Heme as a Playmaker in the Regulation of the Nitric Oxide System

Abstract

founding due to this factor. Our results are thus interpreted as the hazard ratio of recurrence for paravertebral versus general anesthesia for patients at the same histologic grade, and similarly for other factors in the model. This sort of multivariable analysis compensates for small, or even moderate, imbalances at baseline. We adjusted for this factor because of the retrospective nature of the study, even though we did not have evidence of it being a true confounder because it was not associated with the treatment groups (P ϭ 0.16) or the outcome (P ϭ 0.25), both of which are required by the classic definition of confounding. As specified in the article, a single surgeon performed all cases in both groups. And again as specified, all paravertebral anesthesia was performed by a single anesthesiologist (D.J.B.), who also performed some of general anesthesia alone cases. The remainder were performed by three other attending anesthesiologists. The cases were similar, and the primary determinant of anesthetic type was assignment to D.J.B., who was the only anesthesiologist in the group familiar with the paravertebral technique. The substantial limitations of observational studies are well known and were discussed in our article. For example, we specified: "Patients were not randomized and clinical care was not standardized, so that selection bias and the effects of unmeasured confounding variables cannot be excluded. For example, patients in the general anesthesia group had slightly larger tumors, smaller margins, and higher chemotherapy rates than patients in the paravertebral group, factors that could affect mortality, although these differences did not reach statistical significance. Relevant information such as the amount of morphine given and the type of chemotherapy used in each group was not available in the records." Under no circumstances should a small retrospective study be the basis for practice, and we suggested no such thing in our report. In contrast, the conclusion of our article was that "this study should be viewed as generating a hypothesis and an estimated effect size for future large randomized controlled trials, which are being planned and which will require several years for execution and analysis." A prospective trial is now in progress (ClinicalTrials.gov No. NCT00418457). Heme as a Playmaker in the Regulation of the Nitric Oxide System To the Editor:-We read with great interest the article by Tsai et al. The authors showed that lipopolysaccharide treatment resulted in a significant increase in type 2 cationic amino acid transporter expression and this effect was reversed by concomitant treatment with hemin ( 2,3 These observations may be consistent with previous work performed by the same authors 4 showing that propofol treatment resulted in a concomitant reduction of both the inducible isoform of nitric oxide synthase and type 2 cationic amino acid transporter expression. In this regard, we also showed that propofol may act as an inducer of HO-1 via activation of the nuclear factor-B pathway. 5 Another point that we believe needs to be raised is in regard to the authors' choice of adding hemin immediately after lipopolysaccharide stimulation, thus not permitting a strong preinduction of HO-1 activity, which would have allowed increased carbon monoxide levels and a reduction of the intracellular heme pool. Interestingly, the authors also showed that tin protoporphyrin, a strong inhibitor of HO activity, results in a significant increase of HO-1 protein (even though in the Results section it was indicated that tin protoporphyrin did not increase protein expression) and partial reversion of hemin effects. The molecular mechanism underlying this effect is still unclear, and several hypotheses may be carried out. One is that HO activity inhibition after tin protoporphyrin treatment results in increased intracellular heme level after strong HO activity inhibition, thus leading to increased HO-