Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Background: Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA.Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways.Findings: We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. To our knowledge, this study identified for the first time an EA-specific association (rs9823696, P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45).Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.

Application of multivariable control using artificial neural networks in a debutanizer distillation column

LOPES, Jose Soares Batista et al. Application of multivariable control using artificial neural networks in a debutanizer distillation column.In: INTERNATIONAL CONGRESS OF MECHANICAL ENGINEERING - COBEM, 19, 5-9 nov. 2007, Brasilia. Anais... Brasilia, 2007

Effect of Tripanosomicide Benznidazole (Rochagan®) on the Biodistribution of Sodium Pertechnetate (Na99mTcO4) in Wistar Rats

Benznidazole, a drug with specific anti-Trypanosoma cruzi activity, is used in the treatment of Chagas’ disease. The radiopharmaceutical sodium pertechnetate (Na99mTcO4) is used to obtain diagnostic images of the stomach, thyroid, parathyroids, salivary glands, brain and in the study of esophageal reflux and blood flow. This study aimed at evaluating in vivo the influence of benznidazole treatment on the sodium pertechnetate biodistribution in Wistar rats. The percentage of radioactivity per gram (%ATI/g) of various organs (brain, heart, esophagus, stomach, small intestine, large intestine, spleen, liver, muscle and blood) was determined. Comparing the treated rats with the controls, we observed that sodium pertechnetate biodistribution did not change when administered to rats treated for thirty days with benznidazole

Total gastrectomy with substitution of stomach by jejunal pouch with and without duodenal passage. Study in rats

A comparison was done between the F. Paulino jejunal pouch (FP) and a jejunal pouch (JP) as esophagusduodenum interpositional graft, for replacing the stomach after total gastrectomy. It was investigated the effect of the two procedures on esophagus histology, nutritional state and serum gastrin in rats. Methods: Male Wistar rats weighing 282±17g were randomly submitted to sham operation (S), FP and JP after total gastrectomy. After eight weeks the rats were killed with overdose of anesthetic and tissue was taken from the distal esophagus for histology. Serum levels of total proteins, albumin, iron, transferring, folate, cobalamine, calcium, as well as serum gastrin were determined. Survival was considered. Results: Fourty six rats were operated and thirty survived for eight weeks. Five (33.3%) died after FP and 11 (52.3%) after JP (p<0.05). Postoperative esophagitis occurred in 6 JP rats. At 8th week, no difference was observed on body weight when compared FP and JP rats (p>0.05). The JP rats had a significant decrease in serum albumin, glucose, transferrin, iron, folate and calcium, compared to sham (p<0.05). Serum gastrin, iron and calcium were significantly higher in JP rats than in FP rats (p<0.05). In FP rats, transferrin and cobalamine showed significant decrease comparing the preoperative with 8th week levels (p<0.05). Conclusion: F. Paulino pouch in rats had lower mortality than JP, and esophagitis was not detected in it. JP rats had serum gastrin, iron and calcium unaffected, possibly because of preservation of duodenal passage

Application of multivariable control using artificial neural networks in a debutanizer distillation column

LOPES, Jose Soares Batista et al. Application of multivariable control using artificial neural networks in a debutanizer distillation column.In: INTERNATIONAL CONGRESS OF MECHANICAL ENGINEERING - COBEM, 19, 5-9 nov. 2007, Brasilia. Anais... Brasilia, 2007

Effect of Tripanosomicide Benznidazole (Rochagan®) on the Biodistribution of Sodium Pertechnetate (Na99mTcO4) in Wistar Rats

Benznidazole, a drug with specific anti-Trypanosoma cruzi activity, is used in the treatment of Chagas’ disease. The radiopharmaceutical sodium pertechnetate (Na99mTcO4) is used to obtain diagnostic images of the stomach, thyroid, parathyroids, salivary glands, brain and in the study of esophageal reflux and blood flow. This study aimed at evaluating in vivo the influence of benznidazole treatment on the sodium pertechnetate biodistribution in Wistar rats. The percentage of radioactivity per gram (%ATI/g) of various organs (brain, heart, esophagus, stomach, small intestine, large intestine, spleen, liver, muscle and blood) was determined. Comparing the treated rats with the controls, we observed that sodium pertechnetate biodistribution did not change when administered to rats treated for thirty days with benznidazole

Total gastrectomy with substitution of stomach by jejunal pouch with and without duodenal passage. Study in rats

A comparison was done between the F. Paulino jejunal pouch (FP) and a jejunal pouch (JP) as esophagusduodenum interpositional graft, for replacing the stomach after total gastrectomy. It was investigated the effect of the two procedures on esophagus histology, nutritional state and serum gastrin in rats. Methods: Male Wistar rats weighing 282±17g were randomly submitted to sham operation (S), FP and JP after total gastrectomy. After eight weeks the rats were killed with overdose of anesthetic and tissue was taken from the distal esophagus for histology. Serum levels of total proteins, albumin, iron, transferring, folate, cobalamine, calcium, as well as serum gastrin were determined. Survival was considered. Results: Fourty six rats were operated and thirty survived for eight weeks. Five (33.3%) died after FP and 11 (52.3%) after JP (p<0.05). Postoperative esophagitis occurred in 6 JP rats. At 8th week, no difference was observed on body weight when compared FP and JP rats (p>0.05). The JP rats had a significant decrease in serum albumin, glucose, transferrin, iron, folate and calcium, compared to sham (p<0.05). Serum gastrin, iron and calcium were significantly higher in JP rats than in FP rats (p<0.05). In FP rats, transferrin and cobalamine showed significant decrease comparing the preoperative with 8th week levels (p<0.05). Conclusion: F. Paulino pouch in rats had lower mortality than JP, and esophagitis was not detected in it. JP rats had serum gastrin, iron and calcium unaffected, possibly because of preservation of duodenal passage

Characterization of the methanol recovery process at Prio Biocombustíveis S. A.

In a industrial environment, to know the process one is working with is crucial to ensure its good functioning. In the present work, developed at Prio Biocombustíveis S.A. facilities, using process data, collected during the present work, and historical process data, the methanol recovery process was characterized, having started with the characterization of key process streams. Based on the information retrieved from the stream characterization, Aspen Plus® process simulation software was used to replicate the process and perform a sensitivity analysis with the objective of accessing the relative importance of certain key process variables (reflux/feed ratio, reflux temperature, reboiler outlet temperature, methanol, glycerol and water feed compositions). The work proceeded with the application of a set of statistical tools, starting with the Principal Components Analysis (PCA) from which the interactions between process variables and their contribution to the process variability was studied. Next, the Design of Experiments (DoE) was used to acquire experimental data and, with it, create a model for the water amount in the distillate. However, the necessary conditions to perform this method were not met and so it was abandoned. The Multiple Linear Regression method (MLR) was then used with the available data, creating several empiric models for the water at distillate, the one with the highest fit having a R2 equal to 92.93% and AARD equal to 19.44%. Despite the AARD still being relatively high, the model is still adequate to make fast estimates of the distillate’s quality. As for fouling, its presence has been noticed many times during this work. Not being possible to directly measure the fouling, the reboiler inlet steam pressure was used as an indicator of the fouling growth and its growth variation with the amount of Used Cooking Oil incorporated in the whole process. Comparing the steam cost associated to the reboiler’s operation when fouling is low (1.5 bar of steam pressure) and when fouling is high (reboiler’s steam pressure of 3 bar), an increase of about 58% occurs when the fouling increases.

Studies of the gastro-oesophageal junction in normal and overweight healthy volunteers

Introduction: Oesophageal adenocarcinoma has increased dramatically in incidence over the past three decades with a particularly high burden of disease at the gastro-oesophageal junction. Many cases occur in individuals without known gastro-oesophageal reflux disease and in the absence of Barrett’s oesophagus suggesting that mechanisms other than traditional reflux may be important. Distal squamous mucosa may be prone to acid damage even in the absence of traditional reflux by the mechanism of distal opening of the lower oesophageal sphincter. This is splaying of the distal segment of lower oesophageal sphincter allowing acid ingress without traditional reflux. It has been suggested that the cardiac mucosa at the gastro-oesophageal junction, separating oesophageal squamous mucosa and acid secreting columnar mucosa of the stomach may be an abnormal mucosa arising as a consequence of acid damage. By this theory the cardiac mucosa is metaplastic and akin to ultra-short Barrett’s oesophagus. Obesity is a known risk factor for adenocarcinoma at the gastro-oesophageal junction and its rise has paralleled that of oesophageal cancer. Some of this excess risk undoubtedly operates through stress on the gastro-oesophageal junction and a predisposition to reflux. However we sought to explore the impact of obesity on the gastro-oesophageal junction in healthy volunteers without reflux and in particular to determine the characteristics of the cardiac mucosa and mechanisms of reflux in this group. Methods: 61 healthy volunteers with normal and increased waist circumference were recruited. 15 were found to have a hiatus hernia during the study protocol and were analysed separately. Volunteers had comprehensive pathological, physiological and anatomical assessments of the gastro-oesophageal junction including endoscopy with biopsies, MRI scanning before and after a standardised meal, prolonged recording of pH and manometry before and after a meal and screening by fluoroscopy to identify the squamo-columnar junction. In the course of the early manometric assessments a potential error associated with the manometry system recordings was identified. We therefore also sought to document and address this on the benchtop and in vivo. Key Findings: 1. In documenting the behaviour of the manoscan we described an immediate effect of temperature change on the pressure recorded by the sensors; ‘thermal effect’ and an ongoing drift of the recorded pressure with time; ‘baseline drift’. Thermal effect was well compensated within the standard operation of the system but baseline drift not addressed. Applying a linear correction to recorded data substantially reduced the error associated with baseline drift. 2. In asymptomatic healthy volunteers there was lengthening of the cardiac mucosa in association with central obesity and age. Furthermore, the cardiac mucosa in healthy volunteers demonstrated an almost identical immunophenotype to non-IM Barrett’s mucosa, which is considered to arise by metaplasia of oesophageal squamous mucosa. These findings support the hypothesis that the cardia is metaplastic in origin. 3. We have demonstrated a plausible mechanism of damage to distal squamous mucosa in association with obesity. In those with a large waist circumference we observed increased ingress of acid within but not across the lower oesophageal sphincter; ‘intrasphincteric reflux’ 4. The 15 healthy volunteers with a hiatus hernia were compared to 15 controls matched for age, gender and waist circumference. Those with a hiatus hernia had a longer cardiac mucosa and although they did not have excess traditional reflux they had excess distal acid exposure by short segment acid reflux and intrasphincteric acid reflux. Conclusions: These findings are likely to be relevant to adenocarcinoma of the gastro-oesophageal junction

Miotomía extendida en el tratamiento de la acalasia

La acalasia es una enfermedad esofágica poco frecuente que se acompaña de una importante alteración de la calidad de vida de los pacientes. Su etiología no está totalmente aclarada y sus características clínicas principales son la disfagia y la regurgitación. El tratamiento de la acalasia está dirigido al alivio funcional y sintomático mediante la abertura del esfínter esofágico inferior, siendo al momento la miotomía laparoscópica la técnica de elección mientras que las dilataciones neumáticas y la inyección de toxina botulínica deben considerarse como técnicas de recurso en casos seleccionados. Objetivo: Evaluar los resultados de la miotomía extendida más funduplicatura parcial anterior de Dorr como tratamiento de la acalasia por vía laparoscópica, comparándola con nuestra experiencia previa mediante la técnica estándar. Materiales y método: diseño: Estudio prospectivo, descriptivo y longitudinal. Sede: Hospital Latino, Cuenca - Ecuador. Pacientes y método: Desde junio de 1992 hasta diciembre del 2011 se intervinieron 39 pacientes con diagnóstico de acalasia que recibieron tratamiento quirúrgico por medio de cirugía mínimamente invasiva. Se estudió la edad, sintomatología previa, clasificación según Stewart, tiempo de evolución de los síntomas, técnica operatoria realizada, control postoperatorio. Resultados: Se intervinieron 39 paciente, con edad promedio de 66 años, mínima 23 y máxima 81. La sintomatología presentada fue disfagia en el 100%, regurgitación en el 74,4%, pérdida de peso en el 71,8% y odinofagia en el 28.2%. El tiempo de evolución de los síntomas fueron: menor a 2 años 48.7% (n=19), de 2 a 4 años 33.3% (n=13), de 4 a 6 años de 12.8% (n=5), y de 6 a 8 años un 5.1% (n=2). Según Stewart se clasificaron en I 8% (n=3), II 49% (n=19), III 38% (n=15) y IV 5% (n=2).La técnica empleada fue Miotomía + Dorr 57% (n=22), Miotomía extendida + Dorr 20% (n=8), Miotomía sola 18% (n=7), Miotomía + Toupet 5% (n=2). Se ha realizado seguimiento del 75% de pacientes, con resultados excelentes en el 91%, y bueno en el 9%. En los ocho últimos casos se realizó la miotomía extendida más funduplicatura tipo Dorr, brindando resultados excelentes a corto plazo. Conclusión: la miotomía gástrica extendida mejora el resultado de la terapia quirúrgica para la acalasia sin incrementar la tasa de reflujo gastroesofágico anormal cuando se añade una funduplicatura parcial anterior tipo Dorr.

Funduplicatura de Nissen laparoscópico en el tratamiento de la enfermedad por reflujo gastroesofágico. Hospital Vicente Corral Moscoso. Cuenca, 1997-2008

Introducción: Alrededor del 25 a 50% de sujetos con enfermedad por reflujo gastroesofágico tienen enfermedad persistente progresiva, en ellos, la intervención quirúrgica constituye la mejor opción y el único recurso capaz de restaurar la barrera gastroesofágica. La funduplicatura de Nissen de elección, se realiza por laparoscopía desde febrero de 1997 en nuestro hospital. Objetivo: describir aspectos demográficos y clínicos de pacientes sometidos a funduplicatura de Nissen laparoscópico en el hospital Vicente Corral Moscoso. Método: análisis descriptivo y retrospectivo de videos e historias clínicas en estadística y cirugía de las funduplicaturas de Nissen laparoscópico. Resultados: de febrero 1997 a julio 2008, se realizaron 58 funduplicaturas, en 36 hombres y 22 mujeres, con un promedio de 42 años. Síntomas predominantes; pirosis, regurgitación, dolor abdominal y disfagia. Diagnosticados por: endoscopía digestiva alta y serie esófagogastroduodenal en todos. Com - plicaciones posoperatorias inmediatas: íleo 9, disfagia 5, retención urinaria 4. Tiempo operatorio promedio: 181 minutos en 1997, 102 minutos en 2008. Estancia hospitalaria: 4 días. 49 pacientes recibieron alimentación en 24 horas. No hubo conversiones ni mortalidad. Conclusiones: la cirugía laparoscópica en el tratamiento de ERGE va en aumento y constituye un tratamiento eficaz a largo plazo. Pero los cirujanos debemos también examinar los éxitos, los errores, las complicaciones y limitaciones de estas aplicaciones a largo plazo y con más variables estudiadas.

Síntese de ß-cetoésteres graxos a partir do ácido de Meldrum usando DCC e DMAP

Neste trabalho desenvolveu-se a síntese de -cetoésteres, a partir da acilação do ácido de Meldrum usando diferentes ácidos graxos, com cadeias saturadas e insaturadas. Inicialmente, foi realizado o experimento utilizando o ácido palmítico (1e) como modelo para obtenção de cloreto de ácido graxo, usando ácido de Meldrum e piridina como catalisador. Porém, após um longo tempo de reação, o -cetoéster palmítico (4e) foi obtido com baixo rendimento, não ultrapassando os 20%. Posteriormente, os experimentos foram realizados utilizando o ácidos graxos 1e, ácido de Meldrum (2), DCC, DMAP, e piridina à temperatura ambiente sob a atmosfera de nitrogênio. No entanto, o protocolo utilizado resultou no β-cetoéster 4e com rendimentos moderados. Em seguida examinou-se o efeito da adição do ácido de Meldrum após a adição dos ácido graxos e DCC. Neste caso, após a adição do DCC aos ácido graxos 1a-j foi observada a formação imediata das O-aciluréias graxas. A seguir a adição de 2,0 equiv de ácido de Meldrum (2) em diclorometano, revelou a formação dos respectivos enol graxos 3a-j. Posteriormente, os β- cetoésteres 4a-j foram obtidos a partir da reação do enol com o metanol. Este protocolo modificado proporcionou o aumento nos rendimentos (74 a 84%) dos β-cetoéster 4a-j. Após, o β-cetoéster 4k foi sintetizado em 75% utilizando o ácido de Meldrum (2) e ácido ricinoléico (1k), obtido a partir do biodiesel de mamona, à temperatura ambiente e sob a atmosfera de nitrogênio. Portanto, foi desenvolvido um método simples para obter β-cetoésteres graxos, a partir do ácido de Meldrum com cadeias graxas diversificadas utilizando DCC e DMAP. Além disso, o presente trabalho relata pela primeira vez a síntese de novos β-cetoésteres graxos derivados dos ácidos oléico, elaídico, ricinoléico, linoléico e linolênico.

Prevalence of Barrett Esophagus in Adolescents and Young Adults With Esophageal Atresia

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Síntese de nanopartículas de magnetita via decomposição térmica em meio não-aquoso

This work aims at obtaining nanoparticles of iron oxide, the magnetite one (Fe3O4), via synthesis by thermal decomposition through polyol. Thus, two routes were evaluated: a simple decomposition route assisted by reflux and a hydrothermal route both without synthetic air atmosphere using a synthesis temperature of 260ºC. In this work observed the influence of the observe of surfactants which are generally applied in the synthesis of iron oxide nanoparticles decreasing cluster areas. Further, was observed pure magnetite phase without secondary phases generally found in the iron oxide synthesis, a better control of crystallite size, morphology, crystal structure and magnetic behavior. Finally, the introduction of hydroxyl groups on the nanoparticles surface was analyzed besides its employment in the polymer production with OH radicals. The obtained materials were characterized by XRD, DLS, VSM, TEM, TG and DSC analyses. The results for the magnetite obtainment with a particle size greater than 5 nm and smaller than 11 nm, well defined morphology and good magnetic properties with superparamagnetic behavior. The reflux synthesis was more efficient in the deposition of the hydroxyl groups on the nanoparticles surface

Prevalencia del Helicobacter Pylori y factores asociados en escolares de la etnia Shuar del cantón Sucúa –Morona Santiago, 2014.

Introducción: Según la OMS, más del 50% de la población adulta está infectada con el Helicobacter Pylori, con prevalencias de hasta el 90%. La mayoría de contagios se produce antes de los 10 años de edad. Desde el descubrimiento del H. Pylori (1983), se lo ha relacionado con la úlcera péptica, gastritis, reflujo gastroesofágico e incluso, cáncer gástrico. Metodología: Se realizó un estudio transversal analítico. La muestra estuvo conformada por 250 niños escolares de la etnia Shuar del cantón Sucúa. La prueba utilizada para la detección del Helicobacter pylori es la identificación de antígenos en las heces por inmunocromatografía. Para establecer la significancia de asociación de variables se utilizó el OR con su intervalo de confianza al 95%. Resultados: El promedio de edad fue de 8.8 años (DS 2.0), con predominio de las mujeres (54.4%). El 56.4% consume agua potable, el 71.65% vive en hacinamiento, el 42% tiene servicios de letrinización y el 49.2% cuenta con servicios de alcantarillado. Se encontró asociación significativa con el nivel de instrucción OR 1.68, IC95% (1 – 2.84), p=0.049; letrinización OR 1.99, IC95% (1.17 – 3.36), p=0.01; deposiciones al aire libre OR 4.32, IC95% (2.13 – 8.77), p=0.000. Conclusiones: La prevalencia de Helicobacter pylori es alta en la población escolar de la etnia Shuar; está asociada a un nivel bajo de instrucción de los progenitores y una inadecuada infraestructura de servicios básicos.