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We extend the application of the adaptive resolution technique (AdResS) to liquid systems composed of alkane chains of different lengths. The aim of the study is to develop and test the modifications of AdResS required in order to handle the change of representation of large molecules. The robustness of the approach is shown by calculating several relevant structural properties and comparing them with the results of full atomistic simulations. The extended scheme represents a robust prototype for the simulation of macromolecular systems of interest in several fields, from material science to biophysics.
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BACKGROUND: Intestinal absorption capacity is considered to be the best method for assessing overall digestive intestinal function. Earlier reference values for intestinal function in healthy Dutch adults were based on a study that was conducted in an inpatient metabolic unit setting in a relatively small series. The present study aimed to readdress and describe the intestinal absorption capacity of healthy adults, who were consuming their usual (Western European) food and beverage diet, in a standard ambulatory setting. METHODS: Twenty-three healthy subjects (aged 22-60 years) were included in the analyses. Nutritional intake (energy and macronutrients) was determined with a 4-day nutritional diary. Subsequently, mean faecal losses of energy (by bomb calorimetry), fat, protein and carbohydrate were determined following a 3-day faecal collection. Finally, intestinal absorption capacity was calculated from the differences between intake and losses. RESULTS: Mean (SD) daily faeces production was 141 (49) g (29% dry weight), containing 891 (276) kJ [10.7 (1.3) kJ g(-1) wet faeces; 22.6 (2.5) kJ g(-1) dry faeces], 5.2 (2.2) g fat, 10.0 (3.8) g protein and 29.7 (11.7) g carbohydrates. Mean (SD) intestinal absorption capacity of healthy subjects was 89.4% (3.8%) for energy, 92.5% (3.7%) for fat, 86.9% (6.4%) for protein and 87.3% (6.6%) for carbohydrates. CONCLUSIONS: The present study provides normative values for both stool nutrient composition and intestinal energy and macronutrient absorption in healthy adults on a regular Dutch diet in an ambulatory setting. Intestinal energy absorption was found to be approximately 90%.
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Calorimetría/métodos , Calorimetría/normas , Ingestión de Energía , Absorción Intestinal/fisiología , Adulto , Registros de Dieta , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Heces/química , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Evaluación Nutricional , Valores de Referencia , Adulto JovenRESUMEN
BACKGROUND: The rising incidence and histological change to adenocarcinoma in esophageal cancer over the past four decades has been among the most dramatic changes ever observed in human cancer. Recent reports have suggested that its increasing incidence may have plateaued over the past decade. Our aim was to examine the latest overall and stage-specific trends in the incidence of esophageal adenocarcinoma. PATIENTS AND METHODS: We used the Surveillance Epidemiology and End Results (SEER) database of the National Cancer Institute to identify all patients with adenocarcinoma of the esophagus and gastric cardia between 1973 and 2009. Both overall and stage-specific trends in incidence were analyzed using joinpoint regression analysis. RESULTS: The overall incidence of adenocarcinoma of the esophagus and the gastric cardia increased from 13.4 per million in 1973 to 51.4 per million in 2009, a nearly 400 % increase. Jointpoint analysis demonstrated that the yearly increase in incidence has slowed somewhat from 1.27 per million before 1987 to 0.97 between 1987 and 1997 and 0.65 after 1997. Stage-specific analysis suggests that the incidence of noninvasive cancer has actually declined after 2003 with a yearly decrease of 0.22. The percentage of patients diagnosed with in situ cancer declined after 2000 and remained under 2.5 % through the study period. CONCLUSIONS: The incidence of esophageal adenocarcinoma continues to rise in the USA. The percentage of patients diagnosed with in situ cancer has declined in the twenty-first century.
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The introduction of high-resolution manometry (HRM) has been a significant advance in esophageal diagnostics. Normative values however are currently based upon a single set of published reference values, and multiple new metrics have been added over the past several years. Our goal was to provide a second set of 'normal-values' and to include all current metrics suggested by the 2012 Chicago classification. Sixty-eight subjects without foregut symptoms or previous surgery (median age 25.5 years, ranging from 20-58 years, 53% female) underwent esophageal motility assessment via an established standardized protocol. Normative thresholds were calculated for esophago-gastric junction (EGJ) characteristics (resting, relaxation, intrabolus pressure, and lengths) as well as for esophageal body strength (contraction amplitudes at multiple levels, distal contractile integral, integrity of peristalsis) and wave propagation (contractile front velocity, distal latency). Overall, our findings where strikingly similar to the previously described metrics derived from 75 control subjects of the Northwestern group. This suggests a high degree of reproducibility of HRM.
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Esófago/fisiología , Motilidad Gastrointestinal/fisiología , Manometría/métodos , Contracción Muscular/fisiología , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Peristaltismo/fisiología , Presión , Valores de Referencia , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Esophageal motor function is highly coordinated between central and enteric nervous systems and the esophageal musculature, which consists of proximal skeletal and distal smooth muscle in three functional regions, the upper and lower esophageal sphincters, and the esophageal body. While upper endoscopy is useful in evaluating for structural disorders of the esophagus, barium esophagography, radionuclide transit studies, and esophageal intraluminal impedance evaluate esophageal transit and partially assess motor function. However, esophageal manometry is the test of choice for the evaluation of esophageal motor function. In recent years, high-resolution manometry (HRM) has streamlined the process of acquisition and display of esophageal pressure data, while uncovering hitherto unrecognized esophageal physiologic mechanisms and pathophysiologic patterns. New algorithms have been devised for analysis and reporting of esophageal pressure topography from HRM. The clinical value of HRM extends to the pediatric population, and complements preoperative evaluation prior to foregut surgery. Provocative maneuvers during HRM may add to the assessment of esophageal motor function. The addition of impedance to HRM provides bolus transit data, but impact on clinical management remains unclear. Emerging techniques such as 3-D HRM and impedance planimetry show promise in the assessment of esophageal sphincter function and esophageal biomechanics.
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Trastornos de la Motilidad Esofágica/diagnóstico , Trastornos de la Motilidad Esofágica/fisiopatología , Esófago/fisiopatología , Humanos , Manometría/métodosRESUMEN
BACKGROUND: The value of lymphadenectomy in most localized gastrointestinal (GI) malignancies is well established. Our objectives were to evaluate the time trends of lymphadenectomy in GI cancer and identify factors associated with inadequate lymphadenectomy in a large population-based sample. METHODS: Using the National Cancer Institute's Surveillance Epidemiology and End Results Database (1998-2009), a total of 326,243 patients with surgically treated GI malignancy (esophagus, 13,165; stomach, 18,858; small bowel, 7,666; colon, 232,345; rectum, 42,338; pancreas, 12,141) were identified. Adequate lymphadenectomy was defined based on the National Cancer Center Network's recommendations as more than 15 esophagus, 15 stomach, 12 small bowel, 12 colon, 12 rectum, and 15 pancreas. The median number of lymph nodes removed and the prevalence of adequate and/or no lymphadenectomy for each cancer type were assessed and trended over the ten study years. Multivariate logistic regression was employed to identify factors predicting adequate lymphadenectomy. RESULTS: The median number of excised nodes improved over the decade of study in all types of cancer: esophagus, from 7 to 13; stomach, 8-12; small bowel, 2-7; colon, 9-16; rectum, 8-13; and pancreas, 7-13. Furthermore, the percentage of patients with an adequate lymphadenectomy (49 % for all types) steadily increased, and those with zero nodes removed (6 % for all types) steadily decreased in all types of cancer, although both remained far from ideal. By 2009, the percentages of patients with adequate lymphadenectomy were 43 % for esophagus, 42 % for stomach, 35 % for small intestine, 77 % for colon, 61 % for rectum, and 42 % for pancreas. Men, patients >65 years old, or those undergoing surgical therapy earlier in the study period and living in areas with high poverty rates were significantly less likely to receive adequate lymphadenectomy (all p < 0.0001). CONCLUSIONS: Lymph node retrieval during surgery for GI cancer remains inadequate in a large proportion of patients in the USA, although the median number of resected nodes increased over the last 10 years. Gender and socioeconomic disparities in receiving adequate lymphadenectomy were observed.
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Neoplasias Gastrointestinales/cirugía , Disparidades en Atención de Salud/estadística & datos numéricos , Escisión del Ganglio Linfático/estadística & datos numéricos , Escisión del Ganglio Linfático/tendencias , Anciano , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Masculino , Factores de Tiempo , Estados UnidosRESUMEN
BACKGROUND: The assessment of the esophagogastric junction (EGJ) is the most challenging aspect of clinical esophageal manometry. Although conventional manometric systems can be optimized toward interrogating specific aspects of the EGJ, they are too limited in recording channels and/or fidelity for a comprehensive assessment. The technological advantages inherent in high resolution manometry (HRM) with esophageal pressure topography (EPT) analysis substantially change this equation providing a technology sufficiently robust to dynamically record the contractile activity within the EGJ with both good fidelity and good spatial resolution. PURPOSE: This review is an update on our understanding of the application of HRM and EPT to the analysis of EGJ function. With respect to sphincter relaxation, the integrated relaxation pressure (IRP) has proven to be a robust metric in differentiating intact from impaired EGJ relaxation. In the process, it revealed that impaired EGJ relaxation could occur not only in the setting of achalasia but also with other causes of EGJ outflow obstruction including hiatus hernia. The morphological description of the EGJ by EPT has also revealed not only a spectrum of abnormality ranging from an intact sphincter to overt herniation, but also the surprise finding of spontaneous conversion among sphincter configurations, emphasizing its dynamic nature. With respect to barrier function, preliminary data have refocused on the crural diaphragm as a key-differentiating feature between preserved and compromised function. Finally, although the accomplishments summarized above are substantial, much work remains to fully exploit the potential of EPT in the clinical characterization of the EGJ.
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Unión Esofagogástrica/fisiología , Manometría/métodos , HumanosRESUMEN
Our understanding of esophageal disease and the foregut has evolved over the past 100 years, especially in recent times. Modern diagnostic technologies and new management paradigms have provided progressive insights into the anatomy, physiology, and normal and abnormal function of the esophagus, as well as improving patient care. Yet, the relationship between the esophagus and its close neighbor, the spine, is rarely discussed and likely underappreciated. Anatomic proximity and intertwined pathophysiology led early investigators to postulate relationships between esophageal disease and spinal abnormalities. More recent studies have illustrated a link between spinal disease and hiatal hernias. Objective radiographic measurements of kyphoscoliosis have correlated with increased hiatal hernia formation. Spinal abnormalities and disease of the esophageal hiatus are becoming more common in our aging population, with each carrying significant risk of morbidity and decreased quality of life. Operative planning and subsequent hiatal hernia repair must be undertaken in the context of these spinal abnormalities. A historical review of past publications related to the subject forms the basis for this publication, thus revealing insight and improving our understanding of the association between spinal abnormalities and hiatal hernias.
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Hernia Hiatal/historia , Cifosis/historia , Diafragma/fisiopatología , Hernia Hiatal/fisiopatología , Historia del Siglo XVI , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Cifosis/fisiopatología , Columna Vertebral/fisiopatologíaRESUMEN
Small intestinal function in critically ill patients should ideally be assessed in order to determine the preferred feeding route, timing, and composition of enteral nutrition. Additionally, evaluation of small bowel function may lead to new insights aimed to maintain enterocyte integrity. Critically ill patients are likely to have impaired enterocyte function mainly as a consequence of diminished splanchnic blood flow associated with mucosal hyperpermeability and bacterial translocation, a pathological state believed to be pivotal in the development of sepsis and multiple organ dysfunction syndrome (MODS). However, feasible and validated clinical tools to reliably assess enterocyte function are lacking. This explorative review discusses the promising role of citrulline, a nonprotein amino acid almost exclusively generated by the enterocyte, as a biomarker reflecting enterocyte function in critically ill patients. Citrulline metabolism, its potential as enterocyte biomarker, and literature on citrulline in critically illness will be discussed. Finally, a novel test for enterocyte function, the citrulline generation test (enterocytic citrulline production upon stimulation with enteral or intravenous glutamine) will be considered briefly.
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Citrulina/metabolismo , Enfermedad Crítica , Intestino Delgado/fisiopatología , Biomarcadores/metabolismo , Enterocitos/fisiología , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/patologíaRESUMEN
OBJECTIVES: To define, for the C5.18 chondrocyte-restricted rat cell line, (1) the capacities for recognition of alternatively spliced segments of the adhesion protein fibronectin (FN), (2) the integrin subunits required for such recognition, and (3) differences in such FN recognition vs the multipotential chondroprogenitor line, RCJ 3.1. METHODS: C5.18 and RCJ 3.1 cells were tested for their capacities to adhere to recombinant alternatively spliced segments of rat FN, presented on plastic surfaces either in isolation or in partial FNs spanning the 7th through 15th type III repeats (III7-15 FNs). The effects on such adhesion of cations and integrin subunit-specific antibodies were tested. RESULTS: Despite significant augmentation in chondrocyte-specific gene expression in C5.18 relative to the RCJ 3.1 cells, the two lines exhibited similar recognition of FN spliced segments and partial isoforms. Specifically, both lines adhered to the extra type III repeat A (EIIIA) and V, but not extra type III repeat B (EIIIB), segments. There were different cation and integrin subunit requirements for adhesion to EIIIA vs V segments, and only the V segment was recognized in the context of a III7-15 FN. Such recognition was mediated via a "second" arginine-glycine-aspartic acid (RGD) sequence that is present in the V95 subsegment in rat, but not human, FN. CONCLUSION: The chondrocyte lineage-committed C5.18 cell line, similar to its multipotential chondroprogenitor, RCJ 3.1, recognizes the "cartilage-restricted" EIIIA and V segments of FN with cation, integrin, and molecular context requirements that are specific to each of these segments.
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Empalme Alternativo , Adhesión Celular/fisiología , Condrocitos/fisiología , Fibronectinas/fisiología , Empalme Alternativo/fisiología , Animales , Adhesión Celular/genética , Línea Celular Transformada , Condrocitos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Fibronectinas/biosíntesis , Fibronectinas/genética , Integrinas/fisiología , Fragmentos de Péptidos/fisiología , Reacción en Cadena de la Polimerasa/métodos , RatasRESUMEN
BACKGROUND: Proof of the relationship between gastroesophageal reflux disease (GERD) and respiratory symptoms remains a challenge. Our aim was to determine the association between reflux events and O(2) desaturation in GERD patients with primary respiratory symptoms (RS) compared to those with primary esophageal symptoms (ES) using ambulatory monitoring systems. METHODS: One thousand eight hundred fifty-one reflux episodes were detected by multichannel intraluminal impedance (MII)-pH testing in 30 patients with symptoms of GERD (20 RS, ten ES.) All patients underwent simultaneous 24-h MII-pH and continuous O(2) saturation monitoring via pulse oximetry. Reflux-associated desaturation events were determined by correlating synchronized 24-h esophageal pH and/or impedance and O(2) desaturation. RESULTS: One thousand one hundred seventeen reflux events occurred in patients with RS and 734 in those with ES. Nearly 60% of these 1,851 reflux events were associated with O(2) desaturation. Markedly more events were associated with O(2) desaturation in patients with RS (74.5%, 832/1,117) than in patients with ES (30.4%, 223/734, p < 0.0001). The difference in reflux desaturation association was more profound with proximal reflux--80.3% with RS vs. 29.4% with ES (p < 0.0001). CONCLUSIONS: A remarkably high prevalence of O(2) desaturation associated with gastroesophageal reflux was noted in patients with RS. Given further study, simultaneous combined esophageal reflux and O(2) saturation monitoring may prove a useful diagnostic tool in this difficult group of patients.
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Monitoreo de Gas Sanguíneo Transcutáneo , Monitorización del pH Esofágico , Reflujo Gastroesofágico/complicaciones , Hipoxia/diagnóstico , Trastornos Respiratorios/sangre , Trastornos Respiratorios/fisiopatología , Adolescente , Adulto , Anciano , Femenino , Reflujo Gastroesofágico/sangre , Reflujo Gastroesofágico/fisiopatología , Humanos , Hipoxia/etiología , Hipoxia/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Trastornos Respiratorios/etiología , Factores de Riesgo , Adulto JovenRESUMEN
Endoscopic therapies for the treatment of complicated Barret's esophagus should be embraced by the surgical community. While esophagectomy remains the standard of care for early esophageal neoplasia in many centers, endoscopic techniques are being increasingly utilizid. As refinements in both endoscopic and surgical approaches continue to evolve, accurate and contempary assessments of outcomes are critical in assuring that each is applied in appropriate circumstances.
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Adenocarcinoma/cirugía , Esófago de Barrett/cirugía , Neoplasias Esofágicas/cirugía , Esofagoscopía/tendencias , Lesiones Precancerosas/cirugía , Adenocarcinoma/patología , Esófago de Barrett/patología , Difusión de Innovaciones , Neoplasias Esofágicas/patología , Esofagectomía/tendencias , Esófago/patología , Esófago/cirugía , Predicción , Humanos , Lesiones Precancerosas/patologíaRESUMEN
BACKGROUND: The amino acid citrulline is mainly produced by enterocytes from conversion of glutamine. As fasting plasma citrulline proved disappointing as a biomarker for enterocyte dysfunction in clinical practice, we propose a citrulline generation test (CGT) to assess enterocyte function. AIM: To assess the feasibility of a CGT in healthy subjects and patients with decreased enterocyte mass. METHODS: Nineteen healthy subjects, 16 patients with intestinal villous atrophy and nine patients with short bowel syndrome (SBS) were given an oral bolus of 20 g of the dipeptide alanine-glutamine. Subsequent changes in plasma citrulline and other amino acid concentrations were determined using reverse-phase high-performance liquid chromatography. RESULTS: Following the oral bolus of alanine-glutamine, plasma citrulline concentrations showed a time dependent rise in healthy subjects of 44 +/- 13% (38-55 micromol/L, P < 0.0001). The slope from baseline plasma citrulline to peak concentrations was 0.22 +/- 0.08, 0.13 +/- 0.04 and 0.09 +/- 0.04 micromol/L/min in healthy subjects, patients with coeliac disease (CeD) and refractory CeD, respectively (healthy subjects vs. CeD P < 0.05, healthy subjects vs. refractory CeD P < 0.001). In patients with SBS, the CGT was able to distinguish between non-adapted and adapted SBS by means of the incremental area under the CGT curve till 90 min (iAUC T90). The iAUC T90 was 447 +/- 179 and 1039 +/- 178 micromol/L/min in non-adapted and adapted SBS, respectively (P = 0.04). CONCLUSION: An oral bolus of alanine-glutamine induces a time-dependent rise in plasma citrulline concentration to an extent dependent on the existence of villous atrophy or enterocyte hyperplasia in CeD, and adapted SBS, respectively.
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Enfermedad Celíaca/metabolismo , Citrulina/metabolismo , Enterocitos/metabolismo , Absorción Intestinal/fisiología , Adulto , Biomarcadores/metabolismo , Calorimetría , Enfermedad Celíaca/terapia , Citrulina/administración & dosificación , Estudios Transversales , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: Dysphagia following esophagectomy with cervical esophagogastric anastomosis is common and often can be attributed to anastomotic stricture. The prevalence, risk factors, symptomatic and endoscopic severity, and response to dilation of such strictures, however, are poorly defined. METHODS: In the present study the population consisted of 42 patients undergoing esophagectomy with gastric pull-up and cervical anastomosis. Any complaint of postoperative dysphagia was investigated with upper endoscopy. Patients undergoing endoscopy were entered into a prospective randomized trial of graduated balloon versus bougie-over-a-guidewire dilation that will be part of a future report. Dysphagia was assigned a standardized severity score, and stricture diameter pre-dilation was classified as minimal (>12 mm), mild (9-12 mm), moderate (5-8 mm), or severe (<5 mm). Outcome measures included the incidence, time to first dilation, symptomatic and endoscopic severity of anastomotic strictures, number of dilations, and influence of co-morbidities and anastomotic technique on stricture occurrence. RESULTS: Twenty-seven of 41 (66%) surviving patients underwent endoscopy and dilation. Median time to presentation was 2.4 months (min, 27 days; max, 11 months). Most patients (63%) with stricture complained of dysphagia with every meal. The majority (93%) of strictures were mild to moderate (5-12 mm), and there was no correlation between dysphagia frequency and stricture size. Tolerance of an unrestricted diet decreased with increasing stricture severity. In all, 98 dilation sessions were performed without complication. A higher stricture rate was noted following handsewn anastomoses as compared to combined stapled and handsewn anastomoses (85.7% versus 55.5%; p = 0.044). CONCLUSIONS: Most patients with symptomatic anastomotic strictures following esophagectomy with cervical esophagogastrostomy present within the first few months following surgery. Half of such strictures are minimal to mild as endoscopically assessed. Dilation is safe, and most patients experience symptomatic relief after only a few dilation sessions. A combined handsewn and stapled anastomosis may decrease the risk of stricture formation relative to a two-layer handsewn technique.
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Trastornos de Deglución/diagnóstico , Neoplasias Esofágicas/cirugía , Estenosis Esofágica/diagnóstico , Esofagectomía/efectos adversos , Esofagoscopía/métodos , Esófago/cirugía , Estómago/cirugía , Anastomosis Quirúrgica/efectos adversos , Cateterismo/métodos , Trastornos de Deglución/etiología , Trastornos de Deglución/terapia , Estenosis Esofágica/complicaciones , Estenosis Esofágica/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
A recombinantly produced murine leptin analog (MLA) antagonizes leptin-induced signaling in cell lines that express the long form of the leptin receptor. However, the effects of MLA on the activity of leptin-sensitive neurons and on central neural controls of food intake have not been reported. Here we report effects of MLA on food intake and body weight in adult rats and on the activity of cultured rat vagal afferent neurons. Daily intracerebroventricular coinjection of MLA with exogenous leptin significantly attenuated leptin-induced reduction of 48-h food intake and body weight. Coinjection of MLA with leptin also reduced leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. In addition, chronic intracerebroventricular MLA infusion over 14 d via osmotic minipumps significantly increased daily food intake, rate of body weight gain, fat-pad mass, and circulating plasma leptin concentrations. Surprisingly, however, MLA did not antagonize leptin-evoked increases in cytosolic calcium concentrations in vagal afferent neurons in primary culture. Rather, MLA itself produced acute activation selectively in leptin-responsive vagal afferent neurons. These data suggest that MLA is an antagonist for the central effects of leptin on food intake and body weight but an agonist at sites where leptin induces acute neuronal activation. This mixed antagonist/agonist action suggests either 1) that the coupling of a single leptin receptor (ObRb) to acute activation of neurons occurs by a signaling mechanism different from those that mediate centrally evoked reductions in food intake and body weight or 2) that acute neuronal activation and centrally induced reductions of food intake and body weight are mediated by different leptin receptor subtypes.
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Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Leptina/análogos & derivados , Leptina/antagonistas & inhibidores , Neuronas Aferentes/efectos de los fármacos , Proteínas Recombinantes/farmacología , Nervio Vago/efectos de los fármacos , Animales , Células Cultivadas , Bombas de Infusión , Leptina/administración & dosificación , Leptina/farmacología , Masculino , Imitación Molecular , Neuronas Aferentes/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Nervio Vago/metabolismoRESUMEN
PURPOSE: We conducted a pilot trial to assess the feasibility and tolerability of a prime/boost vaccine strategy using interferon-gamma (IFN-gamma) and autologous dendritic cells (DCs) pulsed with HLA-A2-specific prostate-specific antigen (PSA) peptides (PSA-1 [141-150]; PSA-2 [146-156]; PSA-3 [154-163]) for the treatment of 12 patients with hormone refractory prostate carcinoma. PATIENTS AND METHODS: All patients were vaccinated four times with intracutaneously injected PSA-peptide loaded DCs after subcutaneous administration of IFN-gamma 2 hr before DC administration (50 microg/m(2) body surface). Objectives were safety, clinical benefit, clinical and biochemical response, quality of life, and immunological parameters. RESULTS: The vaccination was well tolerated without any vaccination-associated adverse events. One partial and one mixed responder were identified, four patients showed stable diseases. Two patients had a decrease and four a slow-down velocity slope in the PSA serum level. All responders showed a positive DTH-response, but only two a slight increase in PSA-peptide specific T-lymphocytes. CONCLUSION: The immunotherapy with IFN-gamma and PSA-peptide loaded DCs was feasible and well tolerated. The observed responses imply a potential antitumor activity.
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Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Inmunoterapia Adoptiva/métodos , Interferón gamma/uso terapéutico , Antígeno Prostático Específico , Neoplasias de la Próstata/terapia , Anciano , Anciano de 80 o más Años , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Progresión de la Enfermedad , Antígeno HLA-A2/inmunología , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inyecciones Subcutáneas , Interferón gamma/efectos adversos , Interferón gamma/inmunología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Antígeno Prostático Específico/inmunología , Neoplasias de la Próstata/inmunología , Calidad de VidaRESUMEN
The molecular pathogenesis of Barrett's esophagus is poorly understood. Evidence suggests that at a phenotypic level, the metaplastic process begins with the transformation of squamous epithelium in the distal esophagus to cardiac mucosa, which subsequently becomes intestinalized. The homeobox gene Cdx-2 has been shown to be an important transcriptional regulator of embryonic differentiation and maintenance of adult intestinal type epithelium. We hypothesized that Cdx-2 gene expression levels increase with the phenotypic transformation of normal squamous mucosa to the intestinalized columnar mucosa of Barrett's esophagus. Endoscopic biopsies were obtained at the gastroesophageal junction in patients with symptoms of gastroesophageal reflux disease and classified according to histology: normal squamous mucosa (n = 62), cardiac mucosa (n = 19), oxynto-cardiac mucosa (n = 14), and intestinal metaplasia (n = 15). Duodenal biopsies (n = 26) served as the columnar control. After laser capture microdissection and RNA isolation, gene expression levels of Cdx-2 were measured in each tissue type by quantitative reverse transcription polymerase chain reaction. Consistent with its known function, Cdx-2 gene expression levels were highest in duodenal mucosa and nearly absent in squamous epithelium. There was a stepwise increase in Cdx-2 gene expression from cardiac to Barrett's epithelium (P < 0.001). Expression levels of Cdx-2 in cardiac and oxynto-cardiac mucosa were 40-70 times higher and Barrett's mucosa 400 times higher than that found in squamous epithelium. Relative expression of the homeobox gene Cdx-2, known to induce differentiation of intestinal type epithelium, increases in a stepwise fashion during the phenotypic transformation of distal esophageal squamous mucosa to cardiac columnar mucosa and to the intestinalized columnar mucosa of Barrett's esophagus. Therefore, Cdx-2 may be a potential biomarker to detect the early transition to Barrett's esophagus.
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Esófago de Barrett/genética , Esófago de Barrett/patología , Transformación Celular Neoplásica/genética , Unión Esofagogástrica/química , Unión Esofagogástrica/patología , Mucosa Gástrica/química , Mucosa Gástrica/patología , Reflujo Gastroesofágico/genética , Reflujo Gastroesofágico/patología , Proteínas de Homeodominio/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Esófago de Barrett/etiología , Factor de Transcripción CDX2 , Duodeno/patología , Neoplasias Esofágicas/etiología , Esófago/patología , Femenino , Reflujo Gastroesofágico/complicaciones , Expresión Génica , Marcadores Genéticos , Humanos , Mucosa Intestinal/química , Mucosa Intestinal/patología , Masculino , Metaplasia , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
The "art" and science of symptom assessment in the evaluation of patients with gastroesophageal reflux disease has been under emphasized. In fact, it is critical to judgements regarding surgical versus non-surgical therapy and is much more difficult than meets the eye. Many symptoms thought to be secondary to gastroesophageal reflux are not, and some, such as asthma cough and chest pain, which are commonly thought secondary to other causes, are indeed symptoms of reflux. Diagnostic studies are helpful but far from perfect, ultimately requiring the clinician's expert judgement as the key factor in determining a successful outcome. The following outlines both an approach to the assessment of symptoms and when possible, clinical studies shedding light on their cause and interpretation.
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Esófago de Barrett/cirugía , Reflujo Gastroesofágico/cirugía , Anamnesis , Examen Físico , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Angina de Pecho/diagnóstico , Anorexia/diagnóstico , Anorexia/etiología , Asma/diagnóstico , Asma/etiología , Esófago de Barrett/complicaciones , Esófago de Barrett/diagnóstico , Esófago de Barrett/fisiopatología , Esófago de Barrett/terapia , Encéfalo/fisiopatología , Cateterismo , Dolor en el Pecho/etiología , Tos/diagnóstico , Tos/etiología , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Diagnóstico Diferencial , Diagnóstico por Imagen/métodos , Trastornos de la Motilidad Esofágica/diagnóstico , Trastornos de la Motilidad Esofágica/etiología , Potenciales Evocados , Ácido Gástrico , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/etiología , Reflujo Gastroesofágico/fisiopatología , Reflujo Gastroesofágico/terapia , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Ronquera/diagnóstico , Ronquera/etiología , Humanos , Enfermedades Intestinales/complicaciones , Enfermedades Intestinales/diagnóstico , Síndrome del Colon Irritable/diagnóstico , Síndrome del Colon Irritable/etiología , Manometría , Náusea/diagnóstico , Náusea/etiología , Cuidados Preoperatorios , Gastropatías/complicaciones , Gastropatías/diagnóstico , Pérdida de PesoRESUMEN
BACKGROUND: The Bravo catheter-free pH monitoring system uses a capsule attached to the esophageal mucosa to detect acid exposure. Placement of the Bravo capsule is associated with intermittent chest pain in 50% of normal volunteers. The authors hypothesized that chest pain in this setting may be attributable to hypertensive esophageal contractions induced by the Bravo capsule. METHODS: The study population consisted of 40 consecutive patients with reflux symptoms who had stationary esophageal manometry within 1 h after Bravo capsule placement. The control group consisted of 40 patients with symptomatic gastroesophageal reflux disease (GERD) from a population of patients with foregut symptoms who were computer matched to the study group for age, sex, lower esophageal sphincter (LES) pressure, LES length, and 24-h pH composite score. The patients in the control group had manometry before Bravo capsule placement. The occurrence of chest pain was assessed before and during the monitoring period by interview and review of the patient's diary. Mean contraction amplitudes in the distal third of the esophagus after 10 wet swallows were averaged. The prevalence of patients with esophageal contraction amplitudes in the distal third that exceeded the 95th percentile of normal (180 mmHg) and the mean amplitude of distal third esophageal contractions in the study and control populations were compared. In the study group, the incidence of chest pain among the patients with hypercontractility of the esophagus was compared with the incidence among those without hypercontractility. RESULTS: The mean contraction amplitude was higher in the study group (144.7 vs 105.5 mmHg; p = 0.002). The number of patients with a mean distal esophageal contraction amplitude exceeding the 95th percentile of normal also was significantly higher in the study group (13/40 vs 5/40; p = 0.03). A total of 10 patients experienced new onset of chest pain with the Bravo capsule in place, and 6 patients experienced hypertensive esophageal contractions. CONCLUSIONS: The intraesophageal Bravo capsule can cause hypertensive esophageal contractions, which may lead to chest pain.