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G-protein-coupled receptors (GPCR) are present at the cell surface in different conformational and oligomeric states. However, how these states impact GPCRs biological function and therapeutic targeting remains incompletely known. Here, we investigated this issue in living cells for the CC chemokine receptor 5 (CCR5), a major receptor in inflammation and the principal entry co-receptor for Human Immunodeficiency Viruses type 1 (HIV-1). We used TIRF microscopy and a statistical method to track and classify the motion of different receptor subpopulations. We showed a diversity of ligand-free forms of CCR5 at the cell surface constituted of various oligomeric states and exhibiting transient Brownian and restricted motions. These forms were stabilized differently by distinct ligands. In particular, agonist stimulation restricted the mobility of CCR5 and led to its clustering, a feature depending on β-arrestin, while inverse agonist stimulation exhibited the opposite effect. These results suggest a link between receptor activation and immobilization. Applied to HIV-1 envelope glycoproteins gp120, our quantitative analysis revealed agonist-like properties of gp120s. Distinct gp120s influenced CCR5 dynamics differently, suggesting that they stabilize different CCR5 conformations. Then, using a dimerization-compromized mutant, we showed that dimerization (i) impacts CCR5 precoupling to G proteins, (ii) is a pre-requisite for the immobilization and clustering of receptors upon activation, and (iii) regulates receptor endocytosis, thereby impacting the fate of activated receptors. This study demonstrates that tracking the dynamic behavior of a GPCR is an efficient way to link GPCR conformations to their functions, therefore improving the development of drugs targeting specific receptor conformations., Competing Interests: FM, GN, PC, MH, NC, SB, OS, FA, NS, JO, BL, TL, AB The authors declare that no competing interests exist, (© 2022, Momboisse et al.)

This work is an extension of a model previously developed by our group to simulate the electroacoustic response of capacitive micromachined ultrasonic transducer (CMUT)-based linear arrays acoustically loaded by a fluid medium. The goal is to introduce the viscoelasticity effects of the propagation medium into the modeling. These effects are mainly due to the passivation layer used to protect the transducer, i.e., a silicon polymer, a few hundred micrometers thick. The passivation layer is also required to ensure good acoustic coupling between the transducer front face and human skin. The theoretical approach relies on the determination of a new boundary matrix to simulate the acoustic coupling between the CMUT array and the viscoelastic medium. The complete numerical implementation of a 3-D Green's function for a viscoelastic half-space is hence described. In order to reduce computing time, an optimization was carried out through vectorization and parallelization methods. A comparison is then performed with the analytical solutions, from the literature, obtained for elastic half-space. An experimental validation of shear viscosity effects is performed through electrical impedance measurements of the CMUT linear arrays loaded by oils of varying viscosity. A very good agreement is obtained, showing that the model correctly takes the shear viscosity effects on the mechanical response of the CMUT into account, i.e., a shift in the resonance frequency and a diminution in the mechanical quality factor are observed.

Objectives: This study, developed within the frame of the Partnership for European Research on Occupational Safety and Health joint research activities and based on the frame designed by the 2013 European Agency for Safety and Health at Work (EU-OSHA) study, is the first example of using the points of view of European occupational safety and health (OSH) researchers.The objective is to identify priorities for OSH research that may contribute to the achievement of present and future sustainable growth objectives set by the European strategies., Methods: The study was carried out using a modified Delphi method with a two-round survey. Each round involved a panel of about 110 researchers representing the network member institutes was selected according to specific criteria, including the ownership of research expertise in at least one of the four macroareas identified by the reference report developed by EU-OSHA in 2013., Results: The study identified some innovative research topics (for example, 'Emerging technological devices' and 'OSH consequences of markets integration') and research priorities (ie, crowdsourcing, e-work, zero-hours contract s ) that are not reflected in previous studies of this nature.The absence of any reference to violence and harassment at work among the researchers' proposals is a major difference from previous similar studies, while topics related to gender issues and electromagnetic fields show a lower importance., Conclusions: The innovative design of a research priorities identification process, which takes advantage of a large, representative and qualified panel of European researchers allowed the definition of a number of research priorities able to support the inclusion of innovative OSH research issues in the scope of the next European research agenda., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The acid mine drainage (AMD) impacted creek of the Carnoulès mine (Southern France) is characterized by acid waters with a high heavy metal content. The microbial community inhabiting this AMD was extensively studied using isolation, metagenomic and metaproteomic methods, and the results showed that a natural arsenic (and iron) attenuation process involving the arsenite oxidase activity of several Thiomonas strains occurs at this site. A sensitive quantitative Selected Reaction Monitoring (SRM)-based proteomic approach was developed for detecting and quantifying the two subunits of the arsenite oxidase and RpoA of two different Thiomonas groups. Using this approach combined with FISH and pyrosequencing-based 16S rRNA gene sequence analysis, it was established here for the first time that these Thiomonas strains are ubiquitously present in minor proportions in this AMD and that they express the key enzymes involved in natural remediation processes at various locations and time points. In addition to these findings, this study also confirms that targeted proteomics applied at the community level can be used to detect weakly abundant proteins in situ.

Background: In the course of setting up the National Mesothelioma Surveillance Program (PNSM), established in France in 1998, the question arose as to the most suitable method of assessing occupational exposure. The aim of this study was to define the most suitable rating method for assessing occupational asbestos exposure in order to assess medico-social care., Method: The study included 100 subjects-50 cases of mesothelioma and 50 controls-randomly selected and representing 457 jobs held. Job asbestos exposure was assessed by a six-expert panel using two methods: "by job" rating, where all the jobs in were assessed regardless of the subjects; and "by subject" rating, where all the jobs of a subject were assessed at the same time. Consensus was obtained and subjects' exposure was calculated for each rating. Then, two internal experts assessed job asbestos exposure with the "by subject" rating. Kappa coefficients were used to measure agreement between the ratings., Results: Agreement between "by job" and "by subject" ratings was very good for subject probability of exposure (kappa = 0.84) and cumulative exposure index (kappa = 0.80). Agreement between the six-expert panel and the two internal experts was good for subject exposure (kappa for probability = 0.71; kappa for cumulative exposure index= 0.68)., Conclusion: This study shows that the two rating systems have good or very good agreement. These results validate the routine use in the PNSM of the "by subject" rating, with the advantage of being convenient and quick to provide feedback on occupational asbestos exposure to mesothelioma cases for compensation., (Copyright © 2012 Wiley Periodicals, Inc.)

Information on the healthy worker hire effect in relation to asthma is scant. We aimed to assess whether and how childhood asthma-related characteristics (before hire) relate to occupational exposures at first hire. Analyses were conducted in 298 children examined at the first survey of the Epidemiological Study on the Genetics and Environment of Asthma (1991-1995), who reported a training period or a job at follow-up in 2003-2007 (aged 17-29 yrs; 53% males). Exposure likelihood to dust, gases and/or fumes in their first occupation was estimated by the ALOHA job exposure matrix. Asthma before the first occupation and two asthma classifications for severity (Global Initiative for Asthma 2002 guidelines) and symptoms were defined by questionnaire. In their first job, 47% of subjects were exposed. After adjustment (age, sex and education), pre-hire onset asthmatics (59%) were nonsignificantly less likely to be exposed (OR 0.67, 95% CI 0.41-1.11). Associations were stronger when considering those with severe asthma or high symptom score in childhood (OR 0.27 (95% CI 0.11-0.63) and OR 0.49 (95% CI 0.25-0.99), respectively). The association was observed in those who completed a university degree (OR 0.55, 95% CI 0.29-1.04) but not in the others (OR 0.98, 95% CI 0.44-2.22), with consistent results for all asthma characteristics. Results suggest a healthy worker hire effect in subjects with more severe or more symptomatic asthma in childhood. Education may modulate self-selection.

Background: Antidepressant treatments increase neural plasticity and adult neurogenesis, especially in the hippocampus. Here, we determined the effects of agomelatine (S-20098), a new antidepressant, on various phases of neurogenesis in the dentate gyrus of adult rat., Methods: Animals were injected with agomelatine for different time periods. Immunostaining for bromodeoxyuridine, neuron specific nuclear protein, and glial fibrillary acid protein, as well as for the highly polysialylated form of neuronal cell adhesion molecule and doublecortin, was used to detect changes in cell proliferation, neurogenesis, and survival. Cell death was estimated by terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling and cresyl violet staining., Results: Chronic (3 weeks) but not acute (4 hours) or subchronic (1 week) administration of agomelatine increased cell proliferation and neurogenesis in the ventral dentate gyrus, a region notably implicated in response to emotion, which is consistent with the antidepressant-anxiolytic properties of the drug. Extending agomelatine treatment over several weeks, however, increases survival of newly formed neurons in the entire dentate gyrus. Finally, agomelatine treatment does not affect mature granule cells., Conclusions: This study shows that an antidepressant can affect differentially various stages of neurogenesis in the dorsal and ventral hippocampus. Altogether, these changes lead to a pronounced augmentation in the total number of new granule cells.

Neuroplasticity contributes to both normal and pathological brain function. A recent hypothesis links depression to lack of adaptive responses to stress or other aversive stimuli, and effects of antidepressant treatments on adult neurogenesis are more and more extensively studied because of the structural changes involved in the pathophysiology of depression. Indeed, neuronal remodelling in hippocampal formation is associated with chronic stress and is reversed by antidepressant treatments in animals. Decrease in hippocampal volume has also been associated to cognitive deficits in patients with major depression. Interestingly, serotonergic (5-HT) systems play a major role both as antidepressants and by increasing hippocampal neurogenesis through various receptor subtypes. Recently, we have also demonstrated that agomelatine, a new antidepressant drug having serotonergic and melatonergic properties, can increase proliferation and survival of newly formed hippocampal cells. Although the mechanisms underlying such effects are still unknown, these data reinforce the view that changes in hippocampal neurogenesis might belong to the cellular correlates of mood disorders.

Purpose: We reviewed follow-up of patients treated in 19 randomized trials of adjuvant epirubicin in early breast cancer to determine incidence, risk, and risk factors for subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)., Patients and Methods: The patients (N = 9,796) were observed from the start of adjuvant treatment (53,080 patient-years). Cases of AML or MDS (AML/MDS) were reported, with disease characteristics. Incidence and cumulative risk were compared for possible risk factors, for assigned regimens, and for administered cumulative doses of epirubicin and cyclophosphamide., Results: In 7,110 patients treated with epirubicin-containing regimens (92% of whom also received cyclophosphamide), 8-year cumulative probability of AML/MDS was 0.55% (95% CI, 0.33% to 0.78%). The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle, planned epirubicin dose-intensity, and administered cumulative doses of epirubicin and cyclophosphamide. Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in standard regimens (

Increase in serotonin (5-HT) transmission has profound antidepressant effects and has been associated with an increase in adult neurogenesis. The present study was aimed at screening the 5-HT receptor subtypes involved in the regulation of cell proliferation in the subgranular layer (SGL) of the dentate gyrus (DG) and the subventricular zone (SVZ) and to determine the long-term changes in adult neurogenesis. The 5-HT1A, 5-HT1B, and 5-HT2 receptor subtypes were chosen for their implication in depression and their location in/or next to these regions. Using systemic administration of various agonists and antagonists, we show that the activation of 5-HT1A heteroreceptors produces similar increases in the number of bromodeoxyuridine-labeled cells in the SGL and the SVZ (about 50% over control), whereas 5-HT2A and 5-HT2C receptor subtypes are selectively involved in the regulation of cell proliferation in each of these regions. The activation of 5-HT2C receptors, largely expressed by the choroid plexus, produces a 56% increase in the SVZ, while blockade of 5-HT2A receptors produces a 63% decrease in the number of proliferating cells in the SGL. In addition to the influence of 5-HT1B autoreceptors on 5-HT terminals in the hippocampus and ventricles, 5-HT1B heteroreceptors also regulate cell proliferation in the SGL. These data indicate that multiple receptor subtypes mediate the potent, partly selective of each neurogenic zone, stimulatory action of 5-HT on adult brain cell proliferation. Furthermore, both acute and chronic administration of selective 5-HT1A and 5-HT2C receptor agonists produce consistent increases in the number of newly formed neurons in the DG and/or olfactory bulb, underscoring the beneficial effects of 5-HT on adult neurogenesis.

Relations between exposure to chlorinated compounds and biological markers of response to oxidative stimuli were investigated in swimmers, taking into account the effect of training. Twenty-two male swimmers aged 15-25 years were surveyed twice. Prevalence of irritant symptoms and asthma and number of hours of training were reported. Exposure to nitrogen trichloride (NCl3) and blood response to oxidative stimuli [catalase, superoxide dismutase (Cu2+/Zn2+ SOD), glutathione peroxidase (GSH-Px) activities and ceruloplasmin, ferritin and total antioxidant concentrations] were measured. Univariate analyses were completed by multivariate analyses. High prevalences of irritant symptoms and asthma were found. Multivariate analysis confirmed the results of the univariate analyses and showed that Cu2+/Zn2+ SOD activity was increased by exposure and by training (P = 0.01, P = 0.0001, respectively). Erythrocyte GSH-Px was decreased, whereas plasma GSH-Px was increased by exposure (P = 0.002, P = 0.002). No other association was found. Higher irritant symptoms and increases in the activities of erythrocyte Cu2+/Zn2+ SOD and of plasma GSH-Px with exposure support the hypothesis that the production of reactive oxygen species is not only related to training but also to exposure to chlorinated compounds. Other athletes tend to have respiratory problems such as asthma, but the exposure to chlorinated compounds may increase the respiratory disease among swimmers.

Characterizing the mechanisms by which endogenous factors stimulate neurogenesis is of special interest in view of the possible implication of newly generated cells in hippocampal functions or disorders. The aim of this study was to determine whether serotonin (5-HT) and oestradiol (E2) act through a common pathway to increase cell proliferation in the adult dentate gyrus (DG). We also investigated the effects of long-lasting changes in oestrogen levels on cell proliferation. Combining ovariectomy with inhibition of 5-HT synthesis using p-chlorophenylalanine (PCPA) treatment produced approximately the same decreases in the number of bromodeoxyuridine (BrdU) and PSA-NCAM immunolabelled cells in the subgranular layer as ovariectomy alone. Administration of 5-hydroxytryptophan (5-HTP) restored cell proliferation primarily decreased by ovariectomy, whereas oestradiol was unable to reverse this change in ovariectomized rats treated with PCPA. These findings demonstrate that 5-HT mediates oestrogen stimulation of cell proliferation in adult dentate gyrus. However, increase in ovarian hormones during pregnancy has no effect on dentate cell proliferation. This finding suggests that concomitant changes in other factors, such as glucocorticoids, may counterbalance the positive regulation of cell proliferation by 5-HT and oestradiol. Finally, oestrogen may regulate structural plasticity by stimulating PSA-NCAM expression independently of neurogenesis, as shown for instance by the increases in the number of PSA-NCAM labelled cells in pregnants. As 5-HT and oestrogen are involved in mood disorders, our data suggest that the positive regulation of cell proliferation and neuroplasticity by these two factors may contribute to restore hippocampal connectivity in depressive patients.

Many studies have shown the existence of functional interactions between central neurotransmitter systems and the hypothalamo-pituitary adrenal axis. Mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) are regulated by multiple factors including glucocorticoids themselves. Neurotransmitters such as serotonin (5-hydroxytryptamine: 5-HT) can regulate brain corticosteroid receptors in a complex way. The present study examined the short-term (48 h) effects of parachlorophenylalanine (PCPA), a drug which specifically inhibits 5-HT synthesis, on corticosteroid receptor levels and on the expression of their respective messenger ribonucleic acids (mRNA) in the rat hippocampus, hypothalamus and brain stem. The study was performed in bilaterally adrenalectomized animals, in order to avoid potential drug-induced changes in plasma corticosterone levels, which could secondarily regulate MR and GR. Short-term inhibition of 5-HT synthesis by PCPA significantly increased the number of hippocampal MR-binding sites. PCPA treatment did not alter the number of GR-binding sites in the hippocampus, hypothalamus and brain stem. We observed no change in the affinities of GR and MR sites in all the structures studied. In PCPA-treated rats, restoration of control 5-HT levels by injection of its immediate precursor, 5-hydroxytryptophan (5-HTP) brings the number of hippocampal MR-binding sites back to control levels. It can therefore be concluded that the increase in number of MR-binding sites induced by acute PCPA treatment is dependent on the decrease in 5-HT levels. The increase in hippocampal MR binding sites was correlated with an induction of their messengers, suggesting that 5-HT modulates the synthesis of MR protein. Although PCPA did not modify the number of hippocampal GR-binding sites, a decrease in hippocampal GR mRNA expression was observed. This study shows that 5-HT inhibits hippocampal mineralocorticoid receptor synthesis and that this effect is not mediated by changes in corticosterone hormone secretion, and illustrates the existence of complex mechanisms for corticosteroid receptor regulation in the hippocampus.

Acute eye and upper respiratory irritation was reported at an industrial facility that processes green salads in water containing hypochlorite. The irritant agents were chloramines resulting from the reaction of hypochlorite and nitrogen compounds coming from the sap proteins released when the vegetables were cut. Specific sampling and analytical methods were developed in order to assess the workers' exposure. Monochloramine, dichloramine and nitrogen trichloride were found in the atmosphere, which can explain the irritation phenomena of which the workers complained. In the washing room (where salads are processed), the total chloramine concentration ranged from 0.4 to 16 mg.m-3, depending on the day and the location of the area sampling points. The exposure of workers determined by personal sampling ranged from 0.2 to 5 mg.m-3. In a previous study, with swimming pool instructors exposed to the same pollutants, irritation phenomena generally appeared at chloramine values of around 0.5 mg.m-3.

The survival of patients with breast cancer depends on parameters known as prognostic factors. The first generation of prognostic factors are simple, have been validated, and have proved their usefulness. We know the importance of examining axillary lymph nodes. However, because there has been a constant increase in the percentage of patients with no invaded lymph nodes, tumor size has become an important parameter. The 10-year survival rate of patients with tumors less than 1 cm in diameter exceeds 90% suggesting that there might seem to be no need for adjuvant therapy. According to histological grade assessed by the Scarff-Bloom and Richardson method, grade I tumors have a better prognosis than grade II or III tumors. Knowledge of the concentration of estrogen and progesterone receptors in tumors provides not only prognostic information but also indicates whether hormone therapy is justified. All these first generation factors are intimately linked and, taken together, they are the main factors on which the oncologist bases his decision whether or not to prescribe adjuvant therapy. There is still no consensus regarding the assay methods and normal levels of second generation prognostic factors. Amongst these factors, the most promising are those, like S-phase determination by flow cytometry, that evaluate cell proliferation potential and those that investigate tumor invasiveness by assaying urokinase plasminogen activator or its inhibitor.

The pituitary is a rich source of peptidylglycine alpha-amidating monooxygenase (PAM). This bifunctional protein contains peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase catalytic domains necessary for the two-step formation of alpha-amidated peptides from their COOH-terminal glycine extended precursors. Expression of PAM was evaluated in the anterior pituitary of intact cycling adult female rat and after experimental manipulation of estrogen status. PAM messenger RNA (mRNA) levels showed changes inversely related to the physiological variations of plasma estrogen levels during the estrous cycle. Chronic treatment of ovariectomized (OVX) rats with 17 beta-estradiol decreased PAM mRNA levels to values comparable with those found in intact rats at proestrus. In situ hybridization of anterior pituitary sections using 35S-labeled full length RNA antisense transcripts of rat PAM-1 complementary DNA showed that 17 beta-estradiol treatment induced an overall decrease of the hybridization signal, as compared with OVX rats. Progesterone treatment did not change PAM mRNA levels both in OVX or OVX + E2 rats. Based on Northern blot analysis and amplification of fragments derived from rat PAM-1 by RT-PCR, it was found that estrogen status does not affect the distribution of PAM mRNA among its various alternatively spliced forms. In OVX 17 beta-estradiol treated rats, the specific activity of PAM in the anterior pituitary decreased in both soluble and particulate fractions compared with OVX animals. Western blot analysis demonstrated a 105-kDa PAM protein in particulate fractions prepared from OVX and OVX-17 beta-estradiol treated animals. The soluble fraction from OVX animals contained major PAM proteins of 105, 95, 84, 75, and 45 kDa, and 17 beta-estradiol treatment caused a decrease in the prevalence of these proteins. These results indicate that estrogens are involved, either directly or indirectly, in regulating the expression of PAM in several cell types in the anterior pituitary gland.

The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 60-min oronasal exposure to increasing concentrations of chlorine and nitrogen trichloride. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each chemical. Chlorine and nitrogen trichloride showed dissimilar concentration-response curves. While the maximal response of nitrogen trichloride was reached in 10 min, the maximal response of chlorine was reached between 45 and 60 min of exposure. The results showed both chemicals to have an irritant potency of the same order of magnitude. The RD50 values of chlorine and nitrogen trichloride were 3.5 and 2.5 ppm, respectively. On the basis of a TLV-STEL (threshold limit value for short-term exposure limit) equal to 0.1 RD50 and a TLV-TWA (time-weighted average) equal to 0.03 RD50, the current TLVs for chlorine seem too high (1 and 0.5 ppm, respectively) and should be reduced to 0.5 and 0.1 ppm, respectively. For nitrogen trichloride, 0.3 ppm and 0.1 ppm are proposed as TLV-STEL and TLV-TWA, respectively.

Control of serotonin release and synthesis by amino acid neurotransmitters was investigated in rat rostral and caudal rhombencephalic raphe cells in primary cultures respectively. Endogenous amounts of taurine, glycine, GABA and glutamate were measured in both types of cultures. These amino acids were spontaneously released to the incubating medium. Exogenous taurine (10(-4) M) inhibited release and synthesis of newly formed [3H]serotonin [3H]5-HT from [3H]-tryptophan only in rostral raphe cells. Glycine (10(-3) M) decreased [3H]5-HT release in both types of cells, synthesis being diminished only in rostral raphe cells. Glycine inhibitory effect was totally blocked by strychnine (5 x 10(-5) M). GABA (10(-4) M) reduced [3H]5-HT metabolism in rostral as well as caudal raphe cells. This effect was totally antagonized in caudal and partially in rostral raphe cells by bicuculline (5 x 10(-5) M) a GABAA receptor antagonist. Baclofen (5 x 10(-5) M), a GABAB receptor agonist, induced a decrease of 5-HT release in rostral raphe cells. These observations suggest that monoamine release was entirely mediated by GABAA receptors in caudal raphe cells although GABAA and GABAB receptors were involved in control of 5-HT metabolism in rostral raphe cells. L-glutamate (10(-4) M) stimulated 5-HT metabolism in both types of cells, effect totally blocked by PK26124 (10(-6) M). N-methyl-D-aspartate (10(-4) M) enhanced 5-HT metabolism and the induced-effect was antagonized by the selective N-methyl-D-aspartate receptor antagonist D,L-2 amino-5-phosphonovaleric acid. Quisqualate (10(-5) M) stimulated [3H]5-HT release only in caudal raphe cells. This effect was mimicked by (RS)-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, a quisqualate "ionotropic" receptor agonist, this increase being blocked by 6,7-dinitroquinoxaline 2,3-dione. These observations suggest that the glutamate stimulating-induced effect on serotonin metabolism is entirely mediated by N-methyl-D-aspartate receptor-type in rostral raphe cells and that quisqualate "ionotropic" receptors are also involved in caudal raphe cells. Taken together these results show that [3H]5-HT metabolism is controlled by taurine, glycine, GABA and glutamate in rhombencephalic raphe cells in primary cultures. However, some difference in amino acid receptor-types involved in the control of serotonin metabolism are observed according to the rostral or caudal origin of raphe cells.

An assessment of exposure to sulphuric acid and sulphur dioxide was performed in the French titanium dioxide manufacturing industry. The three plants use the sulphuric acid process, with potential exposure mainly to sulphur dioxide and sulphuric acid. The exposures found were below the French limit values, except for some employees using the Moore filtration process in one plant. For sulphuric acid sampling, a comparison was made between thoracic particulate mass and inhalable particulate mass, from samples taken with a Marple cascade impactor. This comparison shows that the suggested new limit value (0.1 mg m-3 in thoracic particulate mass) would be much more severe than the present one (1.0 mg m-3 with no restriction as to the droplet size).

The authors describe 10 cases of malignant non Hodgkin's lymphoma in a mammary site in women aged 38 to 82 years. The clinical examination and the sometimes suggest an adenocarcinomatous lesion, thus leading to a useless surgical exeresis. An initial histological study provides the diagnosis. A complete assessment of extension allows an accurate staging and the refinement of the therapeutic schedule. Exclusive radiation therapy seems to be justified in low-malignancy forms remaining strictly confined to the breast. For the high- and medium-malignancy forms, the essential weapon is chemotherapy, which seems to improve the duration and rate of remission.

The efficiency of a mask currently used in an inorganic pigment manufacturing plant producing suspected carcinogens was assessed and the protection provided by it was found to be insufficient. Three other masks, with better laboratory performances, were tested in field conditions. None of them reduced personal exposures to below the French limit values, and their performance in the field was well below that in laboratory assessments. A similar study in another pigment manufacturing plant gave similar results. Possibly only power-assisted filtering devices will provide satisfactory working conditions.

The authors describe 10 cases of malignant non-Hodgkin's lymphoma in a mammary site in women aged 38 to 82 years. The clinical examination and the sometimes suggest an adenocarcinomatous lesion, thus leading to a useless surgical exeresis. An initial histological study provides the diagnosis. A complete assessment of extension allows an accurate staging and the refinement of the therapeutic schedule. Exclusive radiation therapy seems to be justified in low-malignancy forms remaining strictly confined to the breast. For the high- and medium-malignancy forms, the essential weapon is chemotherapy, which seems to improve the duration and rate of remission.

The hypothalamus of both adult and fetal rats contains a population of cells which can exhibit some features of serotoninergic (5-HT) neurons under certain circumstances. However, their neuronal serotoninergic nature is still controversial. In fact the presence of tryptophan hydroxylase activity has not yet been clearly established. This study attempted to verify whether [3H]5-HT can be synthesized from [3H]tryptophan ([3H]TRP) in hypothalamic cell cultures from 16-day-old fetuses. Data showed that [3H]5-HT was synthesized from [3H]TRP and the amounts of [3H]5-HT increased linearly as a function of time for 60 min. Pargyline markedly increased the quantities of [3H]5-HT and decreased those of [3H]5-hydroxyindole acetic acid. [3H]5-HT synthesis was inhibited by p-chlorophenylalanine, while alpha-methyl-p-tyrosine had no effect. The present biochemical study shows the presence of an intrinsic 5-HT neuronal system in the hypothalamus of the fetal rat.

To evaluate the utility of bone scans for the follow-up of patients with small breast cancers (T less than or equal to 3 cm), the files for 133 patients whose disease was diagnosed between Jan. 1, 1979 and Dec. 31, 1980 were reviewed. At initial presentation, two of these patients already had bone metastases. During their disease course, 30 patients developed metastases and 16 of them had at least one bone metastasis. In 7 of these 16 cases, the bone metastasis was solitary; in 4 cases bone lesions were symptomatic. A total of 178 bone scans were performed during the follow-up of these 133 patients; 16 of these scans were positive, but only 4 examinations allowed the diagnosis of bone metastasis. Despite the slight prognostic value of initial bone scanning in this series, the technique is of little value unless it is combined with clinical examinations aimed at early detection of disease recurrence or metastasis. Except as part of clinical trial protocols, systematic bone scans appear unnecessary for the staging and follow-up of patients with small breast cancers.

Newly synthesized serotonin (5-HT) can be released in the nodose ganglion from the nerve cell bodies of vago-aortic serotoninergic neurones. Free-calcium led to a decrease of spontaneous and potassium-evoked release. The veratridine-stimulating response was abolished by TTX. The concept that 5-HT released from perikarya in the extracellular space could be involved in the self-regulation of the activity of the vago-aortic pathway is discussed.

Abstract The purpose of this study was to test the capacity of oestradiol to modulate the stimulating effect of a-aminobutyric acid (GABA) on serotonin (5-HT) metabolism, previously described in the Suprachiasmatic area of the male rat. After an in vivo stimulation of GABA transmission by systemic administration of a GABA-transaminase inhibitor (amino-oxyacetic acid) or a GABA(B) agonist (RS-baclofen), the 5-HT metabolism was studied in the Suprachiasmatic area of ovariectomized, and ovariectomized oestradiol-treated rats. Amino-oxyacetic acid or RS-baclofen treatment increased the endogenous content of 5-HT in the Suprachiasmatic area of males and ovariectomized rats. These two treatments were without effect in ovariectomized oestradiol-treated rats. GABA transmission stimulation induced by amino-oxyacetic acid treatment failed to affect the release and synthesis of 5-HT in ovariectomized oestradiol-treated rats while it increased these two parameters of 5-HT metabolism in the Suprachiasmatic area of male and ovariectomized rats. To investigate the main target of oestradiol effect, comparative studies of the serotoninergic and GABAergic metabolism in the Suprachiasmatic area were performed in the three experimental groups. Under our experimental conditions the endogenous 5-HT metabolism was similar between ovariectomized and ovariectomized oestradiol-treated rats. Nevertheless, 5-HT metabolism was higher in the two female groups than in the male group. Neither GABA metabolism nor GABAergic response to GABA-related drug treatment differed between ovariectomized, and ovariectomized oestradiol-treated rats. However, the turnover of GABA was higher when compared to the two female groups. It is concluded that the lack of 5-HT responsiveness to GABA transmission stimulation in ovariectomized oestradiol-treated rats was not related to an effect of oestradiol on 5-HT metabolism or to an effect of the steroid on GABA turnover. Furthermore, our results suggest a sex difference in the activity of serotoninergic and GABAergic systems in the Suprachiasmatic area.

The effect of vasoactive intestinal peptide (VIP) on spontaneous and induced release of newly synthesized 5-hydroxytryptamine (5-HT) was studied in the suprachiasmatic area (SCA) using a superfusion system. To test the possible modulation by E2 on the interaction VIP-5-HT, the experiments were conducted on male, ovariectomized (OVX) and ovariectomized oestradiol implanted rats (OVX-E2). VIP (10(-7)M) infused for 15 min caused an increase of 5-HT release from SCA of male and OVX. The positive effect of VIP on 5-HT release results partially from an inhibition of the reuptake of 5-HT: in male and OVX SCA, VIP inhibited the 3H-5-HT uptake by 40 to 50%. The infusion of VIP before a pulse of K+ (10-20-30-56 mM) leads to a potentialisation of the evoked release suggesting that VIP sensitized the presynaptic membrane to the process linking depolarization and release. When SCA taken from OVX-E2 were exposed to VIP, 5-HT uptake and consequently 5-HT release were unchanged. The present results suggest that the metabolism of 5-HT in the SCA is influenced by VIP and that this regulation may be modulated by E2. This interaction between E2, VIP and 5-HT at the SCA level may be involved in the regulation of phasic LH and prolactin surge.

The clonogenicity in soft agar and the labeling index (LI) which represents the percentage of cells in the DNA synthesis phase, were studied in 59 breast cancer patients and these parameters were related to other known clinicopathological features, namely age, histological grading, estrogen and progesterone receptors and the status of axillary lymph nodes. Out of 59 tumors, 49 could be successfully cloned in soft agar and the mean plating efficiency (PE) was 0.1%. Low grade tumors were more frequently encountered in tumors which did not form colonies (P = 0.025). Cloned tumors had a higher mean LI (P = 0.05). A high PE was associated with low estrogen receptors (ER) (P = 0.03). Clonogenicity was not related to patient age, progesterone receptors (PR) or the status of axillary lymph nodes. These results suggest that a successful in vitro cloning and a high PE are associated with unfavorable prognostic factors in breast cancer.

Between 1975 and 1980, 108 cancers of the breast (T1 and small T2) were treated by associated conservative surgery and radiotherapy. Axillary glands were curetted in 92 patients; 17% showed lymph node invasion. Radiotherapy was by telecobalt: 45 grays to the whole breast and 60 grays to the tumor bed. Esthetic results were satisfactory. Intramammary recurrence was rare (6%) and was independent of site or size of tumor and of degree of lymph node involvement. Metastases not associated with local recurrence were very rarely observed (4% of cases) and were present only in patients without glandular involvement. The 5-year actuarial survival rate was 95%.

An experimental increase in serotonin (5-HT) induced shortly before the "critical period" of ovulation control blocks the release of LH. Administration of a synthesis inhibitor of the amine p-chlorophenylalanine, (pCP) is ineffective when given during the critical period. However, pCP given in the evening of dioestrus II (18 to 24 hours before the "critical period") blocks ovulation. That 5-HT is specifically involved in this delayed effect of the drug is shown by the ability of increasing doses of 5-hydroxytryptophane (5-HTP) to induce with pCP a graded restoration of LH release when given together. This result, obtained in immature rats, has been confirmed in cyclic ones. A positive, permissive effect of 5-HT containing neurons on neural processes leading to LH release and ovulation is thus postulated. This action affects early stages of the LH release regulating mechanisms, in contrast to the classically described inhibiting effect of the amine, which blocks the actual release of LH-RH at the median eminence level during the critical period.

Vasoactive intestinal peptide (VIP) inhibits serotonin (5-HT) uptake in the suprachiasmatic area (SCA) of the rat. The present study investigates the possibility of a functional relationship between 5-HT uptake mechanisms and 5-HT autoreceptor activity in this effect of VIP in the SCA. The hypothesis of a linkage between these two mechanisms of 5-HT regulation has been recently proposed. We investigated the possibility of the presence of 5-HT autoreceptors in the SCA. Using superfusion system, exogenous 5-HT (500 and 50 nM) increased the release of newly synthesized 3H-5-HT. In contrast, 5 nM of exogenous 5-HT inhibited this release. This latter effect was antagonized by methiothepin (10(-7) M). In contrast, the concentration of methiothepin required to inhibit the VIP effect was 10(-6) or 10(-5) M, the same molarity found to decrease the 5-HT uptake. On the other hand, the increase of the 3H-5-HT in the synaptic cleft, induced by VIP, did not modify the inhibition of 3H-5-HT release induced by 5 nM of exogenous 5-HT. We conclude that the effect of VIP on 5-HT metabolism in the SCA is linked to the 5-HT uptake mechanism but not to the activity of 5-HT presynaptic autoreceptors. In our experimental conditions, the activity of 5-HT autoreceptors is independent of the 5-HT uptake processes.

Ovariectomized female rats were implanted with estradiol containing silastic implants to induce constant circulating levels of the steroid, and sacrificed every 2 h in order to determine neuroendocrine rhythms. Under these conditions, we observed very marked circadian fluctuations in the hypothalamic concentrations of corticotropin-releasing factor (CRF), luteinizing hormone-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH), and in plasma levels of adrenocorticotropin (ACTH), corticosterone, luteinizing hormone (LH) and prolactin; the amplitude of the prolactin cycle was in particular much higher than in non-chronically estrogenized animals. The daily variation in CRF, ACTH and corticosterone showed significant rank correlations. Changes in hypothalamic content of LHRH and TRH were biphasic; the increase observed during the light period was abruptly interrupted by a depletion episode, coincident with the period of maximal LH and prolactin secretion, respectively. The initial phase of ACTH, LH and prolactin increments occurred between 11.00 and 15.00 h, and was relatively well synchronized. The steepest rise in ACTH and prolactin occurred at the same time, and preceded that of LH by a constant lag of about 2 h. After that initial period, secretion kinetics of the three hormones followed an independent pattern. The data suggest that increased secretion of several hormones results from activation of neural mechanisms occurring within a limited period of the 24-hour cycle.

The clinical and radiological responses after irradiation of brain metastases were compared in 50 patients. A complete response as evidenced by CT scan was achieved in 11 patients, whereas a clinical complete response was observed in 16 cases. There was only 35% agreement between the clinical and the radiological responses. In terms of patient survival, those in whom complete radiological response was obtained has a significantly longer survival time (p = 0.004). Therefore, in evaluating the treatment of brain metastases, it is preferable to determine both the clinical and the radiological responses. The latter seems to be more accurate and justifies the use of repeated CT scans in the follow-up of these patients.

The action of ?-aminobutyric acid (GABA) and related compounds on the spontaneous release of newly synthesized [(3)H]5-hydroxytryptamine ([(3)H]5-HT) was studied in the suprachiasmatic area (SCA) using a superfusion system. GABA (10 ?M) increased [(3)H]5-HT release from SCA by up to 190%. Bicuculline or picrotoxin (10 ?M) failed to inhibit the stimulatory effect of GABA. Muscimol (10 ?M), a GABA(A) agonist, was ineffective, however ?-p-chlorophenyl GABA, R(?)baclofen, enhanced over 200% the release of the indoleamine; this latter effect was stereospecific. RS baclofen was twice less potent than the R(?)isomer in increasing the [(3)H]5-HT release. S(+)baclofen failed to affect the release of the indoleamine, whereas it attenuated the effect of its enantiomer. The effect of R(?)baclofen was Ca(2+) dependent and was abolished by tetrodotoxin (TTX). Taken together these results suggest that in the SCA, [(3)H]5-HT release is facilitated by the stimulation of GABA(B) receptors. The possible localization of these receptors is discussed in the light of morphological data recently reported by Bosler et al. (1985) and results obtained after TTX application.