of gastroesophageal reflux disease submitted to upper digestive endoscopy and esophageal functional dagnostics. Hiatal Hernia was defined endoscopically by a distance equal to or greater than 2 cm between the diaphragmatic constriction and the squamo-columnar junction and esophageal dysmoyility when the esophageal manometry identified the amplitude of the peristaltic waves in the distal esophagus are < 30 mmHg and/or less than 80% of effective contractions. For statistical analysis, the patients were divided into 2 grups: with and without HH. Results: Gastroesophageal reflux disease patients with hiatal hernia had a prevalence of esophageal dysmotility equal to 14.8% and those without hiatal hernia, a prevalence of 7.7% (p = 0.041). The group of patients with hiatal hernia also showed a greater frequency of erosive esophagitis (47.5% versus 24.2%, p <0.001), lower low esophageal sphincter pressure (10.4 versus 13.10; p < 0.001) and greater frequency of individuals with abnormal pH-metry values (p < 0.001). The crude prevalence ratios for esophageal dysmotility, according to the presence of hiatal hernia, was 1.92 (CI: 1.04 - 3.53; p = 0.037), but this association did not persist when controlled for age, esophagitis, altered pH-metry and altered low esophageal sphincter (adjusted PR: 1.69; CI: 0.68 – 4.15; p = 0.257). Conclusion: Despite the prevalence of esophageal dysmotility in the hiatal hernia group being higher than that in the group without hiatal hernia, the association between hiatal hernia and esophageal dysmotility in individuals with gastroesophageal reflux disease disappeared on controlling for relevant co-variables, leading us to believe that in this type of patient, hiatal hernia is not a risk factor independent of these variables.

Objetivos: Avaliar a associação entre a dismotilidade esofágica, caracterizada como Motilidade Esofágica Ineficaz (MEI), com a presença de refluxo ácido patológico avaliado pela pH-metria de 24 horas, controlando por Esfíncter Esofágico Inferior (EEI) estruturalmente defeituoso, Hérnia Hiatal (HH) e Esofagite, em pacientes em investigação de Doença do Refluxo Gastroesofágico. Métodos: Foram estudados 311 pacientes referenciados para investigação de DRGE em laboratório de motilidade esofágica. Os pacientes foram submetidos à Endoscopia Digestiva Alta (EDA), Manometria Esofágica, pHmetria Esofágica de 24 horas e a uma entrevista sobre os sintomas clínicos apresentados. Foram comparados os grupos de pH-metria negativa com o de pH-metria positiva quanto à presença dos fatores de risco – MEI, EEI defeituoso, HH e Esofagite. A associação entre MEI e pH-metria positiva foi primeiramente avaliada através de análise univariada e, posteriormente, através de análise de regressão logística (multivariada). Resultados: Do total de 311 pacientes estudados, 208 preencheram os critérios de inclusão. A idade média foi 47 anos, com 88 pacientes apresentando pH-metria normal e 120 pH-metria positiva. Após a análise univariada, foi observado que a ocorrência de MEI, EEI defeituoso e HH foi significativamente maior no grupo de pH-metria positiva. Após análise de regressão logística, a ocorrência de MEI e EEI defeituoso permaneceram significativamente maior no grupo de pH-metria positiva. Conclusões: MEI está associada à presença de refluxo ácido anormal, avaliado através de pH-metria esofágica de 24 horas, independentemente da presença de EEI defeituoso, HH ou Esofagite. / Objectives: To assess the association between esophageal dysmotility, characterized as inefficient esophageal motility (IEM), and the presence of pathological acid reflux due to a structurally defective lower esophageal sphincter (LES), hiatus hernia (HH), or esophagitis in patients suspected of having gastroesophageal Reflux reflux disease (GERD). Methods: Three hundred and eleven patients referred for GERD diagnostic procedures in a gastroesopahgeal motility laboratory were included in the study. Patients underwent upper endoscopy (UE), esophageal manometry, 24-hour esophageal pH-metry and an interview regarding their clinical symptoms. The following risk factors of patients in the negative pH-metry group were compared to those in the positive pH-metry group: IEM, defective LES, HH, and esophagitis. The association between IEM and positive pH-metry results was first assessed by means of univariate analysis and later determined with logistic regression analysis (multivariate). Results: Of the total 311 patients studied, 208 met the inclusion criteria (mean age 47 years); 88 had normal pH-metry reslults and 120 had positive pH-metry results. Univariate analysis revealed that the occurrence of IEM, defective LES, and HH was significantly greater in the positive pH-metry group. Following logistic regression analysis, the occurrence of IEM remained significantly greater in the positive pH-metry group. Conclusions: IEM is associated with the presence of abnormal acid reflux, as assessed by 24-hour esophageal pH-metry, regardless of the presence of defective LES, HH, or esophagitis.

Objetivos: Avaliar a associação entre a dismotilidade esofágica, caracterizada como Motilidade Esofágica Ineficaz (MEI), com a presença de refluxo ácido patológico avaliado pela pH-metria de 24 horas, controlando por Esfíncter Esofágico Inferior (EEI) estruturalmente defeituoso, Hérnia Hiatal (HH) e Esofagite, em pacientes em investigação de Doença do Refluxo Gastroesofágico. Métodos: Foram estudados 311 pacientes referenciados para investigação de DRGE em laboratório de motilidade esofágica. Os pacientes foram submetidos à Endoscopia Digestiva Alta (EDA), Manometria Esofágica, pHmetria Esofágica de 24 horas e a uma entrevista sobre os sintomas clínicos apresentados. Foram comparados os grupos de pH-metria negativa com o de pH-metria positiva quanto à presença dos fatores de risco – MEI, EEI defeituoso, HH e Esofagite. A associação entre MEI e pH-metria positiva foi primeiramente avaliada através de análise univariada e, posteriormente, através de análise de regressão logística (multivariada). Resultados: Do total de 311 pacientes estudados, 208 preencheram os critérios de inclusão. A idade média foi 47 anos, com 88 pacientes apresentando pH-metria normal e 120 pH-metria positiva. Após a análise univariada, foi observado que a ocorrência de MEI, EEI defeituoso e HH foi significativamente maior no grupo de pH-metria positiva. Após análise de regressão logística, a ocorrência de MEI e EEI defeituoso permaneceram significativamente maior no grupo de pH-metria positiva. Conclusões: MEI está associada à presença de refluxo ácido anormal, avaliado através de pH-metria esofágica de 24 horas, independentemente da presença de EEI defeituoso, HH ou Esofagite. / Objectives: To assess the association between esophageal dysmotility, characterized as inefficient esophageal motility (IEM), and the presence of pathological acid reflux due to a structurally defective lower esophageal sphincter (LES), hiatus hernia (HH), or esophagitis in patients suspected of having gastroesophageal Reflux reflux disease (GERD). Methods: Three hundred and eleven patients referred for GERD diagnostic procedures in a gastroesopahgeal motility laboratory were included in the study. Patients underwent upper endoscopy (UE), esophageal manometry, 24-hour esophageal pH-metry and an interview regarding their clinical symptoms. The following risk factors of patients in the negative pH-metry group were compared to those in the positive pH-metry group: IEM, defective LES, HH, and esophagitis. The association between IEM and positive pH-metry results was first assessed by means of univariate analysis and later determined with logistic regression analysis (multivariate). Results: Of the total 311 patients studied, 208 met the inclusion criteria (mean age 47 years); 88 had normal pH-metry reslults and 120 had positive pH-metry results. Univariate analysis revealed that the occurrence of IEM, defective LES, and HH was significantly greater in the positive pH-metry group. Following logistic regression analysis, the occurrence of IEM remained significantly greater in the positive pH-metry group. Conclusions: IEM is associated with the presence of abnormal acid reflux, as assessed by 24-hour esophageal pH-metry, regardless of the presence of defective LES, HH, or esophagitis.

Introdução: A fisiopatologia da Doença do Refluxo Gastroesofágico (DRGE) é multifatorial, sendo a motilidade esofágica um dos fatores implicados na sua gênese. Todavia, ainda não há consenso sobre a existência de associação entre dismotilidade e Hérnia Hiatal (HH) em pacientes com DRGE. Esse estudo tem como objetivo estabelecer a prevalência de Dismotilidade Esofágica (DE) em pacientes com HH e avaliar se a herniação é fator relacionado à DE. Métodos: Foram estudados 356 pacientes com diagnóstico clínico de DRGE submetidos à Endoscopia Digestiva Alta e Manometria Esofágica. Hérnia Hiatal foi definida endoscopicamente por uma distância igual ou maior que 2 cm entre o pinçamento diafragmático e a junção escamo-colunar e Dismotilidade Esofágica quando a ME identificou amplitude das ondas peristálticas no esôfago distal < 30 mmHg e/ou menos de 80% de contrações efetivas. Foi feita a divisão dos pacientes para a análise estatística em 2 grupos, com e sem HH. Resultados: Pacientes com DRGE portadores de HH tiveram prevalência de DE igual a 14,8% e os sem HH, prevalência de 7,7% (p = 0,041). O grupo de pacientes com HH apresentou também maior frequência de esofagite erosiva (47,5% contra 24,2%, p <0,001), menor valor de pressão no EEI (10,4 versus 13,10; p < 0,001) e maior frequência de indivíduos com valores de pH-metria anormais (p < 0,001). A razão bruta de prevalências de DE, segundo a presença de HH, foi 1,92 (IC: 1,04 - 3,53; p = 0,037), porém essa associação não persistiu quando controlada por idade, esofagite, pH-metria alterada e EEI alterado (RP ajustada: 1,69; IC: 0,68 – 4,15; p = 0,257). Conclusão: Apesar da prevalência de DE no grupo HH ter sido maior do que no grupo sem HH, a associação entre HH e DE em indivíduos com DRGE desaparece ao se controlar por co-variáveis relevantes, levando a crer que neste tipo de paciente, HH não é fator de risco independente destas variáveis. / Introduction: The pathophysiology of gastroesophageal reflux disease is multifactorial, where esophageal motility is one of the factors implicated in its genesis. However, there is still no consensus on the existence of an association between esophageal dysmotility and hiatal hernia in patients with gastroesophageal reflux disease. The objective of this study was to establish the prevalence of esophageal dysmotility in patients with hiatal herina and to determine if herniation is a factor related to esophageal dysmotility. Methods: The study included 356 patients with a clinical diagnosis of gastroesophageal reflux disease submitted to upper digestive endoscopy and esophageal functional dagnostics. Hiatal Hernia was defined endoscopically by a distance equal to or greater than 2 cm between the diaphragmatic constriction and the squamo-columnar junction and esophageal dysmoyility when the esophageal manometry identified the amplitude of the peristaltic waves in the distal esophagus are < 30 mmHg and/or less than 80% of effective contractions. For statistical analysis, the patients were divided into 2 grups: with and without HH. Results: Gastroesophageal reflux disease patients with hiatal hernia had a prevalence of esophageal dysmotility equal to 14.8% and those without hiatal hernia, a prevalence of 7.7% (p = 0.041). The group of patients with hiatal hernia also showed a greater frequency of erosive esophagitis (47.5% versus 24.2%, p <0.001), lower low esophageal sphincter pressure (10.4 versus 13.10; p < 0.001) and greater frequency of individuals with abnormal pH-metry values (p < 0.001). The crude prevalence ratios for esophageal dysmotility, according to the presence of hiatal hernia, was 1.92 (CI: 1.04 - 3.53; p = 0.037), but this association did not persist when controlled for age, esophagitis, altered pH-metry and altered low esophageal sphincter (adjusted PR: 1.69; CI: 0.68 – 4.15; p = 0.257). Conclusion: Despite the prevalence of esophageal dysmotility in the hiatal hernia group being higher than that in the group without hiatal hernia, the association between hiatal hernia and esophageal dysmotility in individuals with gastroesophageal reflux disease disappeared on controlling for relevant co-variables, leading us to believe that in this type of patient, hiatal hernia is not a risk factor independent of these variables.