RESUMEN
Surfactant deficiency is an important contributor to the acute respiratory distress syndrome, a disorder that commonly occurs after bacterial sepsis. CTP:phosphocholine cytidylyltransferase (CCTalpha) is the rate-limiting enzyme required for the biosynthesis of dipalmitoylphosphatidylcholine (DPPC), the major phospholipid of surfactant. In this study, a cDNA encoding a novel, calpain-resistant mutant CCTalpha enzyme was delivered intratracheally in mice using a replication-deficient adenovirus 5 CTP:phosphocholine cytidylyltransferase construct (Ad5-CCT(Penta)) in models of bacterial sepsis. Ad5-CCT(Penta) gene transfer produced high-level CCTalpha gene expression, increased alveolar surfactant (DPPC) levels and improved lung surface tension and pressure-volume relationships relative to control mice. Pseudomonas aeruginosa (PA103) decreased DPPC synthesis, in part, via calpain-mediated degradation of CCTalpha. Deleterious effects of Pseudomonas on surfactant were lessened after infection with a mutant strain lacking the type III exotoxin, Exo U. Replication-deficient adenovirus 5 CTP:phosphocholine cytidylyltransferase gene delivery improved lung biophysical properties by optimizing surface activity in this Pseudomonas model of proteinase-mediated lung injury. The studies are the first demonstration of in vivo gene transfer of a lipogenic enzyme resulting in improved lung mechanics. The studies suggest that augmentation of DPPC synthesis via gene delivery of CCTalpha can attenuate impaired lung function in surfactant-deficient states such as bacterial sepsis.
Asunto(s)
Citidililtransferasa de Colina-Fosfato/genética , Terapia Genética/métodos , Enfermedades Pulmonares/terapia , Infecciones por Pseudomonas/terapia , Surfactantes Pulmonares/administración & dosificación , 1,2-Dipalmitoilfosfatidilcolina/metabolismo , Enfermedad Aguda , Adenoviridae/genética , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Citidililtransferasa de Colina-Fosfato/administración & dosificación , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Pulmón/enzimología , Enfermedades Pulmonares/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones por Pseudomonas/enzimología , Transducción Genética/métodosRESUMEN
We examined the effect of lipoprotein deprivation on the expression of the rate-regulatory enzyme involved in phosphatidylcholine (PtdCho) synthesis, phosphocholine cytidylyltransferase (CCT), within an alveolar type II epithelial cell line (MLE-12). Compared with cells exposed to 10% fetal bovine serum (FBS, control), cells cultured with lipoprotein-deficient serum (LPDS) for 72 h had a 150% increase in CCT activity. Stimulation of CCT activity after LPDS exposure was associated with a 2-fold increase in immunoreactive CCT content and a corresponding increase in [(35)S]methionine incorporation into newly synthesized CCT. LPDS induction of CCT protein was reversible, as it was suppressed to baseline levels by the addition of low density lipoproteins to the culture medium. Northern blotting revealed that LPDS increased CCT mRNA levels 2-fold compared with control. The induction of CCT mRNA by LPDS was not associated with an increase in mRNA half-life. Nuclear run-on assays revealed that LPDS-induced expression of CCT was due, at least in part, to an increase in gene transcription. These studies reveal that lipoprotein deprivation upregulates the activity of a key enzyme involved in the PtdCho biosynthetic pathway. LPDS induction of CCT protein might serve as a novel compensatory mechanism in response to lipid deprivation by increasing cellular transcription of the CCT gene.
Asunto(s)
Citidililtransferasa de Colina-Fosfato/genética , Lipoproteínas/deficiencia , Transcripción Genética , Animales , Sangre , Northern Blotting , Citidililtransferasa de Colina-Fosfato/biosíntesis , Medios de Cultivo , Células Epiteliales/enzimología , Semivida , Immunoblotting , Lipoproteínas/sangre , Fosfatidilcolinas/biosíntesis , Alveolos Pulmonares/enzimología , ARN Mensajero/análisis , ARN Mensajero/metabolismoRESUMEN
Tumor necrosis factor-alpha (TNF-alpha) has been shown to play an integral role in the pathogenesis of the acute respiratory distress syndrome. This disorder is characterized by a deficiency of alveolar surfactant, a surface-active material that is composed of key hydrophobic proteins and the major lipid disaturated phosphatidylcholine (DSPC). We investigated how TNF-alpha might alter DSPC content in rat lungs by instilling the cytokine (2.5 microg) intratracheally for 10 min and then assaying parameters of DSPC synthesis and degradation in alveolar type II epithelial cells, which produce surfactant. Cells isolated from rats given TNF-alpha had 26% lower levels of phosphatidylcholine compared with control. TNF-alpha treatment also decreased the ability of these cells to incorporate [(3)H]choline into DSPC by 45% compared with control isolates. There were no significant differences in the levels of choline substrate or choline transport between the groups. However, TNF-alpha produced a 64% decrease in the activity of cytidylyltransferase, the rate-regulatory enzyme required for DSPC synthesis. TNF-alpha administration in vivo also tended to stimulate phospholipase A(2) activity, but it did not alter other parameters for DSPC degradation such as activities for phosphatidylcholine-specific phospholipase C or phospholipase D. These observations indicate that TNF-alpha decreases the levels of surfactant lipid by decreasing the activity of a key enzyme involved in surfactant lipid synthesis. The results do not exclude stimulatory effects of the cytokine on phosphatidylcholine breakdown.
Asunto(s)
Alveolos Pulmonares/metabolismo , Surfactantes Pulmonares/metabolismo , Mucosa Respiratoria/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Supervivencia Celular/efectos de los fármacos , Colina/metabolismo , Citidililtransferasa de Colina-Fosfato/metabolismo , Activación Enzimática/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilcolinas/biosíntesis , Fosfatidilcolinas/metabolismo , Fosfolipasas A/metabolismo , Alveolos Pulmonares/química , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , Surfactantes Pulmonares/química , Ratas , Ratas Sprague-Dawley , Mucosa Respiratoria/citología , Mucosa Respiratoria/efectos de los fármacos , Tráquea , Factor de Necrosis Tumoral alfa/administración & dosificaciónRESUMEN
Delayed lung maturation and lower levels of surfactant phosphatidylcholine have been previously identified in male fetuses compared with female fetuses in several species. We investigated the mechanisms for sex differences in surfactant content by examining parameters of phosphatidylcholine turnover and biosynthesis; the latter was evaluated by measuring metabolic steps within the biosynthetic pathway. Compared with male lung cells, freshly isolated lung cells from female fetuses contained higher levels of disaturated phosphatidylcholine, a marker of surfactant lipid. Female mixed monolayer cultures exhibited a 71% increase in choline incorporation into disaturated phosphatidylcholine compared with male cultures. Male cultures exhibited significantly greater release of [3H]-arachidonic acid into the medium compared with females, suggesting sex differences in phospholipase activity. However, pulse-chase studies showed no sex differences in degradation of disaturated phosphatidylcholine, which was confirmed by assays of phospholipase A2, phosphatidylcholine-specific phospholipase C, and phospholipase D. Female mixed lung cells, however, had greater rates of cellular choline transport and activity of cytidylyltransferase, the rate-regulatory enzyme for phosphatidylcholine synthesis. Separate studies showed that exposure of sex-specific pretype II cell cultures to cortisol-stimulated fibroblast-conditioned medium plus transforming growth factor-beta-neutralizing antibody stimulated cytidylyltransferase activity to a greater extent in male cells compared with female cells. These studies indicate that sex differences in surfactant phospholipid content are not due to differences in phospholipid turnover, but rather differential regulation of specific metabolic steps within the surfactant biosynthetic pathway. The data also support a role for transforming growth factor-beta as a negative regulator of a key surfactant biosynthetic enzyme within male lungs.
Asunto(s)
Pulmón/fisiología , Surfactantes Pulmonares/biosíntesis , Animales , Células Cultivadas , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
In addition to being a strong psychological stressor in itself, medical illness is associated with risk factors that predispose patients to develop coexisting depression. Patients with conditions such as cancer, cardiovascular disease, and neurologic disorders are particularly prone to depression because these illnesses are severe, chronic, and often fatal. Because an antidepressant may exacerbate an underlying illness, leading to more serious side effects, agents with a poor tolerability profile or that act at multiple receptor sites should be avoided. In many cases, this precludes the use of tricyclic antidepressants and monoamine oxidase inhibitors, and favo's the use of selective serotonin reuptake inhibitors and other new antidepressants because they have fewer anticholinergic, cardiac, or cognitive adverse effects. Depressed medically ill patients clearly benefit from antidepressant therapy. Because mental health influences prognosis and treatment outcome, primary care physicians should maintain a high index of suspicion for depression in patients with significant medical illness and aggressively treat the condition when indicated.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/complicaciones , Depresión/tratamiento farmacológico , Medicina Familiar y Comunitaria , Enfermedades del Sistema Nervioso Central/complicaciones , Depresión/diagnóstico , Diagnóstico Diferencial , Cardiopatías/complicaciones , Humanos , Neoplasias/complicaciones , Factores de RiesgoRESUMEN
Forequarter amputation is a radical surgical procedure initially described for the treatment of traumatic injuries in 1908. This procedure has been used more recently in the treatment of soft tissue tumors. This report describes the experience in the Division of Surgical Oncology at the University of Illinois over a 20-year period. Between 1970 and 1991, 10 patients underwent forequarter amputations for malignant disease. Nine of these patients had soft tissue tumors and one a malignant melanoma. Four patients underwent amputation as primary treatment of their tumor, and six underwent the procedure as treatment for recurrent tumor. All patients are presently alive with a mean follow-up of more than 10 years. Three patients had recurrent tumor after the forequarter amputation. One local failure was salvaged with a chest wall resection, and two patients had distant failure. Forequarter amputation remains an effective procedure for local control of tumors of varying histology involving the shoulder girdle and upper arm. The most common indication for this procedure is a recurrent soft tissue tumor for which limb sparing procedures are not applicable. Forequarter amputation should remain a rarely used, but important, surgical option for the treatment of patients with soft tissue tumors.
Asunto(s)
Amputación Quirúrgica/estadística & datos numéricos , Brazo/cirugía , Hombro/cirugía , Neoplasias de los Tejidos Blandos/cirugía , Adolescente , Adulto , Anciano , Chicago/epidemiología , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Terapia Recuperativa , Neoplasias de los Tejidos Blandos/patología , Tasa de SupervivenciaRESUMEN
Nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) are relatively rare tumors, which nonetheless constitute 50% of the soft tissue sarcomas seen in the pediatric population. The prognosis for these tumors is good, with 92% of patients in our series alive and 61% free of their disease at 5 years follow-up. The most important prognostic factor among our 35 patients was the grade of the tumor. More than 70% of our patients with grade I or II lesions are disease-free at 5 years, compared to only 39% of patients with grade III lesions. The patients with the best outlook are those who can be treated with surgery alone as the definitive care for this disease. Resection remains the primary treatment modality in NRSTS, whereas, unlike the treatment of rhabdomyosarcomas, the value of radiation therapy and chemotherapy in treating NRSTS remains undefined.
Asunto(s)
Sarcoma/mortalidad , Neoplasias de los Tejidos Blandos/mortalidad , Niño , Terapia Combinada , Femenino , Humanos , Masculino , Pronóstico , Sarcoma/cirugía , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/cirugía , Neoplasias de los Tejidos Blandos/terapia , Análisis de Supervivencia , Tasa de Supervivencia , Factores de TiempoRESUMEN
Antiperistaltic and recurrent intussusceptions are extremely rare in the adult. We report a patient with both. The patient developed an antiperistaltic intussusception distal to her Roux enteroenterostomy years after a Roux-en-Y gastric bypass for morbid obesity. The diagnosis was made preoperatively with gastrointestinal contrast radiography and ultrasonography. At surgery, the intussusception was reduced, and 12 inches of nonviable bowel was resected, with a functional end-to-end anastomosis. An isoperistaltic intussusception occurred in the early postoperative period just distal to the anastomosis. Manometric evaluation of the Roux limb after the second operation showed altered gastrointestinal motility, consisting of orad-propagated and aboard-propagated migrating motor complexes, minimal phase 2 activity, and lack of conversion to the fed pattern with a liquid meal. Although manometry was not performed before the development of the intussusception, our findings are consistent with the hypothesis that altered intestinal motility may contribute to the development of intussusception.
Asunto(s)
Derivación Gástrica/efectos adversos , Enfermedades Gastrointestinales/etiología , Motilidad Gastrointestinal , Intususcepción/etiología , Peristaltismo , Adulto , Femenino , Enfermedades Gastrointestinales/diagnóstico por imagen , Humanos , Intususcepción/diagnóstico por imagen , Obesidad/cirugía , Periodo Posoperatorio , Radiografía , RecurrenciaRESUMEN
We have described the successful reconstruction of a completely resected anterior chest wall using autologous tissues. This case demonstrates feasibility despite known potential contamination and serious postoperative physiologic dysfunction.
Asunto(s)
Carcinoma de Células Escamosas/cirugía , Esternón/cirugía , Neoplasias Torácicas/cirugía , Humanos , Masculino , Persona de Mediana Edad , Trasplante AutólogoRESUMEN
Severe forefoot infections may lead to limb loss, even if addressed aggressively. Infection or gangrene that compromises the plantar skin flap may preclude a standard transmetatarsal or midfoot amputation, thereby culminating in a below-knee amputation. We report a series of forefoot infections with loss of the distal plantar skin. Open or guillotine amputation at the mid-metatarsal level led to a high rate of healing and a durable stump, provided that the level of infection did not extend beyond the metatarsal heads. Wound closure was obtained by wound contracture alone or by use of partial-thickness skin grafting. Rehabilitation was dependable. The association of diabetes mellitus or gangrene did not adversely affect outcome. Open transmetatarsal amputation is a safe surgical option preferable to midfoot or below-knee amputation for the treatment of severe forefoot infection that does not extend proximally beyond the metatarsal heads.
Asunto(s)
Amputación Quirúrgica , Enfermedades del Pie/cirugía , Pie/cirugía , Femenino , Humanos , Masculino , Metatarso , Persona de Mediana EdadRESUMEN
This study was undertaken to determine the efficacy and durability of profundaplasty and define preoperative factors predictive of success. The hospital charts, vascular laboratory data, and arteriograms of 20 patients having 21 isolated profundaplasties for ischemic rest pain between 1979 and 1987 were reviewed. Follow-up extended to 72 months (mean, 26 months). Early success was achieved in 12 extremities (57%) and life-table analysis showed continued success to six years in 11 extremities (55%). Of the multiple preoperative factors assessed, only a low-thigh/ankle gradient pressure index (TAGI) of less than 0.55 was predictive of success. Life-table analysis for limbs with a TAGI of less than 0.55 showed an 89% success rate at six years compared with only a 32% success rate for limbs with a TAGI of more than 0.55. Isolated profundaplasty for the treatment of ischemic rest pain can be an efficacious and durable procedure when patients are selected based on objective hemodynamic measurements.
Asunto(s)
Arteria Femoral/cirugía , Isquemia/cirugía , Pierna/irrigación sanguínea , Arterias/cirugía , Presión Sanguínea , Circulación Colateral , Femenino , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/fisiopatología , Humanos , Isquemia/diagnóstico por imagen , Isquemia/fisiopatología , Masculino , Persona de Mediana Edad , Dolor , Arteria Poplítea/fisiopatología , Arteria Poplítea/cirugía , Probabilidad , Radiografía , Descanso , Tibia/irrigación sanguínea , UltrasonografíaRESUMEN
Magnetic resonance imaging (MRI) and computed tomography (CT) scans of 53 evaluable patients with biopsy-proven soft tissue sarcomas were reviewed and compared with operative results to ascertain the accuracy for each imaging modality to predict resectability. Location of soft part sarcomas included: abdomino-pelvic (3), retroperitoneal (7), extremity (35), and other anatomic sites (8). MRI was observed to have greater accuracy than CT to preoperatively predict resectability (96.2% vs. 75.5%, respectively, p = 0.0034) following three-dimensional, multiplanar evaluation. Further, MRI was judged to have superior sensitivity to CT (95.6% vs. 73.3%, respectively, p = 0.006) and equivalent specificity (100% vs. 87.5%, respectively, p = 0.125). MRI represents a sophisticated diagnostic imaging technique to differentiate normal tissue from soft tissue sarcomas with superior contrast resolution in multiplanar imaging. MRI is considered to be the imaging modality of choice for these tumors with the advantage of not exposing the patient to ionizing irradiation or intravenous contrast agents to delineate contiguous structures.
Asunto(s)
Sarcoma/cirugía , Neoplasias de los Tejidos Blandos/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Evaluación como Asunto , Femenino , Humanos , Lactante , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sarcoma/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
There is little agreement as to the precise mechanism of action of muramyl dipeptide (MDP) despite a steadily unfolding series of experiments designed for clarification. This report further defines the role of MDP in nonspecific enhancement of host defenses by examining its effect on in vitro macrophage phagocytosis. Peritoneal macrophages were incubated in vitro with muramyl dipeptide. Phagocytic indices were determined using the iodination technique. The macrophages treated with MDP had a significant increase in their phagocytic function compared to control cells, adding to the understanding of the mechanism of action of MDP and raising the possibility of a trial peritonitis in humans.
Asunto(s)
Acetilmuramil-Alanil-Isoglutamina/farmacología , Macrófagos/efectos de los fármacos , Peritoneo/citología , Fagocitosis/efectos de los fármacos , Animales , Técnicas In Vitro , RatonesRESUMEN
The efficacy of palliative biliary decompression by operative and percutaneous methods was evaluated in 106 patients with unresectable malignancies obstructing the biliary system. Seventy patients had operative and 36 had percutaneous decompression. Primary malignancies of the pancreas and bile ducts were most common. Percutaneous transhepatic decompression was achieved beyond the site of obstruction in 72% of patients. Overall hospital mortality was 25% for patients having percutaneous catheter decompression and 17% for those patients operated upon. Early postoperative death was significantly related to: (1) age greater than 70 years; (2) preadmission weight loss greater than 15 pounds; (3) prothrombin time prolonged more than 2.5 seconds; and (4) hepatic metastases. Major complications were encountered in 56% of survivors of percutaneous drainage and 36% of those surviving operation. Intubation of the bile ducts due to inability to bypass the obstruction at operation was associated with the highest mortality (50%) and morbidity (86%). Mean survival was 14 months after operation, compared to 5 months after percutaneous decompression. The authors concluded that percutaneous decompression of the biliary tree is useful palliative treatment for those patients with proximal biliary obstruction due to malignancy when estimated operative risk is high, but operative decompression offers most patients the opportunity for longer survival with lower ultimate mortality and morbidity.