Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling.

BACKGROUND: Postpartum depression (PPD) affects approximately 13% of women and has a negative impact on mother and infant, hence reliable biological tests for early detection of PPD are essential. We aimed to identify robust predictive biomarkers for PPD using peripheral blood gene expression profiles in a hypothesis-free genome-wide study in a high-risk, longitudinal cohort. METHOD: We performed a genome-wide association study in a longitudinal discovery cohort comprising 62 women with psychopathology. Gene expression and hormones were measured in the first and third pregnancy trimesters and early postpartum (201 samples). The replication cohort comprised 24 women with third pregnancy trimester gene expression measures. Gene expression was measured on Illumina-Human HT12 v4 microarrays. Plasma estradiol and estriol were measured. Statistical analysis was performed in R. RESULTS: We identified 116 transcripts differentially expressed between the PPD and euthymic women during the third trimester that allowed prediction of PPD with an accuracy of 88% in both discovery and replication cohorts. Within these transcripts, significant enrichment of transcripts implicated that estrogen signaling was observed and such enrichment was also evident when analysing published gene expression data predicting PPD from a non-risk cohort. While plasma estrogen levels were not different across groups, women with PPD displayed an increased sensitivity to estrogen signaling, confirming the previously proposed hypothesis of increased sex-steroid sensitivity as a susceptibility factor for PPD. CONCLUSIONS: These results suggest that PPD can be robustly predicted in currently euthymic women as early as the third trimester and these findings have implications for predictive testing of high-risk women and prevention and treatment for PPD.

Fallout radionuclide-based techniques for assessing the impact of soil conservation measures on erosion control and soil quality: an overview of the main lessons learnt under an FAO/IAEA Coordinated Research Project.

This paper summarizes key findings and identifies the main lessons learnt from a 5-year (2002-2008) coordinated research project (CRP) on "Assessing the effectiveness of soil conservation measures for sustainable watershed management and crop production using fallout radionuclides" (D1.50.08), organized and funded by the International Atomic Energy Agency through the Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture. The project brought together nineteen participants, from Australia, Austria, Brazil, Canada, Chile, China, Japan, Morocco, Pakistan, Poland, Romania, Russian Federation, Turkey, United Kingdom, United States of America and Vietnam, involved in the use of nuclear techniques and, more particularly, fallout radionuclides (FRN) to assess the relative impacts of different soil conservation measures on soil erosion and land productivity. The overall objective of the CRP was to develop improved land use and management strategies for sustainable watershed management through effective soil erosion control practices, by the use of ¹³7Cs (half-life of 30.2 years), ²¹°Pb(ex) (half-life of 22.3 years) and 7Be (half-life of 53.4 days) for measuring soil erosion over several spatial and temporal scales. The environmental conditions under which the different research teams applied the tools based on the use of fallout radionuclides varied considerably--a variety of climates, soils, topographies and land uses. Nevertheless, the achievements of the CRP, as reflected in this overview paper, demonstrate that fallout radionuclide-based techniques are powerful tools to assess soil erosion/deposition at several spatial and temporal scales in a wide range of environments, and offer potential to monitor soil quality. The success of the CRP has stimulated an interest in many IAEA Member States in the use of these methodologies to identify factors and practices that can enhance sustainable agriculture and minimize land degradation.

Sediment fingerprinting to determine the source of suspended sediment in a southern Piedmont stream.

Thousands of stream miles in the southern Piedmont region are impaired because of high levels of suspended sediment. It is unclear if the source is upland erosion from agricultural sources or bank erosion of historic sediment deposited in the flood plains between 1830 and 1930 when cotton farming was extensive. The objective of this study was to determine the source of high stream suspended sediment concentrations in a typical southern Piedmont watershed using sediment fingerprinting techniques. Twenty-one potential tracers were tested for their ability to discriminate between sources, conservative behavior, and lack of redundancy. Tracer concentrations were determined in potential sediment sources (forests, pastures, row crop fields, stream banks, and unpaved roads and construction sites), and suspended sediment samples collected from the stream and analyzed using mixing models. Results indicated that 137Cs and 15N were the best tracers to discriminate potential sediment sources in this watershed. The delta15N values showed distinct signatures in all the potential suspended sediment sources, and delta15N was a unique tracer to differentiate stream bank soil from upland subsurface soils, such as soil from construction sites, unpaved roads, ditches, and field gullies. Mixing models showed that about 60% of the stream suspended sediment originated from eroding stream banks, 23 to 30% from upland subsoil sources (e.g., construction sites and unpaved roads), and about 10 to 15% from pastures. The results may be applicable to other watersheds in the Piedmont depending on the extent of urbanization occurring in these watersheds. Better understanding of the sources of fine sediment has practical implications on the type of sediment control measures to be adopted. Investment of resources in improving water quality should consider the factors causing stream bank erosion and erosion from unpaved roads and construction sites to water quality impairment.

Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency.

OBJECTIVE: To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity. METHODS: A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency. RESULTS: Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52). CONCLUSIONS: These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.

The impact of agricultural soil erosion on the global carbon cycle.

Agricultural soil erosion is thought to perturb the global carbon cycle, but estimates of its effect range from a source of 1 petagram per year(-1) to a sink of the same magnitude. By using caesium-137 and carbon inventory measurements from a large-scale survey, we found consistent evidence for an erosion-induced sink of atmospheric carbon equivalent to approximately 26% of the carbon transported by erosion. Based on this relationship, we estimated a global carbon sink of 0.12 (range 0.06 to 0.27) petagrams of carbon per year(-1) resulting from erosion in the world's agricultural landscapes. Our analysis directly challenges the view that agricultural erosion represents an important source or sink for atmospheric CO2.

Impact of soil movement on carbon sequestration in agricultural ecosystems.

Recent modeling studies indicate that soil erosion and terrestrial sedimentation may establish ecosystem disequilibria that promote carbon (C) sequestration within the biosphere. Movement of upland eroded soil into wetland systems with high net primary productivity may represent the greatest increase in storage capacity potential for C sequestration. The capacity of wetland systems to capture sediments and build up areas of deposition has been documented as well as the ability of these ecosystems to store substantial amounts of C. The purpose of our work was to assess rates of sediment deposition and C storage in a wetland site adjacent to a small first-order stream that drains an agricultural area. The soils of the wetland site consist of a histosol buried by sediments from the agricultural area. Samples of deposited sediments in the riparian zone were collected in 5 cm increments and the concentration of 137Cs was used to determine the 1964 and 1954 deposition layers. Agricultural activity in the watershed has caused increased sediment deposition to the wetland. The recent upland sediment is highly enriched in organic matter indicating that large amounts of organic C have been sequestered within this zone of sediment deposition. Rates of sequestration are much higher than rates that have occurred over the pre-modern history of the wetland. These data indicate the increased sedimentation rates in the wetland ecosystem are associated with increased C sequestration rates.

Platelet monoamine oxidase, smoking cessation, and tobacco withdrawal symptoms.

Previous studies have found that constituents in tobacco inhibit both forms of the enzyme monoamine oxidase (MAO-A and MAO-B). This enzyme is important in the breakdown of the amine neurotransmitters, including dopamine, which is thought to mediate the reinforcing effects of nicotine and contribute to tobacco dependence. To further examine the relationship between cigarette smoking, smoking cessation and MAO, we measured platelet MAO-B activity in 16 smokers before and after being switched to smoking denicotinized cigarettes; in a subset of six subjects who subsequently quit-smoking, MAO-B activity was also measured at 1 and 4 weeks following cessation. Smoking cessation treatment was provided in an open-label format, and included nicotine skin patch treatment in conjunction with oral mecamylamine (a nicotinic antagonist) and neostigmine (a peripherally acting acetylcholinesterase inhibitor, administered to counteract constipation experienced from mecamylamine). Results showed that smoking behavior, indexed by expired air carbon monoxide levels, was negatively correlated with platelet MAO-B activity prior to smoking cessation. Moreover, MAO-B activity significantly increased by approximately 100% at 4 weeks after quitting smoking. However, little or no recovery occurred within the first week of abstinence, suggesting that the constituents in tobacco responsible for MAO inhibition may have half-lives of several days. Thus, if relapse to smoking is due in part to withdrawal from the MAO-inhibiting effects of tobacco, this effect likely occurs more than 1 week after quitting. Additionally, low baseline MAO-B activity significantly predicted the intensity of withdrawal symptoms reported upon switching to the denicotinized cigarettes as well as after smoking cessation. These results support the view that MAO inhibition from non-nicotine constituents in cigarette smoke is relevant to tobacco dependence and that continued investigation of the potential use of MAO inhibitors in smoking cessation treatment is warranted.

Regional differences in brain monoamine oxidase subtypes in an animal model of geriatric depression: effects of olfactory bulbectomy in young versus aged rats.

Geriatric depression is often associated dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, and with poor responsiveness to antidepressants that work through inhibition of monoamine reuptake; accordingly, it has been suggested that MAO inhibitors may represent a therapeutic alternative in this group. In the current study, we evaluated expression of MAO subtypes in brain regions of young and aged rats subjected to olfactory bulbectomy (OBX), a procedure that reproduces many of the biochemical and functional changes associated with human depression. Activities of both MAO A and B were elevated in aged rats as compared to young rats in most regions, but not in the midbrain, and the OBX lesion failed to produce any change in this pattern. These results stand in contrast to the differential effects of glucocorticoids, which reduce brain MAO in young animals but induce activity in aged rats. Our results support the view that the aged brain possesses biochemical characteristics that distinguish its monoamine biochemistry from that of young brain, and that these distinctions may work in conjunction with HPA axis dysregulation to influence the etiology and therapy of geriatric depression. The use of appropriate animal models for depression and for disruption of HPA axis function can allow for the testing of potential human biomarkers (such as platelet MAO) that may serve to predict treatment outcome.

Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women.

BACKGROUND: Pregnancy and the postpartum period are a time of increased risk for women to develop mood disorders. As such, the reproductive safety data on antidepressant use during pregnancy have rapidly expanded over the last decade; however, there is relatively sparse information on maternal/fetal exchange of these medications and no data reporting their concentrations in amniotic fluid. METHODS: We report on three women treated during pregnancy with fluvoxamine, sertraline, and venlafaxine, respectively. Amniotic fluid at amniocentesis and umbilical cord blood and maternal blood at delivery were collected and analyzed for antidepressant concentrations using high performance liquid chromatography with UV detection. RESULTS: Antidepressant and metabolite concentrations were detectable in all amniotic fluid samples, though parent compound concentrations were less than maternal serum and umbilical cord blood concentrations. No adverse effects of the medication were reported. CONCLUSIONS: The presence of these antidepressants in amniotic fluid suggests that fetal exposure to these medications is continual and may occur through a variety of paths, thus accounting for increased fetal exposure. These paths include circulatory via placental passage, gastrointestinal via fetal swallowing, and respiratory secondary to fetal lung absorption.

Dexamethasone metabolism in dexamethasone suppression test suppressors and nonsuppressors.

BACKGROUND: Variable dexamethasone kinetics is a possible confound in the dexamethasone suppression test. Modifications to include dexamethasone plasma levels and specific dexamethasone "windows" have been proposed. Our study aims to validate our proposed dexamethasone windows in an independent sample of 121 subjects. METHODS: We performed dexamethasone suppression tests in 162 subjects with mixed psychiatric diagnoses. Dexamethasone levels and beta-phase half-life of dexamethasone were computed for suppressors and nonsuppressors. RESULTS: Dexamethasone levels were lower in nonsuppressors than in suppressors. Dexamethasone levels correlated inversely with cortisol levels in the total sample, but were nonsignificant or weakly associated in those samples restricted to the windows. The beta-phase half-life of dexamethasone was shorter in nonsuppressors. The dexamethasone windows were validated at 3:00 PM and 10:00 PM. We propose 4.0 ng/mL as a revised upper limit of the 8:00 AM dexamethasone window. CONCLUSIONS: The plasma dexamethasone level is confirmed as a confound in the dexamethasone suppression test through more rapid dexamethasone clearance in nonsuppressors. Application of dexamethasone windows will reduce this source of test variance.

Paroxetine in human breast milk and nursing infants.

OBJECTIVE: The purpose of this study was to determine the extent of infant medication exposure through breast-feeding during maternal treatment with paroxetine. METHOD: Breast milk and paired maternal and infant sera were collected after 10 days of maternal treatment with paroxetine at a stable daily dose (10-50 mg/day). All samples were analyzed by means of high-performance liquid chromatography with ultraviolet detection and a limit of detection of 2 ng/ml. RESULTS: Breast milk paroxetine concentrations were highly variable (2-101 ng/ml) and were present in all breast milk samples (N=108). A significant gradient effect was observed, with greater paroxetine concentrations found in later portions of breast milk (hind milk) than in early portions (fore milk). No clear time course of paroxetine excretion into breast milk was demonstrated, although maternal paroxetine daily dose reliably predicted both trough and peak breast milk concentrations over a 24-hour period. In 16 mother and infant serum pairs, no detectable concentrations of paroxetine were found in the serum of the nursing infants. CONCLUSIONS: This study extends previous data by demonstrating the presence of paroxetine in the breast milk of nursing women treated with this medication. The low concentrations of paroxetine in infant serum and lack of any observable adverse effects after maternal use of this medication while breast-feeding parallels the available data on other selective serotonin reuptake inhibitors.

Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration.

BACKGROUND: The purpose of this study was to assess sequential changes in serum parathyroid hormone (PTH) levels during conventional parathyroidectomy. METHODS: Sera were collected before and 10 minutes after resection of each parathyroid tumor from 112 consecutive patients and assayed postoperatively within 48 hours for PTH. RESULTS: PTH reductions corroborated cures for 94 of 112 cases (84%), including 70 of 71 patients with solitary adenomas (SAs). However, there were 15 false positives (13%), in which PTH decreased more than 50% within 10 minutes of resection of 1 parathyroid tumor while additional parathyroid tumors remained in situ (1 of 71 SAs, 4 of 6 double adenomas, 7 of 15 primary hyperplasias, and 3 of 17 tertiary hyperplasias). There were 3 false negatives (3%), with PTH unchanged, even though postoperative PTH and calcium values confirmed cure (1 SA, 1 primary hyperplasia, and 1 tertiary hyperplasia). There were only 2 of 112 failed explorations (1.8%), which would not have been avoided by PTH monitoring because both subsequently were found to have mediastinal parathyroid adenomas. CONCLUSIONS: We conclude that intraoperative PTH changes corroborated outcome in SA but may under-estimate the extent of resection required in parathyroid hyperplasia.

Atypical antipsychotic drugs selectively increase neurotensin efflux in dopamine terminal regions.

Typical antipsychotic drugs, such as haloperidol and chlorpromazine, increase synthesis of the neuropeptide neurotensin (NT) in both the striatum and the nucleus accumbens, whereas atypical antipsychotic drugs, such as clozapine and olanzapine, do so only in the nucleus accumbens. By using in vivo microdialysis, we now report that acute administration of haloperidol, clozapine, or olanzapine failed to alter the release of NT in either the striatum or nucleus accumbens. In contrast, chronic administration of haloperidol for 21 days increased NT release in both the striatum and nucleus accumbens, whereas treatment for 21 days with the atypical antipsychotic drugs, clozapine or olanzapine, increased NT release selectively in the nucleus accumbens. These findings suggest that (i) increased NT mRNA expression and NT tissue concentrations are associated with increases in the extracellular fluid concentrations of the peptide and (ii) atypical antipsychotic drugs may exert their therapeutic effects and produce fewer side effects by virtue of their selectivity in limbic compared with striatal, target neurons.

Plasma dexamethasone concentration and cortisol response during manic episodes.

BACKGROUND: Despite the widespread study of the dexamethasone suppression test (DST) in patients diagnosed with major depression, it has been less well studied during manic and mixed states of bipolar disorder. METHODS: Cortisol response to the administration of 1 mg of dexamethasone was studied in 44 patients diagnosed bipolar disorder, manic (n = 37) or mixed (n = 7). Dexamethasone levels and cortisol responses were compared between these groups. Four patients initially meeting criteria for bipolar disorder, mixed, and 7 patients initially meeting criteria for bipolar disorder, manic, all of whom were characterized as DST nonsuppressors, were retested after remission. RESULTS: Dexamethasone levels were lower and cortisol levels higher in those patients diagnosed bipolar disorder, mixed. An inverse correlation was found between log-transformed dexamethasone levels and log-transformed cortisol levels at 3 PM (r = -.619, p < or = .001) and 10 PM (r = -.501, p < or = .001). In those subjects retested after remission, dexamethasone levels were higher and cortisol levels lower than during the manic and mixed states. CONCLUSIONS: Disturbances in the hypothalamic-pituitary-adrenal axis are observed frequently during mixed states of bipolar disorder, but are also not uncommon in purely manic episodes. These changes appear to be state dependent and revert with treatment.

Effects of aging and glucocorticoid treatment on monoamine oxidase subtypes in rat cerebral cortex: therapeutic implications.

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is more common in elderly depression than in younger cohorts, resulting in elevated glucocorticoid levels. Effectiveness of antidepressant drugs is also impaired in these patients. We evaluated the effects of continuous infusions of dexamethasone on monoamine oxidase (MAO) subtypes in aged rat brain to determine whether unique interactions of glucocorticoids and aging could contribute to abnormal transmitter disposition. Aged rats given dexamethasone showed robust induction of both MAO A (threefold increase) and B (30% increase) in the frontal/parietal cortex, effects in the opposite direction from those seen in young rats treated with glucocorticoids. Our results support the view that depression in the elderly may have biologically discrete components that make it differ from depression in younger people. These distinctions may influence the etiology and therapy of depression, while at the same time providing potential biomarkers (such as platelet MAO) that may serve to predict successful treatment outcome in patient subpopulations.

Serotonin transporter expression in rat brain regions and blood platelets: aging and glucocorticoid effects.

Hyperactivity of the hypothalamus-pituitary-adrenal axis is more common in elderly depression than in younger cohorts and glucocorticoids are known to influence serotonergic systems. The current study explores the interaction of glucocorticoids with aging on serotonin transporter expression and function. Continuous infusions of dexamethasone (26 days) reduced transporter expression in the aged brain but the ability of imipramine to inhibit synaptosomal [3H]serotonin uptake was unimpaired. These effects were unique to aged animals, as prior work with young adults found no effects of dexamethasone on transporter expression. In contrast to the effects in the brain, there were no differences in platelet transporter expression between young and old rats nor did dexamethasone treatment affect the values in the aged group: thus, the platelet may not reliably model these aspects of CNS function. The results suggest that there are basic biologic differences in the effects of glucocorticoids in aged vs. young brain that could contribute to lowered effectiveness to antidepressants in elderly depression; if transport capacity is already reduced by the effects of increased glucocorticoids, further inhibition of transport by antidepressants would have proportionally less impact on synaptic serotonin concentrations.

Do glucocorticoids contribute to the abnormalities in serotonin transporter expression and function seen in depression? An animal model.

Adrenocorticosteroids and serotonergic neurons exert reciprocal regulatory actions, and both are abnormal in depression. We evaluated whether glucocorticoids influence the serotonin transporter in rat platelets and brain by infusing dexamethasone for 26 days, sufficient for replacement of the entire platelet population. Effectiveness was verified by measurement of plasma dexamethasone levels, adrenal atrophy, and growth inhibition. At the end of the infusion, we examined [3H]paroxetine binding to platelet, hippocampal, and cerebrocortical membranes, and [3H]serotonin uptake into platelets and synaptosomes. Dexamethasone slightly reduced platelet [3H]paroxetine binding (12%) and had no effect on binding in brain. Platelet [3H]serotonin uptake was unaffected, but synaptosomal uptake was significantly reduced. In neither platelets nor synaptosomes did dexamethasone alter imipramine's ability to inhibit uptake. Thus, elevated glucocorticoids are not responsible for reduced platelet serotonin transporter expression in depression, nor for resistance to imipramine's effect in platelets in elderly depression; however, reduced synaptosomal [3H]serotonin uptake indicates that glucocorticoids can affect transport efficiency, even when the number of transporter molecules is unaltered.

Use of site-specified tritium labelling to confirm the formation of 17-oxosparteine as a minor urinary metabolite of sparteine in man.

1. The synthesis of [17,17-3H2]-sparteine and its oral administration has enabled the specific identification of 17-oxosparteine as a minor urinary metabolite (approximately 1% dose) in two healthy male volunteers.

Serum prolactin, electrode placement, and the convulsive threshold during ECT.

This study examines the relationship of serum prolactin changes (delta PRL) to variations in electrode placement after controlling for differences in the convulsive threshold. Previous studies showing greater release of PRL with bilateral (BL) compared with right unilateral (RUL) electrode placement were conducted without knowledge of the convulsive threshold. Twenty-two patients each received threshold RUL, threshold BL, 2.25 times threshold RUL, and 2.25 times threshold BL ECT. Serum PRL was collected 5 min before and 15 min after each electroconvulsive therapy (ECT). The convulsive threshold was greater for BL than RUL electrode placement. delta PRL was greater with BL than RUL ECT at comparable relative stimulus intensities. delta PRL was not correlated with seizure duration or absolute stimulus dose.