Effects of mast cell-macrophage interactions on the production of collagenolytic enzymes by metastatic tumor cells and tumor-derived and stromal fibroblasts

Histological examination of the metastatic rat mammary adenocarcinoma line MTLn3 showed that macrophages and mast cells were frequently localized at the tumor periphery in the stromal tissues adjacent to the zones of tumor invasion. The interactions of these host cells with tumor cells and tumor-associated fibroblasts could be important in stimulating the production of extracellular matrix-degrading enzymes that facilitate tumor invasion and metastatic spread. Therefore, we examined the effects of isolated, activated macrophages and mast cells on the secretion of collagenolytic activities by normal fibroblasts, metastatic mammary adenocarcinoma cells and tumor-associated fibroblasts. Medium from activated macrophages or degranulated mast cells stimulated significant increases in production of collagenolytic activities by normal and tumor-associated fibroblasts and MTLn3 tumor cells. Medium from activated macrophages that had been pretreated with medium from degranulated mast cells, however, were less stimulatory to fibroblasts and tumor cell production of collagenolytic activities than medium from degranulated mast cells alone. We also examined the effects of two cytokines, interleukin-1 and tumor necrosis factor-a on activated macrophage- and degranulated mast cell-stimulation of fibroblast and tumor cell collagenolytic activities. The two cytokines alone or in combination stimulated increased production of collagenolytic activities by fibroblasts and tumor cells. Addition of the cytokines to degranulated mast cell products resulted in secretion of higher collagenolytic enzyme activities by normal fibroblasts (but not by tumor-derived fibroblasts or tumor cells) than with degranulated mast cell product-treatment of either target cell alone. Cytokines used in combination with macrophage-conditioned medium were less effective in stimulating fibroblast and tumor cell collagenase activities than cytokines alone. Thus normal infiltrating host cells such as macrophages and mast cells can have profound effects on the production of degradative enzymes by tumor cells and tumor-associated stromal fibroblasts.     

Interaction of a 60-kilodalton D-mannose-containing salivary glycoprotein with type 1 fimbriae of Escherichia coli.

A 60-kilodalton glycoprotein previously isolated and purified from human saliva (J. B. Babu, E. H. Beachey, D. L. Hasty, and W. A. Simpson, Infect. Immun. 51: 405-413, 1986) was found to interact with type 1 fimbriae and prevent adhesion of type 1 fimbriated Escherichia coli to animal cells in a D-mannose-sensitive manner. Purified salivary glycoprotein agglutinated type 1 fimbriated E. coli and, at subagglutinating concentrations, blocked the ability of type 1 fimbriated E. coli to attach to human buccal epithelial cells or agglutinate guinea pig erythrocytes. Both interactions were inhibited by alpha-methyl-D-mannoside but not by alpha-methyl-D-glucoside. Complexing of the glycoprotein to type 1 fimbriae was demonstrated by molecular sieve chromatography and modified Western blots. When mixed with type 1 fimbriae, the radiolabeled salivary glycoprotein coeluted with type 1 fimbriae from a column of Sepharose 4B. When blotted from a sodium dodecyl sulfate gel to nitrocellulose sheets, the glycoprotein interacted directly with type 1 fimbriae applied to the blots. Both of the latter interactions also were blocked by alpha-methyl-D-mannoside but not by alpha-methyl-D-glucoside. Chemical modification of the glycoprotein with sodium metaperiodate abolished its ability to interact with isolated type 1 fimbriae or type 1 fimbriated E. coli. These results suggest that the carbohydrate moiety of the 60-kilodalton glycoprotein serves as a receptor for type 1 fimbriae in the oral cavity, and we postulate that the interaction may cause agglutination and early removal of E. coli, thereby preventing colonization by these organisms of oropharyngeal mucosae and dental tissues.     

Collagens in scar carcinoma of the lung.

Immunohistopathologic and biochemical studies of different collagen types extracted from human scar carcinoma of the lungs have been carried out for definition and evaluation of which types of collagen are involved in the scarring mechanism of such tumors. Tumor homogenates treated with 0.5 M acetic acid and followed by limited proteolysis with pepsin and then by fractional salt precipitation, demonstrated that Type I collagen constitutes the major collagenous component in addition to a significant increase in Type V collagen extracted from human scar carcinoma of the lung. However, when normal membranoalveolar peripheral lung tissues were processed under the same experimental conditions, Type III and IV collagens were relatively higher. Immunohistochemical studies were carried out, and the results confirmed the data above. Furthermore, these studies demonstrated a relative localized increase in Type III collagen in the area surrounding the tumor acini, which suggested that these areas are of active and recent scar formation. This supports the current concept of the scar origin as a desmoplastic reaction of the host tissues toward the neoplastic cell growth.     

Psychosocial and economic profile of a sample of families with thalassaemic children in Lebanon.

Thalassaemia major is a relatively common disease in Lebanon. This study of 41 families with 54 patients attending the American University of Beirut Medical Center was conducted to define some aspects of the disease in Lebanon and to assess the attitudes of affected families on relevant psychosocial and economic issues. We conclude that because of the high frequency of consanguineous marriage, thalassaemia major is more common in Lebanon than might be expected on the basis of the incidence of the trait. Most patients are diagnosed early in life, but their treatment is generally far from adequate; securing desferrioxamine and paying for follow up visits to the doctor seem to be the most important financial burdens. The general population of the country is not properly informed yet and about 70% of the families had not heard about the disease before having an affected child. The inherited nature of the disease is not clear in the minds of a high percentage of the families, and in about 30% of cases the family had not been told about the advisability of screening to detect heterozygotes. The great majority of families favour a preventive approach to thalassaemia, based on heterozygote screening and the possibility of prenatal diagnosis.     

Prediction of post-cardiopulmonary bypass cardiac output by venous oximetry

The present study evaluates two equations for predicting the post-cardiopulmonary bypass cardiac output (CO) in 10 patients undergoing coronary artery bypass grafting. One equation is based on the relationship of CO with mixed venous oxygen saturation (SVO 2), while the second equation is based on the relationship with oxygen extraction (1 - SVO 2). Each patient served as his own control. During bypass, when the patients were normothermic and perfused with a pump flow of 2.4 L/min/m 2, the SVO 2 was monitored by an in-line Bentley oxystat Meter. Just before termination of bypass, the pump flow was decreased to 0.4 L/min/m 2 and the left atrial pressure was increased to 10-15 mmHg; the resulting SVO 2 was recorded. The post-bypass CO was predicted in every patient by the two equations. Immediately after weaning from bypass, the cardiac output was measured by thermodilution. The thermodilutional CO measurement was correlated with the CO predicted by the two equations. Correlation analysis suggests that CO prediction is more accurate and approaches the 1:1 ratio when the calculation of predicted CO is based on the relationship between cardiac output and oxygen extraction.     

Management and outcomes of lower risk patients presenting with acute coronary syndromes in a multinational observational registry

OBJECTIVE: To document patterns of risk stratification, management practices, and outcomes among patients with acute coronary syndromes (ACS) presenting without high risk features. PATIENTS: The study was based on 11,885 consecutive patients presenting with non-ST segment elevation ACS enrolled in GRACE (global registry of acute coronary events). Patients without dynamic ST segment changes, positive troponin (or other cardiac markers), or haemodynamic or arrhythmic instability were defined as being at lower risk. MAIN OUTCOME MEASURES: Management and outcomes were compared with high risk presentations. RESULTS: Of 11,885 patients presenting with unstable angina or non-ST segment elevation myocardial infarction, 4252 (36%) were regarded as being at lower risk. Functional testing for risk stratification was performed in 1163 of 4207 (28%) lower risk and 1531 of 7521 (20%) high risk patients (p < 0.0001). Coronary angiography was performed in 1930 of 4190 (46%) and 3860 of 7544 (51%), and echocardiography in 1692 of 4190 (40%) and 4348 of 7533 (58%) of lower risk and high risk patients, respectively (p < 0.0001 for both). Over one third of patients did not undergo further risk assessment with angiography or functional testing (2746 of 7437 (37%) high risk, 1499 of 4148 (36%) lower risk, not significant). Death occurring in hospital was more likely in the high risk cohort (41 of 4227 (1.0%) lower risk v 215 of 7586 (2.8%) high risk, p < 0.0001), whereas rates of recurrent angina during admission and readmission were similar in both groups (1354 of 4231 (32%) high risk, 2313 of 7587 (31%) lower risk, not significant). In the six months after discharge, death or myocardial infarction occurred in 79 of 3223 (2.5%) lower risk patients and 302 of 5451 (5.5%) high risk patients (p < 0.0001). CONCLUSIONS: Globally, further risk stratification after ACS presentation is suboptimal, regardless of presenting characteristics. Although in-hospital death and myocardial infarction are uncommon, recurrent ischaemia is encountered often in both groups. It remains to be seen whether better outcomes may be achieved with wider application of risk stratification and appropriately directed management strategies.