RESUMEN
BACKGROUND: Small bowel necrosis after enteral feeding through a jejunostomy tube (tube feed necrosis, TFN) is a rare, serious complication of major abdominal surgery. However, strategies to reduce the incidence and morbidity of TFN are not well established. Here, in the largest series of TFN presented to date, we report our institutional experience and a comprehensive review of the literature. METHODS: Eight patients who experienced TFN from 2000 to 2014 after major abdominal surgery for oncologic indications at the University of Cincinnati were reviewed. Characteristics of post-operative courses and outcomes were reviewed prior to and after a change in tube-feeding protocol. The existing literature addressing TFN over the last three decades was also reviewed. RESULTS: Patients with TFN ranged from 50 to 74 years old and presented with upper gastrointestinal tract malignancies amenable to surgical resection. Six and two cases of TFN occurred following pancreatectomy and esophagectomy, respectively. Prior to TF protocol changes, which included initiation at a low rate, titrating up more slowly and starting at one-half strength TF, three of six cases of TFN (50%) resulted in mortality. With the new TF protocol, there were no deaths, goal TF rate was achieved 3 days later, symptoms of TFN were recognized 3 days earlier, and re-operation was conducted 1 day earlier. CONCLUSION: This case series describes a change in clinical practice that is associated with decreased morbidity and mortality of TFN. Wider implementation and further refinement of this tube-feeding protocol may reduce TFN incidence at other institutions and in patients with other conditions requiring enteral nutrition.
Asunto(s)
Nutrición Enteral , Esofagectomía , Enfermedades del Yeyuno/epidemiología , Pancreatectomía , Complicaciones Posoperatorias/epidemiología , Adenocarcinoma/cirugía , Anciano , Cateterismo , Neoplasias Esofágicas/cirugía , Femenino , Humanos , Insulinoma/cirugía , Intubación Gastrointestinal , Enfermedades del Yeyuno/patología , Yeyunostomía , Masculino , Persona de Mediana Edad , Necrosis , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía , Resultado del TratamientoRESUMEN
PURPOSE: To assess the validity of asking prospective medical school students about their planned field of practice during their admissions interview at one United States allopathic medical school, and to compare and contrast the results with the results from a similar study conducted in 2004. METHODS: Anonymous one-page surveys were voluntarily filled out and immediately collected from matriculated freshman medical students who wished to participate in this Institutional Review Board (IRB) approved study. RESULTS: Ninety five medical students voluntarily completed and returned the anonymous survey; 82 were filled out correctly. Of the 82 respondents, 32 were uncertain about the field of medicine they plan to pursue. Of the 50 remaining respondents who felt certain of their future direction, 58% (29/50) reported telling the truth when asked about their future direction during the admissions interview, 34% (17/50) were not completely forthcoming and truthful, and 8% (4/50) were not asked at all. CONCLUSIONS: The findings of this study, along with the findings from our 2004 study, strongly suggest that asking prospective medical students during their medical school interview what type of medicine they wish to practice may not yield valid responses.
Asunto(s)
Selección de Profesión , Entrevistas como Asunto , Criterios de Admisión Escolar , Estudiantes de Medicina/psicología , Revelación de la Verdad , Adulto , Recolección de Datos , Femenino , Humanos , Masculino , Criterios de Admisión Escolar/estadística & datos numéricos , Facultades de Medicina , Incertidumbre , Estados UnidosRESUMEN
BACKGROUND: The objective of this study was to examine equine-related trauma at a trauma center servicing a region in which there is significant contact between horses and humans. METHODS: Data were collected on all patients admitted to the University of Kentucky Medical Center from January 1994 to December 1998 for treatment of horse-related injuries. RESULTS: Seventy-five patients were admitted to our center after injuries due to contact with horses (0.75% of all trauma admissions). There were 42 men (55%). The mean age was 37 years (range, 3 to 81 years). The majority of patients (67/75) were injured during recreational activities, and most fell or were thrown (40/75). Only 14% of patients were wearing helmets. The most common injuries were extremity fractures and head injuries, but thoracic and abdominal injuries were not rare. Of the 75 patients, 34 required surgery. Five patients (6.7%) died, all of head injury. During the study period, 11 people died in Kentucky due to contact with horses. CONCLUSIONS: Injury due to contact with horses is uncommon even at a center servicing a region with a large equine population. However, injuries are often serious and lead to significant morbidity and occasional mortality. Prevention of death from horse-related trauma is synonymous with prevention of head injury.
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Centros Médicos Académicos/estadística & datos numéricos , Caballos , Centros Traumatológicos/estadística & datos numéricos , Heridas y Lesiones/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Niño , Preescolar , Femenino , Humanos , Kentucky/epidemiología , Masculino , Persona de Mediana Edad , Índices de Gravedad del TraumaRESUMEN
BACKGROUND: Arginase is a metabolic enzyme for the amino acid arginine that participates in the immune response to trauma. We hypothesize that surgical trauma induces arginase expression and activity in the human immune system. METHODS: Peripheral mononuclear cell (MNC) arginase activity and expression and plasma nitric oxide metabolites and interleukin (IL)-10 were measured in patients undergoing elective general surgery. Twenty-two healthy volunteers served as a comparison population. RESULTS: MNC arginase activity increased within 6 hours of surgery (p < 0.05) and coincided with increased arginase I protein expression. Plasma nitric oxide metabolites decreased significantly postoperatively (p < 0.05). Patients lacking an elevation in IL-10 failed to demonstrate increased MNC arginase activity. CONCLUSION: Increased MNC arginase expression may contribute to postsurgical immune dysfunction by affecting arginine use and availability and nitric oxide metabolism in the immune system. Plasma IL-10 may play a role in regulating MNC arginase activity.
Asunto(s)
Arginasa/metabolismo , Sistema Inmunológico/enzimología , Leucocitos Mononucleares/enzimología , Procedimientos Quirúrgicos Operativos , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Estudios de Casos y Controles , Femenino , Humanos , Sistema Inmunológico/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Leucocitos Mononucleares/metabolismo , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Óxido Nítrico/sangre , Óxido Nítrico/metabolismoRESUMEN
BACKGROUND: Torso sonography (focused assessment with sonography for trauma [FAST]) has been added to our protocols for the evaluation of penetrating torso injury. The purpose of this study was to evaluate our recent experience and determine whether the use of FAST is beneficial. METHODS: From January 1999 to January 2000, patients with penetrating torso injury and no clinical indication for surgery were evaluated by sonography with a selective use of other investigations. FAST consisted of sonographic views of the peritoneum and/or pericardium to determine the presence or absence of fluid. RESULTS: During the study period, there were 238 victims of penetrating injury assessed by our trauma service, and sonography was performed in 72 (30%) patients as per our protocols. There were 31 stab, 37 gunshot/shotgun and, and 4 puncture wounds. Thirty-eight patients had peritoneal views, 6 patients had pericardial views, and 28 patients had both pericardial and peritoneal views obtained. Thirteen of 66 patients had free fluid in the peritoneal cavity and 12 of the 13 patients had a therapeutic laparotomy. No peritoneal fluid was seen in 53 of 66 patients, of whom 6 had abdominal injuries, 5 requiring surgery for diaphragm or bowel injuries. The sensitivity of FAST alone for abdominal injury was 67%, specificity was 98%, positive predictive value was 92%, and negative predictive value was 89%. Pericardial fluid was seen in 3 of 34 patients; one had a heart wound and two had negative pericardial windows. All 31 patients without pericardial fluid recovered without surgery. CONCLUSION: The routine use of sonography in penetrating torso injury is beneficial. The detection of pericardial or peritoneal fluid is clinically useful. However, a negative FAST examination does not exclude abdominal injury, such as a diaphragm or hollow viscus wound, and further investigation or close follow-up is required.
Asunto(s)
Traumatismos Abdominales/diagnóstico por imagen , Traumatismos Torácicos/diagnóstico por imagen , Heridas Penetrantes/diagnóstico por imagen , Traumatismos Abdominales/cirugía , Adulto , Vías Clínicas , Femenino , Hemoperitoneo/diagnóstico por imagen , Hemoperitoneo/cirugía , Humanos , Masculino , Derrame Pericárdico/diagnóstico por imagen , Derrame Pericárdico/cirugía , Valor Predictivo de las Pruebas , Traumatismos Torácicos/cirugía , Ultrasonografía , Heridas por Arma de Fuego/diagnóstico por imagen , Heridas por Arma de Fuego/cirugía , Heridas Penetrantes/cirugía , Heridas Punzantes/diagnóstico por imagen , Heridas Punzantes/cirugíaRESUMEN
BACKGROUND: Outpatient followup of rural trauma patients is problematic for physicians and patients. Our hypothesis was that telemedicine-based followup of trauma patients discharged to remote areas is feasible and is associated with high patient and physician satisfaction. STUDY DESIGN: We chose 11 counties in Kentucky surrounding a remote telemedicine site as our region of interest. Any adult trauma patient who was discharged from our Level I trauma center to this geographic region was eligible to have routine followup appointment(s) at the TeleTrauma Clinic. Patients were examined and interviewed with the assistance of a nurse, an electronic stethoscope, and a close-up imaging instrument. Radiographs performed at the telemedicine site were viewed. Patients and physicians completed a survey after the appointment. RESULTS: To date, we have conducted 22 telemedicine-based followup assessments of trauma patients. The average age and Injury Severity Score were 42 years and 18, respectively. Plain radiographs were reviewed in 13 cases. Our patient surveys indicated a high degree of satisfaction with the teleappointment. In 15 of 22 patients, no further clinical followup was arranged. The differences in travel distances and times for an appointment at the TeleTrauma Clinic versus an appointment at our Level I trauma center were significant. The average and median duration of the appointments was 14 minutes. All telemedicine encounters were done by two physicians, who recorded a high level of satisfaction. CONCLUSIONS: Our early experience with the outpatient followup of remote trauma victims by telemedicine is encouraging. Patient surveys indicate a high degree of satisfaction. As a result of our favorable experience, telemedicine-based followup may be expanded to other regions of Kentucky.
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Cuidados Posteriores/organización & administración , Atención Ambulatoria/organización & administración , Traumatismo Múltiple/terapia , Servicios de Salud Rural/organización & administración , Telemedicina/organización & administración , Adolescente , Adulto , Cuidados Posteriores/psicología , Anciano , Atención Ambulatoria/psicología , Actitud del Personal de Salud , Estudios de Factibilidad , Investigación sobre Servicios de Salud , Humanos , Puntaje de Gravedad del Traumatismo , Kentucky , Cuerpo Médico/psicología , Área sin Atención Médica , Persona de Mediana Edad , Traumatismo Múltiple/diagnóstico por imagen , Traumatismo Múltiple/psicología , Satisfacción del Paciente , Evaluación de Programas y Proyectos de Salud , Radiografía , Encuestas y Cuestionarios , Factores de Tiempo , Centros TraumatológicosRESUMEN
Arginine is the sole substrate for nitric oxide (NO) synthesis by NO synthases (NOS) and promotes the proliferation and maturation of human T-cells. Arginine is also metabolized by the enzyme arginase, producing urea and ornithine, the precursor for polyamine production. We sought to determine the molecular mechanisms regulating arginase and NOS in splenic immune cells after trauma. C3H/HeN mice underwent laparotomy as simulated moderate trauma or anesthesia alone (n = 24 per group). Six, 12, 24, or 48 h later, 6 animals from each group were sacrificed, and splenectomy was performed and plasma collected. Six separate animals had neither surgery nor anesthesia and were sacrificed to provide resting values (t = 0 h). Spleen arginase I and II and iNOS mRNA abundance, arginase I protein expression, and arginase activity were determined. Plasma NO metabolites (nitrite + nitrate) were also measured. Trauma increased spleen arginase I protein expression and activity (P = 0.01) within 12 and for at least 48 h after injury and coincided with up-regulated arginase I mRNA abundance at 24 h. Neither arginase II nor iNOS mRNA abundance in the spleen was significantly increased by trauma at 24 h. Plasma nitrite + nitrate was decreased in animals 48 h post-injury compared to anesthesia controls (P < 0.05). Trauma induces up-regulation of arginase I gene expression in splenic immune cells within 24 h of injury. Arginase II is not significantly up-regulated at that time point. Arginase I, rather than iNOS appears to be the dominant route for arginine metabolism in splenic immune cells 24 h after trauma.
Asunto(s)
Arginina/metabolismo , Enzimas/metabolismo , Bazo/metabolismo , Heridas y Lesiones/metabolismo , Animales , Arginasa/genética , Arginasa/metabolismo , Enzimas/genética , Regulación Enzimológica de la Expresión Génica , Isoenzimas , Ratones , Ratones Endogámicos C3H , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: To determine the effect of trauma on arginase, an arginine-metabolizing enzyme, in cells of the immune system in humans. SUMMARY BACKGROUND DATA: Arginase, classically considered an enzyme exclusive to the liver, is now known to exist in cells of the immune system. Arginase expression is induced in these cells by cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta, corresponding to a T-helper 2 cytokine profile. In contrast, nitric oxide synthase expression is induced by IL-1, tumor necrosis factor, and gamma interferon, a T-helper 1 cytokine profile. Trauma is associated with a decrease in the production of nitric oxide metabolites and a state of immunosuppression characterized by an increase in the production of IL-4, IL-10, and transforming growth factor beta. This study tests the hypothesis that trauma increases arginase activity and expression in cells of the immune system. METHODS: Seventeen severely traumatized patients were prospectively followed up in the intensive care unit for 7 days. Twenty volunteers served as controls. Peripheral mononuclear cells were isolated and assayed for arginase activity and expression, and plasma was collected for evaluation of levels of arginine, citrulline, ornithine, nitrogen oxides, and IL-10. RESULTS: Markedly increased mononuclear cell arginase activity was observed early after trauma and persisted throughout the intensive care unit stay. Increased arginase activity corresponded with increased arginase I expression. Increased arginase activity coincided with decreased plasma arginine concentration. Plasma arginine and citrulline levels were decreased throughout the study period. Ornithine levels decreased early after injury but recovered by postinjury day 3. Increased arginase activity correlated with the severity of trauma, early alterations in lactate level, and increased levels of circulating IL-10. Increased arginase activity was associated with an increase in length of stay. Plasma nitric oxide metabolites were decreased during this same period. CONCLUSIONS: Markedly altered arginase expression and activity in cells of the human immune system after trauma have not been reported previously. Increased mononuclear cell arginase may partially explain the benefit of arginine supplementation for trauma patients. Arginase, rather than nitric oxide synthase, appears to be the dominant route for arginine metabolism in immune cells after trauma.
Asunto(s)
Arginasa/sangre , Leucocitos Mononucleares/metabolismo , Heridas y Lesiones/inmunología , Adulto , Anciano , Biomarcadores , Estudios de Casos y Controles , Citrulina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico/sangre , Ornitina/sangre , Pronóstico , Estudios Prospectivos , Estadísticas no Paramétricas , Índices de Gravedad del Trauma , Heridas y Lesiones/diagnósticoRESUMEN
Although much has been written about FAST (Focused Assessment with Sonography for Trauma) in the last decade little is known about its present clinical utilization. The purpose of this study was to evaluate and characterize the contemporary utilization of FAST at trauma centers in the United States and Canada. In 1999 trauma directors or their delegates at Level I regional trauma centers in the United States and Canada were surveyed either by fax or phone regarding the present utilization and the future of FAST at their center. The overall survey response rate was 91 per cent with 96 of 105 centers completing the survey. Of the 96 centers surveyed 78 were in the United States and 18 were in Canada. Of the 78 U.S. centers surveyed 62 (79%) routinely use FAST, and it is done by surgeons in 39 per cent, surgeons and emergency departments in 21 per cent, emergency departments in 5 per cent, and radiologists in 35 per cent. Most centers (79%) thought that it sped up their workups, and 89 per cent said it was an advance in patient care. FAST is used in penetrating injury at 58 per cent of centers, and some centers use FAST to assess organ injury. The utilization of diagnostic peritoneal lavage and CT has markedly decreased at many centers. Almost all respondents thought that FAST should be a component of surgery resident training. The utilization of FAST is significantly less in Canada than in the United States (P < 0.05). Our conclusions are the following. FAST has become routinely used at the majority of the U.S. centers surveyed. FAST is performed by clinicians at 65 per cent of the trauma centers surveyed. The utilization of CT and diagnostic peritoneal lavage has changed. Many centers have broadened the scope of FAST to include the assessment of organ, pediatric, and penetrating injury.
Asunto(s)
Ultrasonografía/estadística & datos numéricos , Traumatismos Abdominales/diagnóstico por imagen , Canadá , Recolección de Datos , Humanos , Traumatismos Torácicos/diagnóstico por imagen , Centros Traumatológicos , Estados Unidos , Heridas no Penetrantes/diagnóstico por imagenRESUMEN
BACKGROUND: Arginase, which metabolizes L-arginine within the urea cycle, is essential for production of polyamines and affects production of nitric oxide by depletion of L-arginine, the common substrate for both arginase and nitric oxide synthase. Having shown that trauma increases splenic macrophage arginase activity, we seek to define the mechanisms for this. RAW macrophage arginase activity and expression are increased by 8-bromo-cAMP in vitro. We hypothesize that since catecholamines increase cAMP, trauma-induced splenic arginase activity may be mediated by post-injury catecholamine release. METHODS: RAW 264.7 macrophage arginase activity was measured in vitro in response to 4 catecholamines with or without propranolol or lipopolysaccharide (LPS). C57BL/6 mice underwent laparotomy as a model of moderate trauma after propranolol treatment, with and without intraperitoneal Escherichia coli LPS administration as a simulated pro-inflammatory stimulus. RESULTS: Macrophage arginase activity increased in vitro in response to catecholamines or LPS (P < .05). Propranolol pretreatment blocked macrophage arginase activity induced by epinephrine (10 mumol/L) in vitro (P < .05). Trauma or LPS alone increased splenic arginase activity in vivo (P < .05). Propranolol did not alter LPS-induced splenic arginase activity but did significantly reduce trauma-induced splenic arginase activity (P < .05). CONCLUSIONS: Catecholamines alone increase macrophage arginase activity through beta-adrenoceptor activation. Increased splenic arginase activity induced by moderate trauma is decreased by beta-adrenoceptor blockade, suggesting that trauma-induced arginase activity is partly mediated by endogenous catecholamines.
Asunto(s)
8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Arginasa/metabolismo , Isoproterenol/farmacología , Macrófagos/fisiología , Propranolol/farmacología , Receptores Adrenérgicos beta/fisiología , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Arginasa/biosíntesis , Línea Celular , Dopamina/farmacología , Inducción Enzimática , Epinefrina/farmacología , Cinética , Laparotomía , Lipopolisacáridos/farmacología , Macrófagos/enzimología , Ratones , Ratones Endogámicos C57BL , Norepinefrina/farmacología , Receptores Adrenérgicos beta/efectos de los fármacos , Bazo/efectos de los fármacos , Bazo/enzimología , Heridas y Lesiones/enzimologíaRESUMEN
BACKGROUND: Although expressed primarily in the liver, arginase activity also is present in extrahepatic tissues and specifically in macrophages, where it may play diverse physiologic roles in wound healing, cellular proliferation, and the regulation of nitric oxide production. Arginase activity in immune cells is upregulated by certain cytokines such as IL-4, IL-10, and TGF-beta and by catecholamines. Since the release of these substances is increased after trauma, we hypothesized that arginase activity would also be increased in immune cells after trauma. The current work tests this hypothesis. METHODS: A model of surgical trauma was created in C3H/HeN mice by performing an exploratory laparotomy. Tissue arginase activity and arginase I protein expression were determined. As a control, arginase activity and expression were also stimulated with the use of endotoxin. In addition, we evaluated the expression of inducible nitric oxide synthase and the accumulation of nitric oxide metabolites in plasma. RESULTS: Surgical trauma was associated with a significant increase in arginase activity in splenic and renal tissues (P < .05). Splenic macrophages from trauma animals exhibited arginase activity levels approximately 10 times those of controls (P < .05). Endotoxin alone increased arginase activity in the spleen, but this increase was less than that of trauma alone (P < .05). Arginase activity remained elevated after trauma for up to 4 days and normalized by day 7. Arginase I expression was upregulated by trauma in both splenic and renal tissue and by endotoxin in the spleen only. Despite upregulation of inducible nitric oxide synthase in trauma animals, circulating nitric oxide metabolites were decreased 2 days after trauma compared with controls (P < .05). Endotoxin-induced nitric oxide metabolites were also reduced in trauma animals compared with endotoxin treatment alone (P < .05), but this normalized by day 4. CONCLUSIONS: Extrahepatic arginase expression and activity is increased after trauma and may provide the necessary precursors for cellular proliferation and repair or may play a regulatory role in the production of nitric oxide.
Asunto(s)
Arginasa/biosíntesis , Laparotomía/efectos adversos , Macrófagos/enzimología , Animales , Arginasa/genética , Línea Celular , Regulación Enzimológica de la Expresión Génica , Riñón/enzimología , Lipopolisacáridos/toxicidad , Hígado/enzimología , Pulmón/enzimología , Masculino , Ratones , Ratones Endogámicos C3H , Músculo Esquelético/enzimología , Óxido Nítrico/sangre , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Bazo/enzimología , Heridas y LesionesRESUMEN
The peptide hormone cholecystokinin (CCK) has been shown to stimulate the growth of azaserine-induced preneoplastic nodules in the rat pancreas. Previously, our labortory demonstrated by classical binding studies that CCK receptors are overexpressed in azaserine-induced rat pancreatic neoplasms. In the present study, we utilized autoradiography to determine the temporal course of this increased receptor binding. Male Lewis rats were given azaserine or saline injections and sacrificed at 2, 4, 8, 12, and 18 months of age. Pancreatic tissue was harvested and autoradiography using 125l-labeled. CCK-8 was performed. Densitometry measurements of azaserine-induced pancreatic nodules, internodular pancreas, and normal pancreatic tissue (from saline-treated controls) of each age group were taken with an image analyzer. There was no statistically significant difference in CCK binding to internodular pancreas and normal pancreas at any age. At 2 months of age, there was no significant increase in CCK binding to azaserine-induced pancreatic nodules. However, at 4, 8, 12, and 18 months of age there was significantly greater CCK binding to azaserine-induced pancreatic nodules than to both internodular pancreas and normal pancreas (p < 0.001 for all groups). At 18 months of age, one azaserine-treated animal developed a pancreatic acinar cell carcinoma, which likewise exhibited significantly greater CCK binding than internodular pancreas or normal pancreas (p < 0.001 for both). These findings demonstrate increased CCK binding in azaserine-induced preneoplastic pancreatic nodules and pancreatic acinar cell carcinoma, compatible with our previous demonstration of receptor overexpression in these tissues. Increased CCK binding first becomes apparent by 4 months following exposure to azaserine. These result suggest that overexpression of CCK receptors, located specifically on preneoplastic and neoplastic pancreatic lesions, results in increased CCK binding and is involved in the mediation of CCK-stimulated growth during azaserine-induced pancreatic carcinogenesis.
Asunto(s)
Autorradiografía , Azaserina , Neoplasias Pancreáticas/inducido químicamente , Neoplasias Pancreáticas/metabolismo , Receptores de Colecistoquinina/análisis , Animales , Densitometría , Radioisótopos de Yodo , Masculino , Ratas , Ratas Endogámicas Lew , Receptores de Colecistoquinina/metabolismo , Sincalida/metabolismoRESUMEN
The hormone gastrin is thought to stimulate the growth of certain pancreatic carcinoma cell lines. We have previously detected the presence of the gastrin receptor in rat pancreatic carcinoma cell lines but not in normal rat pancreas. We had not, however, previously demonstrated that gastrin receptor is expressed in pancreatic carcinomas developing in the rat in vivo. Therefore, in the present study, we examined rat pancreatic tissue at various stages in azaserine-induced pancreatic carcinogenesis for gastrin binding and for the presence of gastrin receptor mRNA to determine the temporal expression pattern of the gastrin receptor during the in vivo development of pancreatic cancer. Autoradiography of pancreatic tissue using (125)I-gastrin-17-I from all azaserine-treated and control animals at 2, 4, 8, and 12 months of age demonstrated no specific gastrin binding. At 18 months of age, normal pancreas, azaserine-induced premalignant pancreatic nodules, and internodular pancreas demonstrated no specific gastrin binding. One of three azaserine-treated animals developed an area of pancreatic acinar cell carcinoma at 18 months of age which exhibited significant specific gastrin binding of 141.8 - 32.8 fmole/gm of tissue. Southern blot analysis of pancreatic RNA isolated from animals at 12 months of age revealed no gastrin receptor mRNA; however, by 18 months of age, gastrin receptor mRNA was present in all azaserine-treated animals but absent in control animals. In summary, specific gastrin binding is present in in vivo azaserine-induced pancreatic acinar cell carcinoma but absent in normal pancreas and azaserine-induced premalignant pancreatic nodules. Gastrin receptor mRNA is first expressed in azaserine-treated rat pancreas at some point between 12 and 18 months of age. These results demonstrate that expression of gastrin receptor is altered in azaserine-treated rat pancreas and may play a role in the development of pancreatic cancer.
Asunto(s)
Azaserina/farmacología , Carcinógenos/farmacología , Carcinoma de Células Acinares/patología , Expresión Génica/efectos de los fármacos , Páncreas/metabolismo , Neoplasias Pancreáticas/patología , Receptores de Colecistoquinina/biosíntesis , Animales , Autorradiografía , Secuencia de Bases , Carcinoma de Células Acinares/inducido químicamente , Carcinoma de Células Acinares/metabolismo , Cartilla de ADN , Gastrinas/metabolismo , Masculino , Datos de Secuencia Molecular , Páncreas/efectos de los fármacos , Páncreas/patología , Neoplasias Pancreáticas/inducido químicamente , Neoplasias Pancreáticas/metabolismo , Reacción en Cadena de la Polimerasa , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Ratas , Ratas Endogámicas LewRESUMEN
Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfunctional C1(-)-INH proteins were cleaved to lower mol wt forms that were not seen following the reaction of normal C1(-)-INH with equimolar amounts, or less, of plasma kallikrein. Only the higher mol wt component of normal C1(-)-INH (106,000 mol wt) appeared to form a stable complex with the plasma kallikrein, whereas both the 106,000 and 96,000 mol wt forms made stable complexes with C1-s. When a preparation of normal C1(-)-INH containing a homogeneous single band of C1(-)-INH was exposed to C1-s or kallikrein, a "doublet" form evolved in which the heaviest band was in the original position of native C1(-)-INH; C1-s cleavage provided a second band of 96,000; and cleavage by kallikrein, a second band of 94,000 mol wt. We conclude that dysfunctional C1(-)-INH proteins from plasma of persons with type II hereditary angioneurotic edema have impaired interactions with plasma kallikrein and are heterogeneous with respect to these interactions. Moreover, the requirements for the formation of stable complexes between normal C1(-)-INH and plasma kallikrein differed from those for stable complex formation with C1-s. The doublet form of C1(-)-INH, which purified preparations frequently demonstrate, may be due to prior cleavage by C1-s or kallikrein.