Smoking is associated with a wide variety of adverse health outcomes including cancer, chronic obstructive pulmonary disease, diabetes, depression and heart disease. Unfortunately, the molecular mechanisms through which these effects are conveyed are not clearly understood. To examine the potential role of epigenetic factors in these processes, we examined the relationship of smoking to genome wide methylation and gene expression using biomaterial from two independent samples, lymphoblast DNA and RNA (n=119) and lung alveolar macrophage DNA (n=19). We found that in both samples current smoking status was associated with significant changes in DNA methylation, in particular at the aryl hydrocarbon receptor repressor (AHRR), a known tumor suppressor. Both baseline DNA methylation and smoker associated DNA methylation signatures at AHRR were highly correlated (r=0.94 and 0.45, respectively). DNA methylation at the most differentially methylated AHRR CpG residue in both samples, cg0557592, was significantly associated with AHRR gene expression. Pathway analysis of lymphoblast data (genes with most significant methylation changes) demonstrated enrichment in protein kinase C pathways and in TGF beta signaling pathways. For alveolar macrophages, pathway analysis demonstrated alterations in inflammation-related processes. We conclude that smoking is associated with functionally significant genome wide changes in DNA methylation in both lymphoblasts and pulmonary macrophages and that further integrated investigations of these epigenetic effects of smoking on carcinogenesis and other related co-morbidities are indicated.
To determine the extent to which autologous blood that has been donated in advance ("predeposited") is used in patients undergoing elective surgery and to assess whether predonation decreases the use of homologous blood and the demand on the blood supply, we studied 4996 patients undergoing elective surgery at 18 tertiary care hospitals. Cross-matched blood was ordered for 1287 patients (26 percent), and of these, 590 (46 percent) were considered eligible for predepositing blood. Only 5 percent (32) of the eligible patients actually predeposited blood, indicating that predonation is not widely used. Of those who predeposited, only 13 percent (4 of 32) subsequently received homologous blood, as compared with 36 percent (199 of 558) of those who did not predeposit (P less than 0.01). Among the 199 patients who did not predeposit but required transfusion, we estimate that predonation could have avoided homologous transfusion in as many as 68 percent. If all eligible patients had predeposited autologous blood, they could have supplied as much as 72 percent of their own transfused red cells. The blood for as much as 10 percent of all red-cell transfusions could have been predonated by and transfused into the patients undergoing elective surgery. Greater use of predonation would not only reduce the demand on the blood supply by decreasing the need for homologous transfusion, but would probably also reduce the risk of hepatitis and other transfusion-associated illnesses.
Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune-system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways. A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages.
Before a comprehensive educational program on preoperative autologous blood donation was begun, 118 surgeons from three different areas of the country were tested to assess their baseline knowledge and attitude about this practice. Test results were correlated with the percentage of eligible patients that the surgeons actually referred for preoperative donation during a period of observation. The purpose of this preliminary effort was to identify areas in the educational program that required emphasis. Overall, the surgeons' attitude toward preoperative donation was quite favorable, but their depth of knowledge varied. Misunderstandings may have led to diminished use of this service (eg, about 50% didn't realize that many patients with medical conditions or low hematocrits are permitted to donate). However, it is not clear that simply bolstering surgeons' knowledge will increase their appropriate use of preoperative donation. When all 118 surgeons were studied, their knowledge and attitude were unrelated to the percentage of eligible patients referred. However, when 44 surgeons who managed the largest number of eligible patients were analyzed separately, their use of preoperative donation was directly correlated with their knowledge and attitude. The local awareness of AIDS also significantly influenced the use of this service. It is proposed that knowledge of preoperative donation may be important for inducing surgeons to begin referring patients for this service. Once a pattern of successful participation is established, referral seems to increase with the acquisition of working knowledge.
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