Conversion of TNF alpha from antiproliferative to proliferative ligand in mouse intestinal epithelial cells by regulating mitogen-activated protein kinase.

The mechanisms regulating the balance between intestinal epithelial cell proliferation and differentiation are essential to maintaining an intact mucosal barrier. Mitogen-activated protein (MAP) kinases appear to be key transducers of extracellular signals in these pathways. The goal of this study was to investigate the regulation of MAP kinase by tumor necrosis factor alpha (TNFalpha) and epidermal growth factor (EGF) in intestinal epithelial cells. The young adult mouse colon cell line was studied for TNFalpha and/or EGF regulation of MAP kinase in the presence or absence of the MAP kinase kinase (MEK1) inhibitor PD 98059. Proliferation was determined by hemocytometry, and activated MAP kinase was identified by Western blot analysis, in vitro kinase assay, and confocal laser immunofluorescent microscopy. TNFalpha stimulated sustained nuclear MAP kinase activity, while EGF stimulated transient cytoplasmic MAP kinase activity. Changing TNFalpha's sustained MAP kinase activation to transient converted TNFalpha from an anti-proliferative to a proliferative ligand. These findings demonstrate that both TNFalpha and EGF activate MAP kinase in intestinal epithelial cells. The kinetics and subcellular distribution of this enzyme activity may be pivotal in the transduction of divergent cellular responses in the intestinal epithelium with implications for altered proliferative signals in inflammatory bowel disease.

Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor kappaB activation in mouse colonocytes.

BACKGROUND & AIMS: Derivatives of 5-aminosalicylic acid (mesalamine) represent a mainstay in inflammatory bowel disease therapy, yet the precise mechanism of their therapeutic action is unknown. Because tumor necrosis factor (TNF)-alpha is important in the pathogenesis of inflammatory bowel disease, we investigated the effect of mesalamine on TNF-alpha-regulated signal transduction and proliferation in intestinal epithelial cells. METHODS: Young adult mouse colon cells were studied with TNF-alpha, epidermal growth factor, or ceramide in the presence or absence of mesalamine. Proliferation was studied by hemocytometry. Mitogen-activated protein (MAP) kinase activation and IkappaBalpha expression were determined by Western blot analysis. Nuclear transcription factor kappaB (NF-kappaB) nuclear translocation was determined by confocal laser immunofluorescent microscopy. RESULTS: The antiproliferative effects of TNF-alpha were blocked by mesalamine. TNF-alpha and ceramide activation of MAP kinase were inhibited by mesalamine, whereas epidermal growth factor activation of MAP kinase was unaffected. TNF-alpha-stimulated NF-kappaB activation and nuclear translocation and the degradation of Ikappa-Balpha were blocked by mesalamine. CONCLUSIONS: Mesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-kappaB. Therefore, it may function as a therapeutic agent based on its ability to disrupt critical signal transduction events in the intestinal cell necessary for perpetuation of the chronic inflammatory state.

CASS Registry long term surgical survival. Coronary Artery Surgery Study.

OBJECTIVES: To show the effect of clinical, angio and demographic traits on late survival of Coronary Artery Surgery Study (CASS) patients following coronary artery bypass grafting (CABG) and introduce Hazard Function analysis to CASS survival data. METHODS: Patients were reached by mail survey with 94% response. By National Death Index, vital status was obtained in 99.7% (n = 8221) with a mean follow up of 15 years. Cox proportional hazard and Blackstone Hazard Function regressions were used to assess effects of preoperative traits. RESULTS: Ninety percent of patients were alive at 5, 74% at 10 and 56% at 15 years. Of those age 65 and age 75 at operation, 74% and 59% were living at 10 years and 54% and 33% at 15 years (now age 90), survival exceeding the matched U.S. population. Hazard Function falls rapidly after CABG to 9 to 12 months, then rises, doubling by 15 years. Young patients, below age 35, had lower late survival. The time-segmented Cox model (divided at time suggested by the Hazard Function) identified traits showing predictive power early, throughout and late. Female sex, small body surface, ischemic symptoms and emergency status affected survival early. Heavier weight, infarct(s), diuretics, diabetes, smoking, left main and LAD stenosis and use of vein grafts only increased hazard late only. CONCLUSIONS: There are still lessons from the CASS database. CABG in the elderly is supported by the survival pattern of our patients age 75 at operation. Time-segmented Cox analysis and Hazard Function analysis separate baseline variables into those that predict early mortality and those that predict long survival.

Mitral valve replacement: randomized trial of St. Jude and Medtronic Hall prostheses.

BACKGROUND: This study was designed to better define the merits of the bileaflet and tilting-disc valves. METHODS: We prospectively randomized 156 patients (mean age, 59 years) to receive either the St. Jude (n = 80) or the Medtronic Hall (n = 76) mitral valve prosthesis between September 1986 and December 1997. The two groups were not significantly different with respect to preoperative New York Heart Association class, left ventricular ejection fraction, incidence of mitral stenosis or insufficiency, extent of coronary artery disease, completeness of revascularization, or cross-clamp or bypass time. RESULTS: The operative mortality (11.2% versus 13.1%, St. Jude versus Medtronic Hall, respectively) and late mortality (27% versus 22%, St. Jude versus Medtronic Hall, respectively) were not significantly different. Follow-up was complete in all hospital survivors with a mean of 60.7 months (range, 1 to 133 months). The analysis of 10-year actuarial survival and freedom from valve-related events demonstrated no significant differences between the cohorts. Freedom from reoperation was higher in the St. Jude group (p < 0.01). Comparisons of patient functional status and echocardiographic hemodynamic parameters obtained at the time of follow-up demonstrated no significant differences between the two prostheses. CONCLUSIONS: This study suggests that there is no difference between the St. Jude and Medtronic Hall prostheses with respect to late clinical performance or hemodynamic results and therefore does not support the preferential selection of either prosthesis.

Prospective evaluation of a new through-the-scope nasoduodenal enteral feeding tube.

BACKGROUND: With present techniques, transpyloric feeding tube placement is unreliable. This study evaluated a new nasoduodenal tube placed through a gastroscope. METHODS: A therapeutic gastroscope was advanced into the distal duodenum, and through the 3.7-mm channel this feeding tube was advanced under direct vision into the small bowel. The tube/guidewire combination was then advanced with the concomitant equidistant retraction of the scope until the wire could be grasped at the lips and exchanged to the nose using a nasal transfer tube. The guidewire was removed, and a "Y" connector was then attached to the end of the tube. RESULTS: Successful tube placement in all 21 patients (14M/7F) required an endoscopy time of 31 +/- 3.3 min and the tubes were utilized for 9.24 +/- 0.94 days. Tube tips were confirmed in the distal duodenum (10) or proximal jejunum (11) by radiographic contrast injection. CONCLUSION: This new through-the-scope tube can be placed in the distal duodenum quickly, safely, and consistently.

Tumor necrosis factor alpha regulates proliferation in a mouse intestinal cell line.

BACKGROUND & AIMS: Tumor necrosis factor (TNF)-alpha is a prominent cytokine in the pathogenesis of inflammatory bowel disease, yet its effects on the intestinal epithelium remain poorly understood. This study was designed to investigate the action of TNF-alpha on intestinal cell proliferation. METHODS: Young adult mouse colon cells were studied under nontransformed conditions with epidermal growth factor, keratinocyte growth factor, insulin-like growth factor 1, or serum in the presence or absence of TNF-alpha and cell numbers determined. The expression and independent actions of the 55-kilodalton TNF-alpha R1 and 75-kilodalton TNF-alpha R2 receptors were studied by immunologic methods. RESULTS: TNF-alpha stimulated proliferation at 0.1 and 1 ng/mL and inhibited proliferation at 100 and 1000 ng/mL without altering cell viability. TNF-alpha inhibited the mitogenic effect of growth factors and epidermal growth factor receptor tyrosine phosphorylation. TNF-alpha R1 receptor agonist antibody inhibited proliferation, whereas a TNF-alpha R2 receptor-blocking antibody prevented the proliferative effect of low-dose TNF-alpha. CONCLUSIONS: TNF-alpha displays a novel influence on intestinal cell growth, stimulating proliferation at physiological concentrations and inhibiting proliferation at pathological concentrations. The regulation of intestinal cell mitogenesis by TNF-alpha seems to be mediated differentially by the two TNF-alpha receptors, with the TNF-alpha R1 receptor inhibiting proliferation and the TNF-alpha R2 receptor promoting proliferation.

Valve replacement in the small aortic annulus: prospective randomized trial of St. Jude with Medtronic Hall.

OBJECTIVE: The ideal prosthesis for aortic valve replacement in patients with small annuli remains controversial and has yet to be identified. The purpose of this report is to compare the St. Jude (SJ) Medical and Medtronic Hall (MH) valves for aortic valve replacement in the small aortic root. METHODS: From 1986 to 1994 we prospectively randomized 456 patients to receive either the SJ or the MH valve. From this population, 80 patients (SJ, 42 patients; MH 38 patients) had a 19 or 21 mm aortic prosthesis inserted without annulus enlarging procedure. RESULTS: Follow-up was complete in all 80 patients for 270 patient years (mean 40.5 months). Analysis showed that the SJ and MH groups were similar with respect to age, gender, body surface area, valve area, NYHA class, ventricular function, prosthesis size, frequency of revascularization, bypass and global ischemic time. There were two operative deaths (1 SJ, 1 MH). Clinical performance and Dobutamine stress transesophageal doppler echocardiography could not demonstrate a significant advantage of one prosthesis over the other in this population. The change in aortic valve gradient, and left ventricular mass index measured preoperatively and within 12 months postoperatively were not different in both cohorts. CONCLUSION: The study could not detect a difference in the performance of the SJ and MH heart valves for aortic valve replacement in patients with small aortic annuli.

Management of asymptomatic mild aortic stenosis during coronary artery operations.

BACKGROUND: Management of asymptomatic mild aortic stenosis at the time of coronary artery bypass grafting (CABG) remains controversial. We have retrospectively analyzed a cohort of patients requiring aortic valve replacement (AVR) subsequent to CABG and compared their operative morbidity and mortality with that of a group receiving CABG and AVR simultaneously at the first operation. METHODS: Analysis is drawn from 28 patients who required AVR 8 +/- 4 years subsequent to CABG (group A) and 175 patients receiving AVR along with CABG at the primary operation (group B). Groups were similar with respect to age, sex, risk factors for cardiac disease, extent of coronary artery disease, left ventricular function, New York Heart Association class, aortic valve area, number of grafts, and size of prosthesis inserted. RESULTS: Patients having AVR subsequent to CABG had a significantly prolonged aortic cross-clamp time and global myocardial ischemic time and incurred a twofold increase in operative mortality. The actuarial survival at 10 years was not significantly different between cohorts. In the 28 patients in group A, the aortic valve area during the period between operations decreased 0.05 mm2/y. CONCLUSIONS: The operative mortality and morbidity of a second operation for AVR is high, but there is no significant difference in survival at 10 years. In at least a portion of patients having mild aortic stenosis at the time of CABG there will be progression of the stenosis necessitating reoperation at a later date.

Relation between pulmonary venous flow and pulmonary wedge pressure: influence of cardiac output.

Multiple factors affect the systolic and diastolic components of pulmonary venous flow. It has been suggested that left ventricular function might influence the effects of filling pressures on indexes of pulmonary venous flow. The present study was designed to evaluate the effect of the pulmonary wedge pressures, left ventricular function, and cardiac output on the pulmonary vein flow pattern. Forty-five patients undergoing cardiac surgery were included in this study. Pulmonary venous flow and mitral flow variables were obtained by transesophageal echocardiography with hemodynamic variables obtained simultaneously. In the total group, there was no consistent relation between the pulmonary venous flow or the mitral flow parameters and the capillary wedge pressures. When patients were grouped according to normal (> 2.2 L/min/m2) or low (< 2.2 L/min/m2) cardiac index, a significant and positive relation was found between the systolic component of the pulmonary venous flow and the pulmonary wedge pressure in patients with normal cardiac index (r = 0.69; p = 0.003). Conversely, in patients with low cardiac index there was also a significant although negative correlation between the systolic velocity integral and the pulmonary wedge pressure (r = -0.58; p < 0.001). In conclusion, the systolic component of the pulmonary venous flow correlates closely and significantly with the capillary wedge pressures. The direction of this relation depends to a large extent on the total cardiac output and to a lesser extent on the left ventricular systolic function as assessed by the ejection fraction.

Double-valve replacement with Medtronic-Hall or St. Jude valve.

To define better the performance of the bileaflet St. Jude and the tilting-disc Medtronic-Hall valves, we retrospectively analyzed 122 patients (St. Jude, 80 patients; Medtronic-Hall, 42 patients) who received simultaneous aortic and mitral replacement from May 1984 until June 1994. The two groups were not different with respect to preoperative clinical and hemodynamic parameters and New York Heart Association functional class. The hospital mortality and late mortality were not significantly different. Risk analysis identified advanced age and previous myocardial revascularization as predictors of operative death. Follow-up was complete in 96 of 103 hospital survivors (93%) and was similar in both groups. The actuarial survival, linearized rates of valve-related complications, and actuarial freedom from valve-related complications were similar in both cohorts. The presence of coronary artery disease negatively influenced the actuarial survival after simultaneous aortic and mitral valve replacement. Postoperative New York Heart Association functional class was not significantly different in either group. These data indicate that the Medtronic-Hall and St. Jude prostheses are not significantly different with respect to their clinical performance and valve-related complications for simultaneous double-valve replacement.

Comparison of surgical and medical group survival in patients with left main equivalent coronary artery disease. Long-term CASS experience.

BACKGROUND: Combined severe proximal left anterior descending and proximal left circumflex coronary artery disease, or left main equivalent (LMEQ) disease, defines a prognostic high-risk angiographic subset of patients with chronic ischemic heart disease. While numerous observational and randomized clinical trials showed prolonged survival in surgically compared with medically treated patients with left main coronary artery disease, relatively few observational studies compared surgical and medical therapies in patients with LMEQ disease. The present report of 912 patients with LMEQ disease in the Coronary Artery Surgery Study (CASS) Registry extends the originally published 5-year surgical and medical group survival analysis to more than 16 years of follow-up and permits analysis of LMEQ patient subgroups. METHODS AND RESULTS: The CASS Registry contains 912 patients with LMEQ disease, defined as combined stenoses of > or = 70% in the proximal left anterior descending coronary artery before the first septal perforator and proximal circumflex coronary artery before the first obtuse marginal branch, initially treated with either surgical or nonsurgical therapy. The 15-year cumulative survival estimates were 44% for the 630 patients in the surgical group and 31% for the 282 patients in the medical group. Median survival in the surgical group was 13.1 years (12.7 to 14.1 years, 95% confidence limits) compared with only 6.2 years (4.8 to 7.9 years) in the medical group (difference, 6.9 years; P < .0001). Median survival was also significantly longer in the surgical group stratified by age, sex, anginal class, left ventricular (LV) function, and coronary anatomy. However, coronary artery bypass graft (CABG) surgery did not significantly prolong median survival in patient subgroups with (1) normal LV systolic function, even if a significant right coronary artery stenosis (> or = 70%) also was present, and (2) mildly abnormal (LV score, 6 to 10) LV systolic function. The 15-year cumulative survival in patients with normal LV systolic function in the surgical and medical groups was 63% and 54%, respectively. Median survival was > 15 years in both the surgical and medical groups (P = NS). In patients with normal LV systolic function and right coronary artery stenosis > or = 70%, the 15-year cumulative survival was also similar in the surgical and medical groups (63% and 53%, respectively). Median survival was > 15 years in both the surgical and medical groups (P = NS). The 15-year cumulative survival estimates in all subgroups were affected by convergence of the surgical and medical group survival curves caused by a disproportionate increase in late surgical group mortality. Overall, 26% of patients in the medical group ultimately underwent CABG surgery. If all medical group patients had survived long enough, about 65% would be estimated to have had surgery by 15 years. When the CASS Registry patients with LMEQ disease who participated in the randomized trial or who were randomizable were analyzed, CABG surgery did not prolong the 15-year cumulative survival estimates compared with nonsurgical therapy for randomized (71% versus 67%, respectively) and for randomizable patients (62% versus 92%, respectively) with an LV ejection fraction > or = 50%. CONCLUSIONS: This report, which extends follow-up of more than 16 years in CASS Registry patients with LMEQ disease, shows that CABG surgery prolongs life in most clinical and angiographic subgroups. However, median survival was not prolonged by CABG surgery in patients with normal LV systolic function, even if a significant right coronary artery stenosis (> or = 70%) also was present or in patients with an LV ejection fraction > or = 50% who participated in the CASS randomized trial or who were randomizable.

Comparison of surgical and medical group survival in patients with left main coronary artery disease. Long-term CASS experience.

BACKGROUND: Observational and randomized studies designed to compare surgical and medical therapies in patients with left main coronary artery disease (LMCD) have shown that coronary artery bypass graft (CABG) surgery prolongs life in most patients with LMCD. The present report of 1484 patients with LMCD in the Coronary Artery Surgery Study (CASS) Registry extends the originally published 5-year surgical and medical group survival analysis to more than 16 years of follow-up and permits analysis of LMCD patient subgroups. METHODS AND RESULTS: The CASS Registry contains 1484 patients with > or = 50% left main coronary artery stenosis initially treated with either surgical or nonsurgical therapy. The 15-year cumulative survival estimates were 37% for the 1153 patients in the surgical group compared with 27% for the 331 patients in the medical group. Median survival in the surgical group was 13.3 years (12.8 to 13.8 years, 95% confidence limits) compared with only 6.6 years (5.4 to 7.9 years) in the medical group (difference, 6.7 years; P < .0001). Median survival was also significantly longer in the surgical group stratified by age, sex, anginal class, left ventricular (LV) function, coronary anatomy, and the extent of LMCD. However, CABG surgery did not significantly prolong median survival in patient subgroups with (1) left main coronary stenosis of 50% to 59%; (2) normal LV systolic function; (3) normal or mildly abnormal LV systolic function and a right coronary artery stenosis > or = 70%; and (4) a nonstenotic (< or = 70%) right coronary artery. The 15-year cumulative survival for patients with normal LV systolic function in the surgical and medical groups was 42% and 51%, respectively. Median survival was 14.7 years in the surgical group and > 15 years in the medical group (P = NS). In patients with normal LV systolic function and a right coronary artery stenosis > or = 70%, the 15-year cumulative survival rates were also similar in the surgical and medical groups (40% and 48%, respectively). Median survival was 14.3 years in the surgical group and 14.2 years in the medical group (P = NS). The 15-year cumulative survival estimates for all subgroups were affected by convergence of the surgical and medical survival group curves owing to a disproportionate increase in the late surgical group mortality. Overall, 25% of patients in the medical group ultimately underwent CABG surgery. If all medical group patients had survived long enough, about 47% would be estimated to have had surgery by 15 years. CONCLUSIONS: This report, which extends follow-up of more than 16 years in CASS Registry patients with LMCD, shows that CABG surgery prolongs life in most clinical and angiographic subgroups. However, median survival was not prolonged by CABG surgery in patients with normal LV systolic function, even if a significant right coronary artery stenosis (> or = 70%) also was present. These results extend our understanding of the natural history of LMCD and permit a more accurate estimate of long-term surgical and medical group survival.

Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry.

BACKGROUND: This study describes the impact of clinical, angiographic, and demographic characteristics on the long-term survival of Coronary Artery Surgery Study (CASS) patients while they were under medical treatment. Revascularization rates for the population are also provided. METHODS AND RESULTS: All CASS patients who had not received heart surgery before enrollment (23,467 patients) were included in this survival analysis while they were under medical treatment or surveillance. Follow-up time ranged from 0 to 17 years (median, 12 years). Long-term vital status is known for 95.8% of these patients. Log-rank tests, Kaplan-Meier survival curves, and Cox proportional-hazards regression are used to describe and assess the impact of patient characteristics on survival. Characteristics that had a significant impact on survival, in order of observed explanatory power, are age, number of diseased vessels, congestive heart failure score, smoking history, ejection fraction, sex, presence of left main coronary artery disease, presence of diabetes, left ventricular wall motion score, presence of other illnesses, history of myocardial infarction, and presence of left main equivalent disease. Overall, 12-year survival for patients with zero-, one-, two- and three-vessel disease is 88%, 74%, 59%, and 40%, respectively. Twelve-year survival for patients with at least one diseased vessel and ejection fractions in the ranges of 50% to 100%, 35% to 49%, and 0% to 34% is 73%, 54%, and 21%, respectively. High myocardial jeopardy, high anginal class, and two or three proximal diseased vessels characterize the profile of patients most likely to have received surgical treatment during follow-up. CONCLUSIONS: These results contribute to the understanding of the natural history of coronary artery disease and are also of historical interest. The poor survival of patients with three-vessel disease and low ejection fractions continues to emphasize the importance of considering revascularization for these patients.