The tryptophan (TRP) depletion paradigm has been employed to investigate mood and behavioral effects of acutely lowering plasma TRP, and presumably brain serotonin (5-hydroxytryptamine [5-HT]) levels through administration of a special diet and/or amino acid drink. Our goal was to test the assumption that a corresponding fall in central levels of TRP and 5-HT (measured by its major metabolite, 5-hydroxyindoleacetic acid [5-HIAA]) occurs during the standard execution of this method in healthy adult subjects. Three males and two females completed the protocol, which included a one-day low-TRP diet and a TRP-free amino acid drink. Lumbar puncture was performed, with placement of an indwelling catheter connected to a peristaltic pump and fraction collector.Cerebrospinal fluid (CSF) was sampled continuously for a 13.5-hour period (before, during, and The role of serotonin (5-hydroxytryptamine, 5-HT) in the pathogenesis and treatment of major neuropsychiatric disorders, especially depression, continues to be the subject of intensive research (Maes and Meltzer 1995). One paradigm for studying the role of 5-HT involves acutely manipulating levels of its amino acid precursor, tryptophan (TRP), and measuring corresponding behavioral effects. Because the synthesis of 5-HT is dependent on the availability of TRP, rapidly-induced shifts in the central level of TRP should produce transient alterations in the amount of 5-HT available for neurotransmission (Schaechter and Wurtman 1990;Young 1991). Observed or reported changes in behavior or psychiatric symptoms occurring during acute TRP manipulation have provided clues about the mechanism of action of serotonergic drugs, and the biology of several psychiatric disorders.Beginning in the 1970s, researchers have developed several strategies for altering TRP levels, in efforts to explore the relationship between the precursor amino acid, serotonergic function, and behavior. Preclinical studies demonstrated that dietary restriction of TRP could evoke modest reductions in plasma and brain TRP (Fernstrom 1977), with corresponding behavioral indices reflecting diminished 5-HT function (Lytle et al. 1975;Messing et al. 1976;Gibbons et al. 1979; Moja et al. Walters et al. 1979). Dietary TRP restriction in both animals and humans has subsequently been associated with enhanced response to neuroendocrine challenges in a manner consistent with compensatory postsynaptic supersensitivity (Clemens et al. 1980;Delgado et al. 1989), again suggesting that the depletion is diminishing 5-HT function at a central nervous system (CNS) level. More rapid decreases in plasma and brain TRP levels can be achieved by the administration of a TRP-free amino acid mixture Young et al. 1995;Moja et al. 1988). Here the mechanism involves providing substrate for induction of protein synthesis to such a degree that available peripheral TRP stores are largely used up, resulting in a drop in the ratio of TRP to other large neutral amino acids in plasma (Harper et al. 1970). Because TRP competes with the other lar...

Objective To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women. Design A nested case–control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by pre-eclampsia and 468 normotensive nonproteinuric controls. Setting A multicentre study in 16 academic medical centres in the USA. Population Low-risk nulliparous women. Methods Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9–12, 15–18 and 23–26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics. Main outcome measures Change in PlGF, sFlt-1 and sEng. Results Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not pre-eclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64–99%), 77% (95% CI 50–93%) and 77% (95%CI 50–93%) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester. Conclusion Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia.