Theoretical Study of Barrierless Chemical Reactions Involving Nearly Elastic Rebound: The Case of S(1D) + X2, X = H, D.

For some values of the total angular momentum consistent with reaction, the title processes involve nonreactive trajectories proceeding through a single rebound mechanism during which the internal motion of the reagent diatom is nearly unperturbed. When such paths are in a significant amount, the classical reaction probability is found to be markedly lower than the quantum mechanical one. This finding was recently attributed to an unusual quantum effect called diffraction-mediated trapping, and a semiclassical correction was proposed in order to take into account this effect in the classical trajectory method. In the present work, we apply the resulting approach to the calculation of opacity functions as well as total and state-resolved integral cross sections (ICSs) and compare the values obtained with exact quantum ones, most of which are new. As the title reactions proceed through a deep insertion well, mean potential statistical calculations are also presented. Seven values of the collision energy, ranging from 30 to 1127 K, are considered. Two remarkable facts stand out: (i) The corrected classical treatment strongly improves the accuracy of the opacity function as compared to the usual classical treatment. When the entrance transition state is tight, however, those trajectories crossing it with a bending vibrational energy below the zero point energy must be discarded. (ii) The quantum opacity function, particularly its cutoff, is finely reproduced by the statistical approach. Consequently, the total ICS is also very well described by the two previous approximate methods. These, however, do not predict state-resolved ICSs with the same accuracy, proving thereby that (i) one or several genuine quantum effects involved in the dynamics are missed by the corrected classical treatment and (ii) the dynamics are not fully statistical.

Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis.

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

Experimental and theoretical study of the collisional quenching of S(1D) by Ar.

We present an experimental and theoretical investigation of the deactivation rate of S(1D) atoms by collisions with argon. Kinetic measurements were performed at temperatures from 5.8 K to 298 K in cold uniform supersonic flows using a CRESU (Cinétique de Réaction en Ecoulement Supersonique Uniforme or Reaction Kinetics in a Uniform Supersonic Flow) apparatus. In order to simulate them, ab initio electronic structure calculations using internally contracted MRCI methodology were performed to describe the interaction. Starting from them, close-coupling calculations were carried out to determine collisional quenching probabilities for the transition S(1D) → S(3P) in the energy range 1-3000 K (1 K ≈ 0.7 cm-1), sufficient to calculate thermal rate coefficients up to 300 K. Stückelberg-like oscillations in the quenching probabilities as a function of the energy are found and interpreted using a semiclassical model. Differences between the temperature dependence of the experimental and theoretical rate coefficients are detected at low temperatures. They are discussed in the light of a study of the high sensitivity of the theoretical results to the potential curves, due to the interference mechanisms which underlie the process.

Decreased tryptophan and increased kynurenine levels in mastocytosis associated with digestive symptoms.

The main metabolism pathway of tryptophan is protein formation, but it can also be metabolized into serotonin and kynurenine. Indoleamine 2,3-dioxygenase (IDO) is the enzyme that catalyzes the degradation of tryptophan into kynurenine. Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in various tissues with 57% of patients having gastrointestinal involvement. We studied tryptophan metabolism in mastocytosis patients displaying or not gastrointestinal features and healthy subjects (n = 26 in each group). Mastocytosis patients with digestive symptoms displayed significantly increased kynurenine level and IDO activity as compared to healthy controls and mastocytosis patients without digestive symptoms. This could be linked to mast cell-mediated digestive inflammation among patients with mastocytosis. This work is the first focusing on kynurenine pathway in a mast cell disease and could help to understand the pathogenesis of digestive features in mastocytosis as well as in other mast cell-mediated diseases.

Cold and ultracold dynamics of the barrierless D(+) + H2 reaction: Quantum reactive calculations for ∼R(-4) long range interaction potentials.

Quantum reactive and elastic cross sections and rate coefficients have been calculated for D(+) + H2 (v = 0, j = 0) collisions in the energy range from 10(-8) K (deep ultracold regime), where only one partial wave is open, to 150 K (Langevin regime) where many of them contribute. In systems involving ions, the ∼R(-4) behavior extends the interaction up to extremely long distances, requiring a special treatment. To this purpose, we have used a modified version of the hyperspherical quantum reactive scattering method, which allows the propagations up to distances of 10(5) a0 needed to converge the elastic cross sections. Interpolation procedures are also proposed which may reduce the cost of exact dynamical calculations at such low energies. Calculations have been carried out on the PES by Velilla et al. [J. Chem. Phys. 129, 084307 (2008)] which accurately reproduces the long range interactions. Results on its prequel, the PES by Aguado et al. [J. Chem. Phys. 112, 1240 (2000)], are also shown in order to emphasize the significance of the inclusion of the long range interactions. The calculated reaction rate coefficient changes less than one order of magnitude in a collision energy range of ten orders of magnitude, and it is found in very good agreement with the available experimental data in the region where they exist (10-100 K). State-to-state reaction probabilities are also provided which show that for each partial wave, the distribution of HD final states remains essentially constant below 1 K.

Rate coefficients from quantum and quasi-classical cumulative reaction probabilities for the S(1D) + H2 reaction.

Cumulative reaction probabilities (CRPs) at various total angular momenta have been calculated for the barrierless reaction S((1)D) + H(2) → SH + H at total energies up to 1.2 eV using three different theoretical approaches: time-independent quantum mechanics (QM), quasiclassical trajectories (QCT), and statistical quasiclassical trajectories (SQCT). The calculations have been carried out on the widely used potential energy surface (PES) by Ho et al. [J. Chem. Phys. 116, 4124 (2002)] as well as on the recent PES developed by Song et al. [J. Phys. Chem. A 113, 9213 (2009)]. The results show that the differences between these two PES are relatively minor and mostly related to the different topologies of the well. In addition, the agreement between the three theoretical methodologies is good, even for the highest total angular momenta and energies. In particular, the good accordance between the CRPs obtained with dynamical methods (QM and QCT) and the statistical model (SQCT) indicates that the reaction can be considered statistical in the whole range of energies in contrast with the findings for other prototypical barrierless reactions. In addition, total CRPs and rate coefficients in the range of 20-1000 K have been calculated using the QCT and SQCT methods and have been found somewhat smaller than the experimental total removal rates of S((1)D).

Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension.

Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.

Reaching the cold regime: S((1)D) + H2 and the role of long-range interactions in open shell reactive collisions.

Reactive cross-sections for the collision of open shell S((1)D) atoms with ortho- and para-hydrogen, in the kinetic energy range 1-120 K, have been calculated using the hyperspherical quantum reactive scattering method developed by Launay et al. [Chem. Phys. Lett., 1990, 169, 473]. Short-range interactions, described using the ab initio potential energy surface by Ho et al. [J. Chem. Phys., 2002, 116, 4124], were complemented with an accurate description of the long-range interactions, where the main electrostatic (∼R(-5)) and dispersion (∼R(-6)) contributions were considered. This allows the comparison with recent experimental measurements of rate constants and excitation functions for the title reaction at low temperatures [Berteloite et al., Phys. Rev. Lett., 2010, 105, 203201]. The agreement is fairly good. The behavior in the considered energy range can be understood on average in terms of a classical Langevin (capture) model, where the centrifugal barriers determine the amount of reactive flux which reaches the barrierless transition state. Additionally, the structure of the van der Waals well provides temporal trapping at intermediate intermolecular distances thus allowing the system to find its way to the reaction at some classically-forbidden energies. Interestingly, the cross-section for para-hydrogen shows clearly oscillating features associated with the opening of new partial waves and with shape resonances which may be amenable to experimental detection.

On the role of dynamical barriers in barrierless reactions at low energies: S(1D) + H2.

Reaction probabilities as a function of total angular momentum (opacity functions) and the resulting reaction cross sections for the collision of open shell S((1)D) atoms with para-hydrogen have been calculated in the kinetic energy range 0.09-10 meV (1-120 K). The quantum mechanical hyperspherical reactive scattering method and quasi-classical trajectory and statistical quasi-classical trajectory approaches were used. Two different ab initio potential energy surfaces (PESs) have been considered. The widely used reproducing kernel Hilbert space (RKHS) PES by Ho et al. [T.-S. Ho, T. Hollebeek, H. Rabitz, S. D. Chao, R. T. Skodje, A. S. Zyubin, and A. M. Mebel, J. Chem. Phys 116, 4124 (2002)] and the recently published accurate double many-body expansion (DMBE)/complete basis set (CBS) PES by Song and Varandas [Y. Z. Song and A. J. C. Varandas, J. Chem. Phys. 130, 134317 (2009)]. The calculations at low collision energies reveal very different dynamical behaviors on the two PESs. The reactivity on the RKHS PES is found to be considerably larger than that on the DMBE/CBS PES as a result of larger reaction probabilities at low total (here also orbital) angular momentum values and to opacity functions which extend to significantly larger total angular momentum values. The observed differences have their origin in two major distinct topographic features. Although both PESs are essentially barrierless for equilibrium H-H distances, when the H-H bond is compressed the DMBE/CBS PES gives rise to a dynamical barrier which limits the reactivity of the system. This barrier is completely absent in the RHKS PES. In addition, the latter PES exhibits a van der Walls well in the entrance channel which reduces the height of the centrifugal barrier and is able to support resonances. As a result, a significant larger cross section is found on this PES, with marked oscillations attributable to shape resonances and/or to the opening of partial wave contributions. The comparison of the results on both PESs is illustrative of the wealth of the dynamics at low collision energy. It is also illuminating about the difficulties encountered in modeling an all-purpose global potential energy surface.

Systemic mastocytosis and bone involvement in a cohort of 75 patients.

OBJECTIVES: To investigate bone involvement in a large cohort of systemic mastocytosis (SM) patients, and evaluate the efficacy of bisphosphonate therapy. PATIENTS AND METHODS: From 2000 to 2004, 75 patients with SM according to WHO criteria underwent skeletal x-rays and bone mineral density (BMD) assessment. Sequential BMD assessments were performed in nine patients treated with bisphosphonate (mean follow-up 65 months). RESULTS: 37 patients (49%) had bone involvement according to both x-rays and BMD evaluations: osteoporosis (23 patients, 31%, mean lumbar spine T score: -3 SD), with vertebral fracture (13 patients, 17%), axial skeleton osteosclerosis (six patients, 8%), mixed patterns (three patients), osteopenia with pre-existing fractures (four patients) and focal osteolytic lesion (one patient). Blood count abnormalities were associated with osteosclerosis (p=0.005). In nine patients with osteoporosis and bisphosphonate therapy, mean lumbar spine BMD increased from 0.83 to 0.92 g/cm(2) (+11.1%; ie, +2.05% per year) without recurrence of vertebral fracture. CONCLUSION: Half of adult patients with SM have bone involvement. Osteoporosis is the most prevalent bone manifestation in SM (31%). Bisphosphonate therapy seems efficient to improve lumbar spine BMD during SM-related osteoporosis. Spine x-ray and BMD should be performed in all SM patients to detect those who may benefit from anti-osteoporotic therapy.

The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation.

The monoamine serotonin (5-HT), a well-known neurotransmitter, is also important in peripheral tissues. Several studies have suggested that 5-HT is involved in bone metabolism. Starting from our original observation of increased 5-HT(2B) receptor (5-HT(2B)R) expression during in vitro osteoblast differentiation, we investigated a putative bone phenotype in vivo in 5-HT(2B)R knockout mice. Of interest, 5-HT(2B)R mutant female mice displayed reduced bone density that was significant from age 4 months and had intensified by 12 and 18 months. This histomorphometrically confirmed osteopenia seems to be due to reduced bone formation because 1) the alkaline phosphatase-positive colony-forming unit capacity of bone marrow precursors was markedly reduced in the 5-HT(2B)R mutant mice from 4 to 12 months of age, 2) ex vivo primary osteoblasts from mutant mice exhibited reduced proliferation and delayed differentiation, and 3) calcium incorporation was markedly reduced in osteoblasts after 5-HT(2B)R depletion (produced genetically or by pharmacological inactivation). These findings support the hypothesis that the 5-HT(2B)R receptor facilitates osteoblast recruitment and proliferation and that its absence leads to osteopenia that worsens with age. We show here, for the first time, that the 5-HT(2B)R receptor is a physiological mediator of 5-HT in bone formation and, potentially, in the onset of osteoporosis in aging women.

Signal transduction through prion protein.

The cellular prion protein PrPc is a glycosylphosphatidylinositol-anchored cell-surface protein whose biological function is unclear. We used the murine 1C11 neuronal differentiation model to search for PrPc-dependent signal transduction through antibody-mediated cross-linking. A caveolin-1-dependent coupling of PrPc to the tyrosine kinase Fyn was observed. Clathrin might also contribute to this coupling. The ability of the 1C11 cell line to trigger PrPc-dependent Fyn activation was restricted to its fully differentiated serotonergic or noradrenergic progenies. Moreover, the signaling activity of PrPc occurred mainly at neurites. Thus, PrPc may be a signal transduction protein.

Effects of the rotational excitation of D2 and of the potential energy surface on the H+ + D2 --> HD + D+ reaction.

The H(+) + D(2) --> HD + D(+) reaction has been theoretically investigated by means of an exact quantum mechanical approach, a quasiclassical trajectory method, and two statistical methods based in the propagation of either wave functions or trajectories. The study addresses the possible changes on the overall dynamics of the title reaction when the D(2) diatom is rotationally excited to its v = 0, j = 1 state. In addition, the reactivity for the ground rotational state on two different potential energy surfaces (PESs), namely, the surface by Aguado et al. [J. Chem. Phys. 112, 1240 (2000)] and the PES by Kamisaka et al. [J. Chem. Phys. 116, 654 (2002)], is examined. Reaction probabilities and cross sections at 0.524 and 0.1 eV collision energies are calculated. The major differences with respect to the reaction initiated with D(2) in its ground rovibrational state are observed for the lowest collision energy E(c) = 0.1 eV. Differential cross sections have been found to depend to some extend on the PES employed. In addition, at E(c) = 0.1 eV further discrepancies in the total and rotational cross sections are noticeable.

Computational approaches for the study of serotonin and its membrane transporter SERT: implications for drug design in neurological sciences.

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter of the central nervous and peripheral systems (CNS), plays a critical role in a wide variety of physiological and behavioral processes. In the serotonergic system, deregulation of the tightly controlled extracellular concentration of 5-HT appears to be at the origin of a host of metabolic and psychiatric disorders. A key step that regulates 5-HT external level is the re-uptake of 5-HT into cells by the 5-HT transporter (SERT), which is besides the target of numerous drugs interacting with the serotonergic system. Therapeutic strategies have mainly focused on the development of compounds that block the activity of SERT, for instance reuptake inhibitors (e.g. tricyclics, "selective" serotonin reuptake inhibitors) and in the past, specific substrate-type releasers (e.g. amphetamine and cocaine derivatives). Today, generation of new drugs targetting SERT with enhanced selectivity and reduced toxicity is one of the most challenging tasks in drug design. In this context, studies aiming at characterizing the physicochemical properties of 5-HT as well as the biological active conformation of SERT are a prerequisite to the design of new leads. However, the absence of a high-resolution 3D-structure for SERT has hampered the design of new transporter inhibitors. Using computational approaches, numerous efforts were made to shed light on the structure of 5-HT and its transporter. In this review, we compared several in silico methods dedicated to the modeling of 5-HT and SERT with an emphasis on i) quantum chemistry for study of 5-HT conformation and ii) ligand-based (QSAR and pharmacophore models) and transporter-based (homology models) approaches for studying SERT molecule. In addition, we discuss some methodological aspects of the computational work in connection with the construction of putative but reliable 3D structural models of SERT that may help to predict the mechanisms of neurotransmitter transport.

Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice.

Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung. In the present study, the role of serotonin in lung fibrosis was investigated using the bleomycin mouse model. Serotonin concentrations in lung homogenates increased significantly over the time course of bleomycin-induced fibrosis, with a maximum at day seven. The expression of serotonin receptors 5-HT2A and 5-HT2B increased in the lung after bleomycin treatment, as assessed by PCR, specific binding and immunohistochemistry. Blockage of 5-HT2A receptors by ketanserin and 5-HT2B receptors by SB215505 reduced bleomycin-induced lung fibrosis, as demonstrated by reduced lung collagen content and reduced procollagen 1 and procollagen 3 mRNA expression. Serotonin antagonists promoted an antifibrotic environment by decreasing the lung mRNA levels of transforming growth factor-beta1, connective growth factor and plasminogen activator inhibitor-1 mRNA, but had minimal effects on lung inflammation as assessed by bronchoalveolar lavage cytology analysis. Interestingly, the 5-HT2B receptor was strongly expressed by fibroblasts in the fibroblastic foci in human idiopathic pulmonary fibrosis samples. In conclusion, the present study showed involvement of serotonin in the pathophysiology of bleomycin-induced lung fibrosis in mice and identified it as a potential therapeutic target in lung fibrotic disorders.

Stepwise control of osteogenic differentiation by 5-HT(2B) receptor signaling: nitric oxide production and phospholipase A2 activation.

During development, antagonists of 5-HT(2) receptor subtypes cause morphological defects of mesodermal and neural crest derivatives including the craniofacial skeleton. We used an inducible mesoblastic cell line, C1, able to fully convert into osteocytes within 12 days, to assess the involvement of 5-HT(2) receptors during osteogenic differentiation. On day 5 of the osteogenic program, immediately before matrix mineralization, the cells selectively implement 5-HT(2B) receptors (5-HT(2B)R) which remain functional until terminal differentiation. In 5-HT-depleted medium, the receptor exhibits a constitutive activity leading to basal nitric oxide (NO) release and phospholipase A2 (PLA2)-dependent arachidonic acid (AA) production. Blockade of this intrinsic activity affects the efficiency of mineralization by decreasing calcium incorporation within the matrix by 40%. Optimal bone matrix mineralization involves both NO and PLA2 signaling pathways. Moreover, between day 5 and day 10, at the beginning of mineral deposition, the 5-HT(2B)R promotes prostaglandin E2 production through AA-dependent cyclooxygenase (COX) activation. From day 10 onwards, when C1 osteoblasts undergo conversion into osteocyte-like cells, COX activity is quenched. Altogether these observations indicate that the 5-HT(2B)R contributes in an autocrine manner to osteogenic differentiation and highlight a switch in the downstream targets of the receptor at the terminal stage of the program. Finally, in addition to its autocrine function, the 5-HT(2B)R responds to 5-HT by increasing NO production and AA release. These findings raise concern regarding the use of 5-HT(2B)R-related drugs that may interfere with bone metabolism in physiological or pathological situations.

Inflammation versus mechanical stretch biomarkers over time in acutely decompensated heart failure with reduced ejection fraction.

Heart failure can be associated with inflammation but it is unclear if inflammation is directly related to hemodynamic worsening or is an independent pathway. Our aim was to investigate inflammation and mechanical stress using serial measurements of biomarkers in acute and chronic heart failure with reduced ejection fraction (AHF and CHF). METHOD: The following biomarkers were measured on admission, at discharge and one month after discharge: B-type natriuretic peptide (BNP), high-sensitivity C-Reactive protein (hsCRP), Tumour Necrosis Factor alpha (TNFα), interleukin 6 (IL6), myeloperoxidase (MPO), suppression of tumorigenicity 2 (ST2), mid-regional pro-adrenomedullin (MR-proADM), galectin 3 (Gal3), Growth differentiating factor 15 (GDF15) and procalcitonin (PCT). RESULTS: In control CHF group (n=20, 69±11y, NYHA 1-2), most biomarker levels were low and stable over time. In AHF (n=55, 71±14y), BNP, ST2 and GDF15 levels were highly increased on admission and then decreased rapidly with clinical improvement; BNP, ST2 and GDF15 levels were statistically correlated (r=0.64, 0.46 and 0.39; p<0.001 for both). Both hsCRP, MPO, TNFα and Gal3 levels were increased in most AHF patients (70, 56, 83 and 98% respectively) with poor change over time. HsCRP, MPO and TNFα levels were correlated. IL6, MR-proADM and PCT levels were slightly increased, without change over time. Highest quartiles of BNP and ST2 were associated with death or readmission at one year (HR 2.33 [95CI 1.13-4.80] and 2.42 [1.27-4.60]). CONCLUSION: AHF is associated with systemic inflammation. This inflammatory response continued up to one month after discharge despite normalisation of mechanical stress-related markers.

Decreased brain tryptophan availability as a partial determinant of post-partum blues.

BACKGROUND: The post-partum blues is a transient mood alteration affecting most women a few days after delivery. Its stereotypic pattern of symptoms and time course, peaking on post-partum day 3-5, is suggestive of biological determinants superimposed on psycho-social factors. This study was designed to evaluate the possible role of the serotonin system during this period through assessment of brain tryptophan availability. METHODS: Blood samples from 50 women were collected just before (D0) and 3 days after (D3) delivery. Based on plasma concentration of tryptophan, amino acids competing with tryptophan for transport across the blood-brain barrier and on their respective affinities for this transporter, a brain tryptophan availability index (BTAI) was calculated and its variation correlated with the intensity of post-partum blues evaluated through the Kennerley and Gath score at D3. RESULTS: The BTAI showed a -15% decrease between D0 and D3 (p < 0.01, paired t-test). This decrease was not supported by a drop in plasma tryptophan since its level rather increased (+19%). There was no evidence for change in placental indoleamine-2,3-dioxygenase activity since the variation in plasma l-kynurenine (+12%) paralleled the change in tryptophan level. The decreased BTAI appeared the consequence of a dramatic increase in plasma levels of most amino acids, particularly the competitor aminoacids leucine, isoleucine, valine and tyrosine, during the early post-partum. This decrease in brain tryptophan availability was concomitant to the post-partum blues, whose intensity significantly correlated with the amplitude of BTAI variation (Pearson's coefficient -0.283, p < 0.05). CONCLUSION: This study suggests that generalized, large amplitude metabolic and/or nutritional changes occurring in the early post-partum result in a transient decrease in brain tryptophan availability, partly accounting for the mood alteration referred to as the post-partum blues, a model for the triggering of puerperal mood disorder in vulnerable women.

Serotonin and histamine production by human carcinoid cells in culture.

We are reporting on the first human carcinoid cells ever cultured in vitro. These cells, termed CGP, originated from a jejunal carcinoid tumor. Before tumor resection, the 29-year old male patient presented high levels of blood serotonin and histamine and also of urinary serotonin and 5-hydroxyindole-acetic acid; values returned to normal 9 days after resection. CGP cells exhibit a very slow multiplication rate; generation time is about 10 days. From the first subculture, the main cytological, ultrastructural, and biochemical features of CGP cultures remain unchanged. The cells show most of the enterochromaffin cell histomorphological characteristics; for example, cytoplasmic granulations, specific of argyrophilic cells, can be seen both by electron microscopy and by light microscopy (preceded by silver impregnation). The high amounts of serotonin and histamine found by highly specific radioenzymatic assay in the supernatant of CGP cultures indicate that, after 6 months (25 subcultures), CGP cells have retained the main metabolic characteristics of the original tumor, i.e., the ability to synthesize, store, and release both serotonin and histamine.

Biochemical and ultrastructural study of the disruption of blood platelets by streptolysin O.

The membrane-damaging protein toxin, streptolysin O, proved highly lytic on human, guinea-pig and rabbit platelets. About 15 molecules of toxin were sufficient to lyse one cell. Platelet disruption was assessed by electron microscopy, clearing of cell suspensions and assay of lactate dehydrogenase, serotonin, monoamine oxidase and glutathione peroxidase released in the extracellular fluid. This egress reflected the damage of both plasmic and organelle membranes. A quantitative study of lactate dehydrogenase and serotonin liberation taken as respective markers of the cytosol and dense bodies was undertaken as a function of toxin concentration. No platelet aggregation or shape change was elicited by streptolysin O. The ghosts resulting from platelet lysis retained properties of the native membrane such as aggregability and serotonin uptake. Dense bodies were easily separated after gentle disruption of the plasmic membrane by small amounts of toxin. Platelet lysis by streptolysin O proved a useful procedure for the determination of protein content, enzyme activities and serotonin assay on the same lysate in contrast to usual methods.