Epstein-Barr virus and childhood Hodgkin's disease in Honduras and the United States

In industrialized populations, Hodgkin's disease (HD) has an initial peak in young adulthood, whereas in economically developing populations the initial peak occurs in childhood. This pattern resembles that of infection with poliovirus and suggests an infectious cofactor in the etiology. Serologic studies have linked Epstein-Barr virus (EBV) to young adult and adult HD, and viral nucleic acids and antigens have been detected in a subset of Hodgkin's tumor specimens. To investigate the association of childhood HD with EBV we studied tumor specimens from 11 children treated in Honduras and 25 children treated in the United States using in situ hybridization and antigen detection techniques. Among the patients from Honduras, tumor specimens from all cases were EBV positive. Among the patients from the United States, tumor specimens from six of seven patients with mixed cellularity histology, 2 of 15 with nodular sclerosis histology, and neither of two patients with lymphocyte-predominant histologies were EBV positive. These findings support the hypothesis that EBV contributes to the pathogenesis of HD in children, particularly in mixed cellularity HD, and raises the possibility that there are important geographic, racial, or ethnic factors in the EBV association with HD.     

Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease

BACKGROUND & AIMS: The aim of this study was to determine the risk of endoscopic/radiological recurrence of Crohn's disease postoperatively and the long-term outcome. METHODS: A randomized placebo-controlled trial was performed to determine the effectiveness of mesalamine in preventing recurrent Crohn's disease postoperatively. Patients in the control group were examined endoscopically/radiologically before entry into and annually during the trial. Findings were classified as minimal or severe. RESULTS: There were 76 patients (49 men and 37 women; mean age, 37.1 +/- 13.2 years). Fifty (61.7%) had terminal ileal resections. Overall, 55 endoscopic/radiological recurrences were observed in 51 patients (67.1%). Expressed actuarially, the recurrence rate was 27.5% at 1 year (95% confidence interval [CI], 15.8%-37.6%), 60.8% at 2 years (95% CI, 46%-71.3%), and 77.3% at 3 years (95% CI, 62.7%-86.3%). Nineteen (37%) were symptomatic and 12 (24%) were initially asymptomatic but later became symptomatic (mean, 13.0 +/- 8.8 months), whereas 20 (39%) remained asymptomatic (mean, 16.9 +/- 17.4 months). Patients with severe endoscopic/radiological disease were significantly more likely to be or become symptomatic than those with minimal disease (23 of 32 vs. 8 of 19, respectively; P = 0.0437). CONCLUSIONS: This study suggests that postoperative endoscopic/radiological recurrences occur later than previously reported. Furthermore, many of these patients, especially with minimal disease, will remain asymptomatic. (Gastroenterology 1997 Dec;113(6):1823-7)     

Inflammation and outcome after general thoracic surgery.

OBJECTIVE: To determine whether preoperative inflammation predisposes to major postoperative complications (PC) and poor outcome. METHODS: Prospective data collection of 153 consecutive patients aged 73+/-6 years scheduled for lung resection at a tertiary cancer center. High sensitivity C-reactive protein (CRP) and interleukin (IL)-6 levels were measured before surgery, on arrival to the postanesthesia care unit, and on the first morning after surgery. RESULTS: PC occurred in 9/153 (5.9%) patients. In comparison to patients without PC, those with PC had a greater history of hypertension (P=0.047), higher frequency of non-steroidal anti-inflammatory drug use (P=0.007) and had a lower preoperative albumin level, 3.75+/-0.65 g/dl versus 4.28+/-0.33 g/dl, P=0.03. Receiver operating characteristic analysis demonstrated a strong association between PC and preoperative CRP (area under the curve of 0.86), albumin (area under the curve of 0.86) and less so for IL-6 (area under the curve of 0.79). CONCLUSIONS: Markers of inflammation, CRP and IL-6, can help distinguish patients who are at high risk for major PC. These preliminary and novel data suggest that in addition to low albumin, a previously described marker of outcome, systemic inflammation is likely to be important in the pathogenesis of important PC.     

Growth properties of colonic tumor cells are a function of the intrinsic mitochondrial membrane potential

Development of malignant transformation in the colonic mucosa includes disruption in the equilibrium between proliferation and apoptosis, decreased expression and deletions of the mitochondrial genome, alterations in mitochondrial enzymatic activity, and elevations in the mitochondrial membrane potential (Deltapsim). Focusing on the role of the Deltapsim in tumor development and progression, we generated novel isogenic colonic carcinoma cell lines that exhibit highly significant, stable differences in their intrinsic Deltapsim. Using these cell lines, we have recently shown that the intrinsic Deltapsim has a significant influence on steady state mitochondrial activity and the extent to which cells enter butyrate-mediated growth arrest and apoptotic cascades. Here, we report that the Deltapsim is also profoundly linked to important tumorigenic properties of the cells. Compared with cells with lower Deltapsim, cells with elevated intrinsic Deltapsim have an enhanced capacity to (a) respond to hypoxia by avoiding apoptosis and initiating angiogenesis, (b) escape anoikis and grow under anchorage-independent conditions, and (c) invade the basement membrane. Combined with our previous work, these data implicate the intrinsic Deltapsim of colonic carcinoma cells in determining the probability of tumor expansion and progression.     

Cardiopulmonary effects of the novel neuromuscular blocking drug GW280430A (AV430A) in dogs

BACKGROUND: This investigation determined the cardiopulmonary side effects of a novel nondepolarizing neuromuscular blocking drug with an ultrashort duration of action in anesthetized male beagles. METHODS: The ED95 for GW280430A was first determined in four animals. These data were then used to guide bolus dosing in multiples of ED95 in six dogs instrumented for hemodynamic measurements as well as inspiratory pressure and pulmonary compliance. Cardiopulmonary data were compared before and after the conclusion of a 60- to 90-min GW280430A infusion and in response to subsequent incremental bolus dosing starting with 3.125 x ED95. An adverse response was regarded as an alteration of 10% or greater in any variable. Arterial blood was obtained for histamine analysis before and 1 min after each dose. RESULTS: The ED95 of GW280430A was 0.064 +/- 0.01 mg/kg, and stable neuromuscular blockade was maintained with infusion of 0.012 +/- 0.002 mg.kg(-1).min(-1). With the exception of a late 14% increase in heart rate, there were no cardiopulmonary changes during infusion. Bolus dosing produced no cardiopulmonary change until a decrease in mean arterial pressure was elicited in four of six dogs at 25 x ED95. This response was modest, transient, and associated with a concomitant increase in plasma histamine concentration. There were no accompanying changes indicative of direct myocardial depression, pulmonary vasoconstriction, or bronchospasm. CONCLUSIONS: These data indicate that GW280430 does not produce demonstrable cardiovascular effects in the anesthetized dog until doses far in excess of the ED95 are administered as a bolus.     

Phospholipid abnormalities in children with Barth syndrome

OBJECTIVES: We sought to identify characteristic lipid abnormalities in patients with Barth syndrome (BTHS) and to correlate the lipid profile to phenotype and genotype. BACKGROUND: Barth syndrome typically includes cardiomyopathy, skeletal myopathy, neutropenia, growth retardation, and 3-methylglutaconic aciduria, and it is commonly associated with mutations in the tafazzin (TAZ) gene, whose products are homologous to phospholipid acyltransferases. However, clinical features of BTHS have also been found in patients with normal TAZ gene. METHODS: We analyzed molecular species of phospholipids in left and right ventricle, skeletal muscle, platelets, lymphoblasts, and fibroblasts from 19 children with BTHS (positive TAZ mutation), 6 children with BTHS-like syndromes (wild-type TAZ), 4 children with isolated cardiomyopathy (wild-type TAZ), and various controls. RESULTS: Cardiolipin, the specific lipid found only in mitochondria, was decreased in all tissues from BTHS patients, whereas concentrations of other phospholipids were normal. The molecular composition of cardiolipin was altered in all tissues from BTHS patients. The molecular compositions of phosphatidylcholine and phosphatidylethanolamine were altered in the heart. Cardiolipin abnormalities were only found in children with true BTHS, not in children with BTHS-like disease or with isolated cardiomyopathy. The degree of cardiolipin deficiency was tissue-specific but did not correlate with severity or specific phenotypic expression of BTHS. CONCLUSIONS: Abnormal cardiolipin is a specific diagnostic marker of cardiomyopathies caused by TAZ mutations. These mutations lead to alterations in the fatty acid composition of several phospholipids, supporting the idea that TAZ encodes a human acyltransferase.     

TR3/Nur77 in colon cancer cell apoptosis

The orphan nuclear receptor TR3/Nur77 has emerged as a viable candidate in the coordinate regulation of cell proliferation and apoptosis, essential for maintaining normal architecture in rapidly renewing tissues such as the colonic mucosa. TR3 induces apoptosis in a number of cell lineages exposed to proapoptotic stimuli by directly targeting the mitochondria, inducing cytochrome c release. Here we report a distinctly different mechanism of TR3-mediated apoptosis in colon cancer cells. Nucleus-to-cytoplasm translocation of a green fluorescent protein-TR3 construct, but not its direct mitochondrial targeting, was associated with apoptosis induced by the short-chain fatty acid, butyrate. Similar results were observed for the nonsteroidal anti-inflammatory drug, sulindac, and the chemotherapeutic drug, 5-fluorouracil. A mutant TR3 construct lacking DNA-binding ability exerted a potent proapoptotic effect in colon cancer cells that was associated with cytochrome c release, an action dependent upon cytoplasmic localization of the construct, but, again, not its direct mitochondrial targeting. We identified a potential role for BAX recruitment to the mitochondria, secondary to cytoplasmic translocation of TR3, in inducing cytochrome c release and in mediating apoptosis. Therefore, TR3 translocation from the nucleus may initiate the apoptotic cascade in colon cancer cells by stimulating other cytosolic proapoptotic molecules to associate with mitochondria.