RESUMEN
BACKGROUND: This is the fourth updated Enhanced Recovery After Surgery (ERAS®) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded recommendations for each ERAS item within the ERAS® protocol. METHODS: A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: All recommendations on ERAS® protocol items are based on best available evidence; good-quality trials; meta-analyses of good-quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly. CONCLUSIONS: The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS® Society in this comprehensive consensus review.
Asunto(s)
Colon/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo , Procedimientos Quirúrgicos Electivos , Atención Perioperativa , Guías de Práctica Clínica como Asunto , Recto/cirugía , Protocolos Clínicos , Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Procedimientos Quirúrgicos Electivos/métodos , Humanos , Atención Perioperativa/métodos , Recuperación de la FunciónRESUMEN
HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. Roles of HMGA1 in mediating the malignant phenotype of this cancer are poorly understood. We tested the hypothesis that overexpression of HMGA1 promotes resistance to anoikis (apoptosis induced by anchorage deprivation) in pancreatic cancer cells. HMGA1 cDNA was stably transfected into MiaPaCa2 human pancreatic adenocarcinoma cells (which have low baseline expression levels of HMGA1). Cells were grown in suspension on PolyHEMA-coated plates and their susceptibility to anoikis was assayed using flow cytometry. Overexpression of HMGA1 was associated with marked reductions in susceptibility to anoikis in concert with increases in Akt phosphorylation (Ser473) and in Akt kinase activity and with reductions in caspase 3 activation. Inhibition of phosphoinositidyl-3 (PI3-K)/Akt pathway with either the small molecule inhibitor LY294002 or dominant-negative Akt resulted in reversal of anoikis resistance induced by HMGA1 overexpression. Further, RNA interference-mediated HMGA1 silencing in MiaPaCa2 and BxPC3 (a human pancreatic adenocarcinoma cell line with high baseline levels of HMGA1 expression) cells resulted in significant increases in susceptibility to anoikis. Our findings suggest HMGA1 promotes anoikis resistance through a PI3-K/Akt-dependent mechanism. Given the putative associations between anoikis resistance and metastatic potential, HMGA1 represents a potential therapeutic target in pancreatic adenocarcinoma.
Asunto(s)
Anoicis/fisiología , Carcinoma Ductal Pancreático/patología , Proteínas HMGA/biosíntesis , Proteína Oncogénica v-akt/metabolismo , Neoplasias Pancreáticas/patología , Apoptosis/genética , Apoptosis/fisiología , Carcinoma Ductal Pancreático/enzimología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Activación Enzimática , Proteínas HMGA/genética , Proteínas HMGA/metabolismo , Humanos , Proteína Oncogénica v-akt/antagonistas & inhibidores , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Interferencia de ARN , Transducción de SeñalRESUMEN
Pancreatic adenocarcinoma is among the most aggressively invasive malignancies. The immunoglobulin superfamily member carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is emerging as an important determinant of the malignant phenotype in a range of cancers. We sought to define the role of CEACAM6 in pancreatic adenocarcinoma cellular invasiveness. CEACAM6 was stably overexpressed in Capan2 cells, which inherently express low levels of CEACAM6. Retrovirally mediated RNA interference was used to silence CEACAM6 expression in BxPC3 cells, which inherently overexpress CEACAM6. Cellular invasiveness was quantified using a modified Boyden chamber assay. Overexpression of CEACAM6 increased Capan2 cellular invasiveness, whereas CEACAM6 knockdown attenuated BxPC3 invasiveness. A role for the c-Src tyrosine kinase in mediating CEACAM6-dependent invasiveness was defined using constitutively active and dominant-negative c-Src expression constructs. c-Src-dependent modulation of matrix metalloproteinase-9 activity contributes significantly to the increased cellular invasiveness induced by CEACAM6 overexpression. Levels of CEACAM6 expression can modulate pancreatic adenocarcinoma cellular invasiveness in a c-Src-dependent manner. This pathway warrants further investigation as a target for therapy.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/farmacología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/farmacología , Perfilación de la Expresión Génica , Invasividad Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Animales , Antígenos CD , Western Blotting , Proteínas Ligadas a GPI , Genes src , Humanos , Ratones , Ratones Desnudos , Interferencia de ARN , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Inadequate or inappropriate cell-substrate contact triggers a subset of apoptotic cell death, termed anoikis. Resistance to anoikis is a characteristic of malignant cells that is associated with increased tumorigenesis and metastasis. Focal adhesion kinase (FAK) is an important regulator of cell survival and migration and cell cycle progression. We tested the hypothesis that FAK gene silencing would promote anoikis and reverse acquired anoikis resistance in human pancreatic adenocarcinoma cells. METHODS: FAK expression was assessed by Northern and Western blot analysis. Anoikis was induced in PANC1, BxPC3, MiaPaCa2, and Mia(AR) (an anoikis-resistant derivative of MiaPaCa2) with the use of polyHEMA culture. FAK expression was suppressed by RNA interference. Anoikis was detected by YO-PRO-1/propidium iodide staining and flow cytometry. Fluorometric caspase profiling was performed. Metastasis was assayed in a nude mouse orthotopic xenograft model. RESULTS: The cell lines that were tested showed marked variation in their anoikis resistance, greater resistance being associated with higher levels of FAK expression. FAK gene silencing promoted anoikis in all cell lines and reversed acquired anoikis resistance in Mia(AR), which was associated with increased caspase activation. Suppression of FAK expression also inhibited metastasis in the nude mouse model. CONCLUSION: FAK gene silencing suppresses anoikis resistance in pancreatic adenocarcinoma cells. FAK represents a potential target for novel antimetastatic therapies.
Asunto(s)
Adenocarcinoma/fisiopatología , Adenocarcinoma/secundario , Anoicis , Silenciador del Gen , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/fisiopatología , Proteínas Tirosina Quinasas/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Caspasas/metabolismo , Línea Celular , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Humanos , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/metabolismo , Proteínas Tirosina Quinasas/metabolismoRESUMEN
BACKGROUND: Although telerobotic technology has entered clinical application, its value for gastrointestinal surgery is unclear. Our objective was to evaluate the performance characteristics of telerobotically assisted laparoscopic cholecystectomy (TALC). METHODS: All TALCs performed using the da Vinci Surgical System between January 2000 and September 2001 at a tertiary academic medical center were analyzed. RESULTS: For this study, 20 patients (80% female) with a mean age of 47 +/- 4 years underwent TALC. All had symptomatic cholelithiasis, and all had successful TALC results without complications or need for conversion to conventional laparoscopic cholecystectomy (CLP). The mean procedure time was 152 +/- 8 min. The procedures were performed by one of three staff surgeons experienced in laparoscopic surgery who had training in telerobotic surgery. The perceived advantages of TALC over CLP included easier tissue dissection, enhanced dexterity, and stimulated interest in biliary surgery. The disadvantages included increased operating time and lack of tactile feedback. CONCLUSIONS: The TALC procedure is effective and safe when performed by appropriately trained surgeons. Telerobotic technology has the potential to reinvigorate gastrointestinal surgery.
Asunto(s)
Procedimientos Quirúrgicos del Sistema Digestivo , Robótica/normas , Centros Médicos Académicos , Colecistectomía Laparoscópica/normas , Colelitiasis/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
OBJECTIVE: To analyze the impact of a conservative strategy of management in patients with necrotizing pancreatitis, reserving intervention for patients with documented infection or the late complications of organized necrosis. SUMMARY BACKGROUND DATA: The role of surgery in patients with sterile pancreatic necrosis remains controversial. Although a conservative approach is being increasingly used, few studies have evaluated this strategy when applied to the entire spectrum of patients with necrotizing pancreatitis. METHODS: The authors reviewed 1,110 consecutive patients with acute pancreatitis managed at Brigham and Women's Hospital between January 1, 1995, and January 1, 2000, focusing on those with pancreatic necrosis documented by contrast-enhanced computed tomography. Fine-needle aspiration, the presence of extraintestinal gas on computed tomography, or both were used to identify infection. RESULTS: There were 99 (9%) patients with necrotizing pancreatitis treated, with an overall death rate of 14%. In three patients with underlying medical problems, the decision was made initially not to intervene. Of the other 62 patients without documented infection, all but 3 were managed conservatively; this group's death rate was 11%. Of these seven deaths, all were related to multiorgan failure. Five patients in this group eventually required surgery for organized necrosis, with no deaths. Of the 34 patients with infected necrosis, 31 underwent surgery and 3 underwent percutaneous drainage. Only four (12%) of these patients died, all of multiorgan failure. Of the total 11 patients who died, few if any would have been candidates for earlier surgical intervention. CONCLUSIONS: These results suggest that conservative strategies can be applied successfully to manage most patients with necrotizing pancreatitis, although some will eventually require surgery for symptomatic organized necrosis. Few if any patients seem likely to benefit from a more aggressive strategy.
Asunto(s)
Pancreatitis Aguda Necrotizante/diagnóstico , Pancreatitis Aguda Necrotizante/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos , Drenaje/métodos , Quimioterapia Combinada/administración & dosificación , Endoscopía del Sistema Digestivo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pancreatectomía/métodos , Pancreatitis Aguda Necrotizante/mortalidad , Estudios Retrospectivos , Medición de Riesgo , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Growth hormone (GH) has been used alone or as part of a defined regimen in the treatment of patients with short bowel syndrome; however its mode of action remains unclear. Growth hormone has been shown to increase amino acid, water, and electrolyte absorption from the small intestine. The acute effect of growth hormone on intestinal sugar transport has not been described previously. METHODS: Mucosal preparations of rat jejunum were mounted in the Ussing chamber. Growth hormone (2 x 10(-6) M or 8 x 10(-6) M) or vehicle was added to the serosal chamber 1, 3, or 5 hours later. Twenty or 40 minutes after growth hormone addition, 30 mmol/L 3-O-methylglucose was added to both chambers, and the change in short-circuit current (deltaIsc) was recorded. In separate experiments, tissues were pretreated with phloridzin, an inhibitor of Na+/glucose cotransport, before the addition of 3-O-methylglucose. In the final set of experiments, kinetic studies were performed. RESULTS: GH did not induce any alterations in baseline electrical parameters. Only tissues left in the chambers for 5 hours, but not 1 or 3 hours, before GH treatment displayed a greater 3-O-methylglucose-induced deltaIsc than controls (p < .05). The increase in Isc induced by 3-O-methylglucose was 100% phloridzin-inhibitable. Kinetic analysis showed that growth hormone administration is associated with an increase in Na+/glucose cotransporter maximal velocity (Vmax) but no significant change in carrier affinity for substrate (Km). CONCLUSIONS: Growth hormone increases intestinal sugar transport, but only in tissue that has not been exposed to endogenous GH for over 3 hours.
Asunto(s)
Hormona del Crecimiento/farmacología , Yeyuno/metabolismo , Proteínas de Transporte de Monosacáridos/efectos de los fármacos , Síndrome del Intestino Corto/tratamiento farmacológico , 3-O-Metilglucosa/farmacocinética , Animales , Transporte Biológico/efectos de los fármacos , Hormona del Crecimiento/uso terapéutico , Técnicas In Vitro , Yeyuno/efectos de los fármacos , Masculino , Proteínas de Transporte de Monosacáridos/antagonistas & inhibidores , Florizina/farmacología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Mechanisms underlying the circadian rhythmicity in intestinal sugar absorption remain unclear. To test whether this rhythmicity is caused by changes in Na(+)-glucose cotransporter 1 (SGLT-1) function, we measured phloridzin-inhibitable sugar fluxes as an index of SGLT-1 activity. Jejunum obtained from rats killed at 6-h intervals during a 12-h light-dark cycle (CT0 is circadian time 0 h, time of light onset) were mounted in Ussing chambers, and 3-O-methylglucose (3-OMG) fluxes were calculated before and after addition of phloridzin. 3-OMG-induced change in short-circuit current and absorptive flux were significantly greater at CT9 than at CT3. This increase was phloridzin inhibitable. Kinetic studies indicated a significant increase in SGLT-1 maximal velocity (V(max)) at CT9. Food intake between CT3 and CT9 was <10% of the daily total, indicating that the increased SGLT-1 activity was anticipatory. Diurnicity of SGLT-1 mRNA was confirmed by Northern blotting. Expression topography analyzed by in situ hybridization revealed more intense labeling along the entire villus axis at CT9 and CT15 compared with CT3 and CT21. We conclude that diurnicity in intestinal sugar absorption is caused by periodicity in SGLT-1 V(max).
Asunto(s)
Ritmo Circadiano , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiología , Proteínas de Transporte de Monosacáridos/genética , Proteínas de Transporte de Monosacáridos/fisiología , ARN Mensajero/metabolismo , Animales , Ingestión de Alimentos/efectos de los fármacos , Conductividad Eléctrica , Femenino , Guanosina/análogos & derivados , Guanosina/farmacocinética , Guanosina/farmacología , Técnicas In Vitro , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Yeyuno/fisiología , Cinética , Florizina/farmacología , Ratas , Ratas Sprague-Dawley , Transportador 1 de Sodio-Glucosa , Factores de TiempoRESUMEN
Juvenile pythons undergo large rapid upregulation of intestinal mass and intestinal transporter activities upon feeding. Because it is also easy to do surgery on pythons and to maintain them in the laboratory, we used a python model to examine signals and agents for intestinal adaptation. We surgically isolated the middle third of the small intestine from enteric continuity, leaving its mesenteric nerve and vascular supply intact. Intestinal continuity was restored by an end-to-end anastomosis between the proximal and distal thirds. Within 24 h of the snake's feeding, the reanastomosed proximal and distal segments (receiving luminal nutrients) had upregulated amino acid and glucose uptakes by up to 15-fold, had doubled intestinal mass, and thereby soon achieved total nutrient uptake capacities equal to those of the normal fed full-length intestine. At this time, however, the isolated middle segment, receiving no luminal nutrients, experienced no changes from the fasted state in either nutrient uptakes or in morphology. By 3 days postfeeding, the isolated middle segment had upregulated nutrient uptakes to the same levels as the reanastomosed proximal and distal segments, but it still lacked any appreciable morphological response. These contrasting results for the reanastomosed intestine and for the isolated middle segment suggest that luminal nutrients and/or pancreatic biliary secretions are the agents triggering rapid upregulation of transporters and of intestinal mass and that systemic nerve or hormonal signals later trigger transporter regulation but no trophic response.
Asunto(s)
Adaptación Fisiológica , Boidae/fisiología , Intestinos/fisiología , Animales , División Celular , Dieta , Enterocitos/fisiología , Enterocitos/ultraestructura , Absorción Intestinal/fisiología , Microvellosidades/fisiologíaRESUMEN
The clinical distinction between cystic and mucinous carcinomas of the pancreas has been poorly defined. Therefore we sought to stratify the entity known as pancreatic mucinous adenocarcinoma based on pathologic and clinical criteria. Clinical data and pathology specimens were reviewed for patients (n = 40) who had been diagnosed as having mucin-producing pancreatic adenocarcinoma and had undergone either resection or intraoperative biopsy of their pancreatic tumor during a 40-year period at the UCLA Medical Center. Based on histologic criteria, three distinct classes of pancreatic adenocarcinoma were identified: mucinous noncystic (colloid) adenocarcinoma (group I), mucinous cystadenocarcinoma (group II), and ductal adenocarcinoma (group III). Based on clinical behavior, groups I and III were indistinguishable. Compared to patients from groups I and III, those from group II were younger, more likely to be female, and had a better prognosis. Among mucin-producing adenocarcinomas of the pancreas, mucinous noncystic adenocarcinoma and ductal adenocarcinoma share similar clinical features, whereas true cystic lesions represent a distinct clinical entity.
Asunto(s)
Adenocarcinoma Mucinoso/metabolismo , Mucinas/biosíntesis , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Fosfatasa Alcalina/sangre , Amilasas/sangre , Bilirrubina/sangre , Antígeno Carcinoembrionario/análisis , Colangiopancreatografia Retrógrada Endoscópica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Cuidados Preoperatorios , Pronóstico , Tasa de Supervivencia , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Although numerous important contributions have originated from basic science research performed by surgeons, it seems that such dedicated work is becoming increasingly difficult to accomplish. What are the reasons for this change and what improvements can be made? This study aims to characterize the basic research training and careers of senior academic surgeons to assess and devise strategies for sustaining productive and quality surgical research. METHODS: A 25-item survey was sent to 850 senior-level members of academic societies, including the Association of Academic Surgeons, Society of University Surgeons, and American Surgical Association. It addressed each surgeon's clinical and research training and career, as well as opinions concerning surgical research. RESULTS: Three hundred seventy-seven (44%) surveys were received. Mean age was 64 years, and 73% were full professors. Seventy-two percent of respondents performed basic science research during training, and for 71% of this group, research was a significant reason for choosing a clinical specialty. Ninety-one percent performed research in the same specialty area during and after training. Of those who performed research during training, a full 99% continued to perform research on completion of training. However, 38% stopped performing basic research by age 39. Seventeen and twenty-three percent stopped basic research between 40 and 49 and between 50 and 59 years of age, respectively. The most common factors causing them to stop were increased clinical load (40%) and increased administrative duties (38%). For respondents who had stopped research prior to age 40, 73% cited increased clinical load as the primary reason. Eighty-five percent felt a dedicated research period should be included in surgery training. CONCLUSIONS: Most respondents had participated in basic research during training, and continued similar research after training. However, an overwhelming clinical practice at the junior faculty level seemed to hinder research. We conclude: (1) the majority consensus is that research training is integral to the development of academic surgeons; (2) such research training opportunities appear adequate; however, (3) faculty performing research, particularly at the junior level, need to be better protected from other academic duties, such as clinical practice and administration. The challenge to the leadership of academic surgery will be to enhance such research productivity in the context of increasing academic demands.
Asunto(s)
Actitud del Personal de Salud , Educación de Postgrado en Medicina/normas , Cirugía General/educación , Cirugía General/normas , Investigación , Adulto , Anciano , Anciano de 80 o más Años , Recolección de Datos , Educación Médica , Humanos , Medicina/normas , Persona de Mediana Edad , EspecializaciónRESUMEN
BACKGROUND: Glucagon-like peptide 2 (GLP-2) is a recently identified intestinal epithelium-specific growth factor that has been shown to reduce the severity of inflammatory disorders of the intestine in rodent models. We hypothesized that GLP-2 administration would be beneficial in chemotherapy-induced enteritis either by preventing injury or by promoting recovery. MATERIAL AND METHODS: Rats received no drug (control), chemotherapy alone [5-fluorouracil (5-FU), 190 mg/kg, ip] (Chemo), 5-FU followed by 3 days of GLP-2 analog (ALX-0600, 0.1 microg, sc twice daily) (CH-G), or GLP-2 analog for 6 days prior to 5-FU and for 3 days afterward (G-CH-G). Animals were pair fed. Rats received 5-bromo-2-deoxyuridine (Br-dU, 50 mg/kg, 2.5 h prior to sacrifice on Day 3 postchemotherapy) for immunohistochemical assessment of cellular proliferation. RESULTS: Chemotherapy induced significant reductions in body weight, villus height, and crypt depth compared with controls. Intestinal wet weight, villus height, and crypt depth were significantly higher for the CH-G group compared with the Chemo group. The CH-G group also showed a significant improvement in villus height compared with the G-CH-G group. Crypt depth, but not jejunal wet weight or villus height, was significantly improved in the G-CH-G group compared with the Chemo group. The percentage of Br-dU-labeled cells in the intestinal crypts did not differ among the groups. CONCLUSIONS: These results suggest, for the first time, that GLP-2 treatment initiated after chemotherapy administration enhances intestinal recovery. In contrast, GLP-2 treatment initiated prior to chemotherapy administration to prevent injury has less beneficial effect. GLP-2 administration may be beneficial to patients suffering from chemotherapy-induced enteritis.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Enteritis/inducido químicamente , Enteritis/tratamiento farmacológico , Fluorouracilo/efectos adversos , Péptidos/farmacología , Animales , Peso Corporal , Bromodesoxiuridina/análisis , Péptido 2 Similar al Glucagón , Péptidos Similares al Glucagón , Mucosa Intestinal/química , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Yeyuno/química , Yeyuno/citología , Yeyuno/efectos de los fármacos , Masculino , Morbilidad , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Glucagon-like peptide 2 (GLP-2) stimulates intestinal epithelial growth with high potency and specificity. However, the intracellular signaling pathways responsible for the growth-stimulatory action of GLP-2 are not clearly understood. Here we report possible signaling pathways mediating GLP-2's proliferative actions in the human intestinal epithelial cell line Caco-2. MATERIALS AND METHODS: Caco-2 cells were subcultured under serum-deprived conditions in the presence or absence of GLP-2 (10 microM) and varying concentrations of inhibitors of three candidate kinases: genistein, a global tyrosine kinase inhibitor; LY294002, a phosphatidylinositide (PI) 3-kinase inhibitor; and PD 098059, a mitogen-activated/extracellular signal-regulated kinase (MEK) inhibitor. Proliferation was assessed using [(3)H]thymidine incorporation. Relative abundance of the phosphorylated forms of two specific mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, was assessed by Western blotting. RESULTS: GLP-2-treated cells demonstrated a greater than 10-fold increase in proliferation. This response was inhibited by genistein, LY294002, and PD 098059 in a dose-dependent fashion. A significantly greater abundance of the phosphorylated forms of both ERK-1 and ERK-2 was present in cells within 5 min of treatment with GLP-2. CONCLUSIONS: GLP-2 stimulates the proliferation of Caco-2 cells in vitro. This increase in Caco-2 proliferation in response to GLP-2 may be due, at least in part, to the involvement of both the PI 3-kinase and the MAPK pathways.
Asunto(s)
Mucosa Intestinal/efectos de los fármacos , Péptidos/farmacología , Transducción de Señal , Células CACO-2 , División Celular/efectos de los fármacos , ADN/biosíntesis , Péptido 2 Similar al Glucagón , Péptidos Similares al Glucagón , Humanos , Mucosa Intestinal/citología , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/fisiología , Fosfatidilinositol 3-Quinasas/fisiologíaRESUMEN
In awake dogs, meal ingestion stimulates the absorption of water and electrolytes from neurovascularly intact jejunal Thiry-Vella loops, even though these loops are isolated from the remainder of the gut. This study was designed to investigate the role of Na+-glucose cotransport in mediating this event. Meal ingestion enhanced absorption when the jejunal lumen was perfused with an isotonic solution containing D-glucose, D-galactose, or 3-O-methylglucose. This response was absent when the perfusate contained mannitol or when phlorizin was added to the D-glucose solution. Mucosa from the jejunal loops was serially biopsied and assayed for brush-border Na+-glucose cotransporter (SGLT1) mRNA and protein expression. Although no changes in SGLT1 mRNA levels were observed, protein levels significantly increased within 30 min following meal ingestion. The time course of SGLT1 protein expression corresponded with that of increased Na+ and water absorption. These results suggest that meal-stimulated jejunal absorption may be mediated through an induction of mucosal SGLT1.
Asunto(s)
Absorción Intestinal , Yeyuno/fisiología , Glicoproteínas de Membrana/biosíntesis , Proteínas de Transporte de Monosacáridos/biosíntesis , Proteínas de Transporte de Monosacáridos/fisiología , Adaptación Fisiológica , Animales , Perros , Femenino , Alimentos , Glucosa/metabolismo , Fístula Intestinal/fisiopatología , ARN Mensajero/genética , Sodio/metabolismo , Transportador 1 de Sodio-Glucosa , Factores de TiempoRESUMEN
Traditionally, intestinal glucose absorption was thought to occur through active, carrier-mediated transport. However, proponents of paracellular transport have argued that previous experiments neglected effects of solvent drag coming from high local concentrations of glucose at the brush-border membrane. The purpose of this study was to evaluate glucose absorption in the awake dog under conditions that would maximize any contribution of paracellular transport. Jejunal Thiry-Vella loops were constructed in six female mongrel dogs. After surgical recovery, isotonic buffers containing L-glucose as the probe for paracellular permeability were given over 2-h periods by constant infusion pump. At physiological concentrations of D-glucose (1-50 mM), the fractional absorption of L-glucose was only 4-7% of total glucose absorption. Infusion of supraphysiological concentrations (150 mM) of D-glucose, D-maltose, or D-mannitol yielded low-fractional absorptions of L-glucose (2-5%), so too did complex or nonabsorbable carbohydrates. In all experiments, there was significant fractional water absorption (5-19%), a prerequisite for solvent drag. Therefore, with even up to high concentrations of luminal carbohydrates in the presence of significant water absorption, the relative contribution of paracellular glucose absorption remained low.
Asunto(s)
Glucosa/metabolismo , Yeyuno/metabolismo , Absorción/fisiología , Animales , Transporte Biológico/fisiología , Carbohidratos/farmacología , Permeabilidad de la Membrana Celular/fisiología , Perros , Femenino , Glucosa/farmacología , Yeyuno/citología , Maltosa/farmacología , Manitol/farmacología , Agua/metabolismoRESUMEN
OBJECTIVES: To characterize the career choices and developments made by leading senior surgeons in this country and to examine hypothetically whether application of a short tracking program would have hindered their career decisions. DESIGN: A survey pertaining to each surgeon's career, decisions, and opinions concerning surgical training. SETTING AND PARTICIPANTS: Senior surgeons of regional and national surgical societies. MAIN OUTCOME MEASURE: Survey responses. RESULTS: A total of 352 surveys (41.4%) were received. Respondents answered that the most common reasons for choosing a specialty were role models or mentors (56%), research (51%), and available patient population (23%). The 2 most common stages in a career at which the respondents became interested in a specialty, or an area of expertise, were at the junior residency level (when the specialty was chosen) and at the assistant professor level (when a more specific topic within the specialty was chosen). The most common stage at which the group believed they acquired their expertise was also at the assistant professor level. Seventy-one percent of respondents believed broad training was superior to a short tracking system, although none had participated in shortened surgical training. CONCLUSIONS: Most leading senior surgeons in this country still believe that broad surgical training is superior and should be maintained. Because career specialties in this surveyed group were generally chosen in early residency, a hypothetical application of the short tracking system would have still allowed for these important decisions to be made. Also, it seems likely that specialty and career development would not have been hindered because "expertization" mostly occurred after training was completed. Regardless of training method, a role model or mentor seems most important in career choices and developments.
Asunto(s)
Educación de Postgrado en Medicina/métodos , Cirugía General/educación , Adulto , Anciano , Anciano de 80 o más Años , Selección de Profesión , Humanos , Persona de Mediana Edad , Estados UnidosRESUMEN
Peptide YY (PYY) is a potent regulator of intestinal secretion. These studies investigated the role of Y1 and Y2 receptor subtypes in mediating the antisecretory effects of PYY on mucosa-submucosa preparations of rat distal colon. Addition of vasoactive intestinal peptide (VIP) to these tissues resulted in a 140 +/- 18% increase in basal short-circuit current (Isc) and the induction of Cl- secretion. VIP-stimulated increases in Isc were abolished by the addition of each of PYY, (Pro34)-PYY, a Y1 receptor-selective agonist, and PYY-(3-36), an endogenous Y2 receptor-selective ligand. However, when tissue neural transmission was blocked with tetrodotoxin, neither PYY nor its receptor subtype-selective analogs were able to inhibit VIP-stimulated increases in Isc. These results suggest that in the rat distal colon, the antisecretory actions of PYY are mediated through a combination of Y1 and Y2 receptor subtypes or through a novel receptor subtype that is unable to discriminate between (Pro34)-PYY and PYY-(3-36).
Asunto(s)
Colon/metabolismo , Hormonas Gastrointestinales/fisiología , Péptidos/fisiología , Receptores de la Hormona Gastrointestinal/fisiología , Animales , Colon/inervación , Hormonas Gastrointestinales/farmacología , Transporte Iónico , Masculino , Fragmentos de Péptidos , Péptido YY , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/clasificación , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
BACKGROUND: The intestine is a target of septic insult. The aims of this study were to characterize sepsis-induced alterations in intestinal ion transport and to determine the role endotoxin plays in mediating these changes. METHODS: Rats underwent cecal manipulation alone (control), cecal ligation and puncture (CLP), or CLP plus intraperitoneal injection of 0.2 mg of a recently synthesized endotoxin inhibitor. At 24 hours, distal ileum was harvested, and transport parameters were determined. RESULTS: Cecal ligation and puncture produced a significant increase in short-circuit current (Isc) that was attributable to the induction of chloride secretion. There were no alterations in transepithelial resistance or fluxes of mannitol and sodium. The sepsis-induced increase in Isc was prevented by administration of the endotoxin inhibitor. CONCLUSIONS: In this model of sepsis, the primary alteration in ileal ion transport is an induction of electrogenic chloride secretion. Endotoxin inhibition may represent a strategy for prophylaxis against the intestinal effects of sepsis.
Asunto(s)
Endotoxinas/antagonistas & inhibidores , Enteritis/metabolismo , Mucosa Intestinal/metabolismo , Animales , Ciego/lesiones , Ciego/cirugía , Modelos Animales de Enfermedad , Técnicas In Vitro , Mucosa Intestinal/efectos de los fármacos , Transporte Iónico/efectos de los fármacos , Ligadura , Permeabilidad/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Meal-stimulated colonic absorption has recently been described, but the cellular transport mechanisms mediating this response are unknown. The purpose of this study was to determine the contribution of Na+ transport pathways to colonic proabsorption. Distal colonic Thiry-Vella loops were constructed in six dogs. Absorption was measured by infusing the loops with a physiological electrolyte solution containing [14C] polyethylene glycol as the impermeant marker. In the first set of experiments, the dose dependence of amiloride-induced inhibition of basal colonic absorption was determined. In the second set of experiments the effect of amiloride, which inhibits both Na+ channels and Na+/H+ exchange in colonocytes, on meal-stimulated colonic absorption was determined. Luminal amiloride inhibited basal colonic absorption in a dose-dependent manner, with significant reductions in Na+ absorption occurring with concentrations of 10(-2)M and higher. Infusion with 10(-3)M amiloride, a concentration that did not alter basal absorption, resulted in significant reductions in postprandial water, Na+, and Cl- absorption. These results suggest that meal-stimulated colonic absorption is mediated, at last in part, by transcellular Na+ absorptive pathways.