ABSTRACT
Background: Previous research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers. Objective: It is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans. Methods: Serotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts. Results: Pharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics. Conclusions: Serotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.
ABSTRACT
OBJECTIVE: To evaluate the utility of the substituted judgement standard in terminally ill patients by determining agreement between patients, family proxies and physicians. BACKGROUND: Several studies have addressed the utility of substituted judgement, showing conflicting data whether surrogates are accurate predicting patient's wishes. METHODS: Patients with acquired immunodeficiency syndrome, congestive heart failure, chronic liver disease admitted to the San Juan Veterans Affairs Medical Center in Puerto Rico from November 1997 to February 1998 were evaluated. A questionnaire presented three hypothetical situations on withholding and withdrawal of life-support and CPR. The percent agreement was used as a measure of concordance between choices made by physician, surrogate and patients. RESULTS: Twenty patients met inclusion criteria (5 chronic liver disease, 9 heart failure, 6 AIDS). Relatives had a higher percent of agreement as compared to physicians in all vignettes. Even though, none did better than chance in predicting patient's wishes (k < 0.4). There was a tendency for relatives not to provide a wanted life-support measure, and for physicians to provide an unwanted life-support measure. CONCLUSION: The poor agreement between patients and surrogates suggests that substituted judgement is not an accurate tool to make end-of-life decisions. These findings, although similar to previous published studies, are unique because the direction of discrepant responses is opposite to the findings of studies published elsewhere. These results could reflect religious, cultural and socioeconomic differences.