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International audience; Background: Intracranial solitary fibrous tumour (iSFT) is an exceptional mesenchymal tumour with high recurrence rates. We aimed to analyse the clinical outcomes of newly diagnosed and recurrent iSFTs.Methods: We carried out a French retrospective multicentre (n = 16) study of histologically proven iSFT cases. Univariate and multivariate Cox models were used to estimate the prognosis value of the age, location, size, WHO grade, and surgical extent on overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS).Results: Eighty-eight patients were included with a median age of 54.5 years. New iSFT cases were treated with gross tumour resection (GTR) (n = 75) or subtotal resection (STR) (n = 9) and postoperative radiotherapy (PORT) (n = 32, 57%). The median follow-up time was 7 years. The median OS, PFS, and LRFS were 13 years, 7 years, and 7 years, respectively. Forty-two patients experienced recurrence. Extracranial metastasis occurred in 16 patients. Median OS and PFS after the first recurrence were 6 years and 15.4 months, respectively. A higher histological grade was a prognosis factor for PFS (p = 0.04) and LRFS (p = 0.03). GTR influenced LRFS (p = 0.03).Conclusion: GTR provided benefits as a first treatment for iSFTs. However, approximately 40% of patients experienced relapse, which remains a challenging state.

Introduction: Admission of metastatic cancer patients to the intensive care unit (ICU) poses medical and ethical challenges in the absence of reliable prognostic tools to guide decision-making. Material and Methods: We retrospectively analyzed the medical charts of 129 consecutive patients with metastatic solid tumors admitted to the ICU between January and September 2014 and identified prognostic factors (PFs) using Cox models. Results: The mean patient age at ICU admission was 58.9 years (range, 25–81 years; males, 51%). Performance status (PS) was 0–1 and 2–3 in 61% and 39% of the patients, respectively. The most prevalent cancers were lung cancer (20%), sarcoma (17%), and breast cancer (16%). ICU admission was attributable to the cancer itself (53%), cancer treatment toxicity (43%), and comorbidities (37%). The median overall survival (OS) after ICU admission was 2.6 months; 15% of the patients died during the ICU stay. Poor PFs for OS were PS >1 before ICU admission (p = 0.007) and ICU admission for the cancer itself (p < 10−3). After ICU discharge, 58% and 42% of the patients received systemic treatment within 12 months and showed good PS recovery, respectively. Multiple organ failure and a multidisciplinary decision to limit therapeutic efforts were poor PFs for reinitiation of systemic treatment (p = 0.2 and 0.006, respectively), and the latter was also a poor PF for PS recovery (p = 0.004). Discussion: In the ICU, the OS of adult patients with solid tumors was similar to that of the noncancer population. For ICU admissions related to the cancer itself, the prognosis is poor.

Background: Air pollution is increasingly associated with cardiovascular events. As for ozone (O3 ) pollution, results are inconsistent though O3 levels are associated with hospital admissions, global mortality, and respiratory, and cardiovascular mortality. Methods: In this time-stratified case-crossover study, the associations between short-term exposure to O3 (on an hourly and daily scale) and out-of-hospital cardiac arrests (OHCA) were investigated. Specific subgroups were explored by sex, age, diabetes status, for OHCA during non-holiday periods. Data were collected in the Nord-Pas-de-Calais region, France, in 2015. Data were statistically analyzed using conditional logistic regression (CLR). Results: The study included 1039 cases of OHCA. Significant negative associations were found between OHCA and O3 levels measured in 3 or 4 days before the arrest for all the people, and 1, 2 or 3 days before the arrest for men. As for OHCA during non-holiday periods, there was no significant negative associations but a positive association was revealed for women between OHCA and O3 levels measured in 5 days before the arrest (OR=1.53, P=0.008). Conclusion: According to the results, OHCA should be investigated during non-holiday periods to control potential confounders that would lead to negative associations. Women might be a susceptible subgroup to O3 pollution.

Introduction:Resistant dextrins are glucose polymers with atypical linkages making them non-digestible in the upper part of the gastrointestinal tract. NUTRIOSE® is slightly digested in the small intestine and then, progressively fermented in the colon. The objective of this study is to investigate the beneficial effects resulting from the colonic fermentation of NUTRIOSE® and the underlying mechanism of action in rats.Materials & Methods:This experiment was conducted according to the French Regulations for Animal Experimentation and authorized under the project Number 00619.01. After acclimatisation on maintaining diet, 20 Sprague-Dawley rats were blocked by body weight and randomly split into 2 groups. The control group was given a fibre-free diet where corn starch was used to replace fibre and the experimental group was supplemented with 10% NUTRIOSE®. Feces were collected for enzymatic activities measurement. Caecal contents were collected so as caecal cell walls and colon biopsies for gene expression analysis.Results:The significant increases in caecal content weight (p < 0.001) fecal activity of saccharolytic enzymes (p < 0.05) and the decrease in caecal pH (p < 0.001) after the supplementation of NUTRIOSE® suggested its fermentation in the colon and caecum. It is also known from literature that NUTRIOSE® fermentation leads to higher levels of short chain fatty acids including higher levels of propionate and butyrate. This enhanced fermentation induced several positive impacts in the colon such as an increased caecal wall weight (p < 0.001) demonstrating beneficial effect on colon epithelial cells, an up-regulation of genes involved in membrane integrity (occludin (p = 0.01), ZO-1(p = 0.01)), and a positive impact on genes involved in inflammation (Tnf-α (p = 0.03), FOXP3 (p = 0.01)). The present study demonstrated the positive effects of NUTRIOSE® supplementation on glucose metabolism through the up-regulation of PEPCK in the colon (p < 0.001). This effect may also be mediated by the up-regulation of the GPR41 receptor in the colon (p < 0.001) and probably activated by butyrate.Conclusions:All together, these results confirmed that NUTRIOSE® is well fermented in the colon and that these fermentations may be associated with beneficial impacts on colonic epithelial integrity, inflammation and neoglucogenesis. Here we demonstrate a putative mechanism of action of NUTRIOSE® to improve the colonic health which is through the production of butyrate and the resulting activation of GPR41 receptor. Thus, this study helps us to understand the physiological impact of NUTRIOSE® fermentation in colon to produce several health benefits as observed in clinical studies.

Saponins exhibit several biological and pharmacological activities, such as antibacterial, anti-inflammatory and anticancer effects. Many studies attribute their activities to their interactions with cholesterol. In this study, we focus on the steroid saponin ginsenoside Rh2, one of the active principles of Panax ginseng root. Some evidence suggests that lipid rafts, defined as nanodomains enriched in cholesterol and sphingolipids, could be involved in the Rh2-induced apoptosis. However, the role of membrane lipids, especially cholesterol, in this process is still poorly understood. Here, we demonstrate that (i) A549, THP-1 and U937 cells are all susceptible to the Rh2-induced apoptosis but to a differential extent and (ii) the cytotoxic effect inversely correlates with the cell membrane cholesterol content. Upon cholesterol depletion via methyl-β-cyclodextrin, those three cells lines become more sensitive to Rh2-induced apoptosis. Then, focusing on the cholesterol-auxotroph U937 cell line, we showed that Rh2 alters plasma membrane fluidity by compacting the hydrophobic core of lipid bilayer (DPH anisotropy) and relaxing the interfacial packaging of the polar head of phospholipids (TMA-DPH anisotropy). The treatment with Rh2 conducts to the dephosphorylation of Akt and the activation of the intrinsic pathway of apoptosis (loss of mitochondrial membrane potential, caspase-9 and -3 activation). All these features are induced faster in cholesterol-depleted cells, which could be explained by faster cell accumulation of Rh2 in these conditions. This work is the first reporting that membrane cholesterol could delay the activity of ginsenoside Rh2, renewing the idea that saponin cytotoxicity is ascribed to an interaction with membrane cholesterol.

There is increasing evidence of association between particulate matter air pollution and cardiovascular mortality and morbidity. However, the association with the out-of-hospital cardiac arrest (OHCA) event is less clear. We investigated the effects of short-term particulate matter exposure on OHCA especially among specific subgroups. The study included OHCA that occurred in the Nord-Pas-de-Calais region, France, in 2015. A time-stratified case-crossover study design coupled with a conditional logistic regression was used to evaluate the association between OHCA and particle levels of 10 or 2.5 micrometers or less (PM10 or PM2.5 respectively) measured within the hour of the arrest up to 5 days before. Susceptible subgroups by sex, age, diabetes status among OHCA that occurred during non-holiday periods were investigated. In all, 1039 cases were included. Significant associations were found between OHCA during non-holiday periods and PM2.5 and PM10 exposure four days before the arrest and on the day of the arrest. The largest OR were found for the cumulative average twelve hours before the arrest of PM2.5 (OR = 1.17, p = 0.016) and PM10 (OR = 1.33, p < 0.001). With PM2.5, larger OR with smaller p-values were generally obtained within the subgroups of men, age 50 to 75 years old and cases with diabetes. The findings show a significant link between short-term exposure to particulate matter and OHCA during non-holiday periods, with susceptible subgroups to PM2.5 (men, age 50 to 75 years old and diabetics).

Immunotargeting of extracellular tau could slow the prion-like spreading of neurodegeneration. Albert et al. report that antibodies that recognize a central epitope on tau are the most effective at blocking both seeding and propagation of tau pathological species in transgenic mouse models seeded by materials derived from Alzheimer’s disease brains., Tauopathies are neurodegenerative diseases characterized by the intraneuronal accumulation of aggregated tau. The staging of this neurodegenerative process is well established for Alzheimer’s disease as well as for other tauopathies. The stereotypical pattern of tau pathology in these diseases is consistent with the hypothesis that the tau protein can spread in a ‘prion-like’ manner. It proposes that extracellular pathological tau species can transmit pathology from cell to cell. Accordingly, by targeting these spreading species with therapeutic antibodies one should be able to slow or halt the progression of tau pathology. To be effective, antibodies should neutralize the pathological species present in Alzheimer’s disease brains and block their cell-to-cell spread. To evaluate both aspects, tau antibody D, which recognizes an epitope in the central region of tau, and was selected for its outstanding ability to block tau seeding in cell based assays, was used in this study. Here, we addressed two fundamental questions: (i) can this anti-tau antibody neutralize the pathological species present in Alzheimer’s disease brains; and (ii) can it block the cell-to-cell spread of tau seeds in vivo? First, antibody D effectively prevented the induction of tau pathology in the brains of transgenic mice that had been injected with human Alzheimer’s disease brain extracts, showing that it could effectively neutralize the pathological species present in these extracts. Second, by using K18 P301L tau fibrils to induce pathology, we further demonstrated that antibody D was also capable of blocking the progression of tau pathology to distal brain regions. In contrast, an amino-terminal tau antibody, which was less effective at blocking tau seeding in vitro showed less efficacy in reducing Alzheimer’s disease patient tau driven pathology in the transgenic mouse model. We did not address whether the same is true for a spectrum of other amino-terminal antibodies that were tested in vitro. These data highlight important differences between tau antibodies and, when taken together with other recently published data, suggest that epitope may be important for function.

e24074 Background: Admission of cancer pts in ICU is a medical and ethical challenge, since there is no reliable prognostic tool for guiding decision making. Therefore, recent progress in cancer management improved the OS of advanced cancer pts, rendering this issue more and more frequent. Methods: We have retrospectively analyzed the medical charts of 129 consecutive pts treated in our institution and admitted in ICU from 01/2014 and 04/2019. We identified PF using Cox Models. We analyzed PF for OS or for ability to restart systemic treatment. Results: At the time of ICU admission, the mean age was 58.9 (range, 25-81). The were 51% of men. PS were 0-1 in 61% and 2-3 in 39%. The most prevalent cancers were lung (20%), sarcoma (17%), breast (16%) and gynecological cancers (11%). The number of metastatic sites was 1 (17%), 2 (39%), 3 (26%) and more (19%). The malignancy was stable in 69% and progressive in 31%. Pts currently received systemic treatment in 78%, were free of treatment in 5% and were not yet treated in 16%. Cancer itself (53%), toxicity of treatment (43%) and underlying comorbidities (37%) contributed to ICU admission. The number of organ failures was 0 in 12%, 1 in 40%, 2 in 26% and 3 or more in 22%. The 4 most symptoms were dyspnea (34%), severe infection (25%), cardiac event (23%) and bleeding (10%). Pt management required vasoamines administration (38%), ventilation (31%) and dialysis (4%). The median duration of stay in ICU was 4 days (range, 0-71). 21 (16%) pts died in ICU and 16 (12%) just after ICU discharge. 83 pts returned to home (64%). Systemic treatment was done in 61% of pts who left hospitalization alive after ICU. 1-month, 6-month and 12-month OS were 67, 36 and 21%, respectively. Multivariate analysis identified the following PF for OS: PS = 0 (HR = 0.57 [0.38-0.79]; p = .007), admission related to underlying comorbidity (HR = 0.63 [0.41-0.98], p = .0001) or admission related to treatment toxicity (HR = 0.31 [0.17-0.56] p = .0001). Multivariate identified 1 PF for ability to restart systemic treatment: one or less organ failure (HR = 0.34 [0.14-0.83], p = 0.02). Conclusions: In ICU, OS of adult pts with solid tumors looks like the non-cancer population. ¼ of admitted pts died in ICU or just after. Key PF were PS and cause of critical state. When ICU admission is related to cancer itself, the prognosis was poor.

Krabbe disease is a fatal rare inherited lipid storage disorder affecting 1:100,000 births. This illness is caused by mutations in the galc gene encoding for the enzyme galactosylceramidase (GALC). Dysfunction of GALC has been linked to the toxic build-up of the galactolipid, galactosylsphingosine (psychosine), which induces cell death of oligodendrocytes. Previous studies show that phospholipase A2 (PLA2) may play a role in psychosine induce cell death. Here, we demonstrate that non-selective inhibition of cPLA2/sPLA2 and selective inhibition of cPLA2, but not sPLA2, also attenuates psychosine-induced cell death of human astrocytes. This study shows that extracellular calcium is required for psychosine induced cell death, but intracellular calcium release, reactive oxygen species or release of soluble factors are not involved. These findings suggest a cell autonomous effect, at least in human astrocytes. Supporting a role for PLA2 in psychosine-induced cell death of oligodendrocytes and astrocytes, the results show inhibition of PLA2 attenuates psychosine-induced decrease in the expression of astrocyte marker vimentin as well as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and the neuronal marker SMI-32 in organotypic slice cultures. These findings provide further mechanistic details of psychosine-induced death of glia and suggest a role for PLA2 in the process. This work also supports the proposal that novel drugs for Krabbe disease may require testing on astrocytes as well as oligodendrocytes for more holistic prediction of pre-clinical and clinical efficacy.

Alors que le Venezuela est confronte a une severe crise de balance des paiements suite a la chute du prix du petrole, il apparait essentiel de comprendre les origines de cette situation. Cet article etudie tout d’abord les distorsions et les desequilibres economiques majeurs sous-jacents a cette economie, dont l’hyperinflation, pour ensuite evaluer la capacite du pays a faire face au risque de defaut de paiement. Nous construisons pour cela deux scenarios de besoin et capacite de financement, fortement dependants du prix du petrole et du soutien de la Chine. Ainsi nous montrons que, en l’absence d’un rebond tres important du prix du petrole, le defaut de paiement apparait inevitable. Enfin nous analysons la montee des tensions sociales et politiques qui accompagnent ce contexte economique degrade.Classification JEL : E31, F31, H63, O54, Q32.

After three decades of rapid growth, the Chinese economy has been slowing; at the same time, concerns about the sustainability of its growth model are mounting, calling for urgent rebalancing. This paper provides an assessment of how, and to what extent, the rebalancing process may impact China’s potential growth in the next fifteen years. After reviewing the main reasons behind China’s high growth and imbalances (and the role of factor price distortions), as well as its rising vulnerabilities (overinvestment, excessive credit growth, and a real estate bubble), we adopt a production function approach to derive potential growth. However we depart from the standard methodology in two important ways: first, we correct China’s capital stock for overinvestment by taking into account the credit cycle; second, we disentangle the effects of sectoral reallocations from within-sector productivity, allowing for a better assessment of the expected shift from manufacturing to services. Our results indicate that growth would be currently slightly higher than its potential, with a positive output gap, thus questioning the rationale for additional stimulus measures. Moreover, in our scenario potential growth would fall more quickly than currently expected by the Consensus, to around 5 percent by 2020

The intracellular organization of dinoflagellate protists, particularly the cytoskeleton, the cell cycle and mitosis (“dinomitosis”), presents peculiar features governed by specific proteins. We have previously biochemically isolated and characterized a protein of 72 kDa (P72) conserved from dinoflagellates to humans. The microsequencing of the NH2-terminal sequence and the reaction with a monoclonal antibody suggested that this protein belongs to the HSP70 chaperone family (Perret et al. 1991, 1995). Using a polyclonal antibody raised against P72, we have immunolocalized this protein using standard fluorescence microscopy on cryosections, confocal laser scanning microscopy on whole mounted cells and transmission electron microscopy after fast-freeze preparation with or without high pressure during freezing. We have localized P72 in specific dense aggregates at the cortical and centrosome level, in the cytoplasmic channels passing through the nucleus during mitosis and in the cleavage furrow. We completed this study by double labelling with anti-P72/anti-β-tubulin to analyse relationships between P72 and the cytoskeleton and to discuss the possible function of P72.

Lean management principles have been used extensively in manufacturing for decades and are increasingly being utilized in healthcare settings over the last 10 years. Lean principles, developed as part of the Toyota Management System, their simultaneous focus on waste reduction and customer satisfaction are vital for healthcare to reach its potential. Lean begins with mapping process flow and then applying lean tools and techniques to optimize the current state, including waste removal, inventory optimization through kanban (signal) systems and standard work. The translation of this manufacturing philosophy to healthcare involves the use of huddles in order to optimize situational awareness and develop clinical standard pathways to ensure that patients with similar pathophysiological abnormalities are treated in a similar fashion.

We examined the association between intimate partner violence and unmet need for modern contraception in post-conflict Liberia. This is a secondary analysis of data collected using the Priorities for Local AIDS Control Efforts (PLACE) method. Data from 499 sexually experienced young women (aged 14-25) in Montserrado County, Liberia were examined. Intimate partner violence (55.7%), unintended pregnancy (83.2%), and abortion (45.3%) were pervasive in the study population. An estimated 35.9% of respondents had an unmet need for modern contraception. However, multivariate logistic regression results did not reveal an association between intimate partner violence and unmet need (OR 1.11; 95% CI 0.70-1.75). Among covariates examined, only contraceptive use at sexual debut (26.1%) was significantly associated with unmet need (OR 0.27; 95% CI 0.14-0.52). Liberian youth need information about and access to modern contraceptive methods besides condoms. Interventions to identify and treat victims of violence are also needed.

Summary In Dinoflagellate protists, the centrosome is localized close to the nucleus and surrounded by a complex Golgi apparatus as shown in the two phylogenetically distant species, Prorocentrum micans and Crypthecodinium cohnii . Dinoflagellate centrosomes have been identified previously by using anti-β-tubulin antibody and CTR 210, an antibody raised against human cell centrosomes. Cryofixation and cryofracture techniques enabled us to describe the ultrastructure of these centrosome regions which are devoid of classical centriolar structures. We also describe centrosome associated proteins in dinoflagellates and their behaviour during the cell cycle: p80, a nuclear and cytoplasmic protein recently characterized, myosin II antigens and γ-tubulin. We review also the previously described dinoflagellate centrosome associated proteins: β-tubulin, CTR 210 antigens, p72 (HSP 70), α-actin and p56cdc13, a homologue of Schizosaccharomyces pombe cyclin B. The functions of these proteins and their interactions in the centrosome of dinoflagellates are discussed.

Objective. To compare the risk of complications following Bacillus Calmette-Guérin(BCG) vaccination among children by maternal and infant HIV-1 infection status as part of an investigation of an outbreak of BCG complications. Methods. A nonconcurrent cohort study of BCG complications among 125 infants born to HIV-1 seropositive and 166 infants born to HIV-1 seronegative mothers was conducted in Cité Soleil, Haiti. Infants were examined at regular intervals until 15 months of age, and complications from BCG were documented. An investigation of BCG vaccination practices was conducted. Results. Mild or moderate complications occurred among 16 of 166 (9.6%) infants born to HIV-1 seronegative mothers compared with 4 of 13 HIV-1-infected infants (30.8%, P = .04) and 10 of 75 (13.3%, P = .39) uninfected infants born to HIV-1-infected mothers. No serious complications were noted. The outbreak of complications was associated with administration of 2.0 to 2.5 times the recommended dose of BCG vaccine. Conclusions. This and five other cohort studies indicate that there may be a small increased risk of complications following BCG vaccination among HIV-1-infected children, but the reactions are usually mild and the risk does not outweigh the benefits of BCG vaccination in populations at high risk of tuberculosis during infancy and childhood.

Despite their early emergence in evolution, the protist dinoflagellates present similarities in cell cycle regulation with higher eukaryotes and yeasts. Using antibody directed against the p56edc13 of the fission yeast, we present evidence for the presence of a cyclin B homolog in the dinoflagellate Crypthecodinium cohnii. Biochemistry, immunofluorescence and electron microscopy show the continuous presence of the cyclin B homolog during the C cohnii cell cycle progression. Cyclin B, which appears to be exclusively cytoplasmic, is associated with a specific H1 kinase activity more active in M phase.

A mathematical model of glycolysis in bloodstream form Trypanosoma brucei was developed previously on the basis of all available enzyme kinetic data (Bakker, B. M., Michels, P. A. M., Opperdoes, F. R., and Westerhoff, H. V. (1997) J. Biol Chem. 272, 3207-3215). The model predicted correctly the fluxes and cellular metabolite concentrations as measured in non-growing trypanosomes and the major contribution to the flux control exerted by the plasma membrane glucose transporter. Surprisingly, a large overcapacity was predicted for hexokinase (HXK), phosphofructokinase (PFK), and pyruvate kinase (PYK). Here, we present our further analysis of the control of glycolytic flux in bloodstream form T. brucei. First, the model was optimized and extended with recent information about the kinetics of enzymes and their activities as measured in lysates of ire vitro cultured growing trypanosomes. Second, the concentrations of five glycolytic enzymes (HXK, PFK, phosphoglycerate mutase, enolase, and PYK) in trypanosomes were changed by RNA interference. The effects of the knockdown of these enzymes on the growth, activities, and levels of various enzymes and glycolytic flux were studied and compared with model predictions. Data thus obtained support the conclusion from the in silica analysis that HXK, PFK, and PYK are in excess, albeit less than predicted. Interestingly, depletion of PFK and enolase had an effect on the activity (but not, or to a lesser extent, expression) of some other glycolytic enzymes. Enzymes located both in the glycosomes (the peroxisome-like organelles harboring the first seven enzymes of the glycolytic pathway of trypanosomes) and in the cytosol were affected. These data suggest the existence of novel regulatory mechanisms operating in trypanosome glycolysis.

The eucaryote cell cycle is driven by a set of cyclin dependent kinases (CDKs) associated to cyclins, which confer not only the activity but also the substrate specificity and the proper localization of the kinase activity. In the fission yeast Schizosaccharomyces pombe, only one cyclin, the product of the cdc13 gene (p56cdc13), is required to be associated with p34cdc2, to control the complete cell cycle. Earlier studies have localized this complex mainly in the nucleus and its periphery. Using new improved electron microscopy (EM) technologies, based on high pressure freezing fixation, we refined previous studies, evidencing cytoplasmic localization of p56cdc13, in addition to the nuclear localization previously observed. Further immunofluorescence studies, performed on aldehydically fixed cells, confirmed our EM results, emphasizing the major cytoplasmic localization of p56cdc13 in interphase cells and the relocalization towards the nucleus in mitotic cells, suggesting that the S pombe cyclin B localization is cell cycle-regulated.

The maze test is a complex cognitive task involving visuoperceptual, planning and foresight abilities. EEGs were recorded from 20 healthy subjects according to the 10/20 system. Coherence is analogous to a correlation coefficient between the signals recorded by two electrodes and is computed between each electrode paired to all other electrodes. The maze test provoked changes of coherence mainly within the prefrontal regions, between parietal and central electrodes paired with frontal electrodes, especially the right frontopolar and the left prefrontal electrodes, and in the posterior temporal, parietal and occipital regions. EEG coherence analysis detects changes in regions known to be involved in visual processing and executive functions.

The complete microtubular system of the dinoflagellate Crypthecodinium cohnii Biecheler is described, as seen by confocal laser scanning fluorescence microscopy and labelling with anti-beta-tubulin antibody. This technique allowed us to observe the organization of the subcortical and internal cytoskeletons and the mitotic microtubular system, and their changes during the cell cycle. These observations are compared with those made in cryosections by light microscopy and in fast-freeze-fixed, cryosubstituted cells by electron microscopy. We show the organization of the cortical microtubules, and in particular of the thick microtubular bundles arranged as a three-pronged fork from which they seem to emanate. This fork emerges from a peculiar cytoplasmic zone at the pole of the cell and is in contact with the region of the kinetosomes, at the cingulum. During the G1 phase, only a single, radial microtubular bundle (a “desmose”) is observable in the inner part of the cytoplasm. One of its ends is near the flagellar bases and the other end is close to the nucleus in the centrosome region. During the S phase, the flagella drop off, the cell encysts and the kinetosomes duplicate. In mitosis, the cortical microtubules and the intracytoplasmic microtubular bundles do not depolymerize. The microtubular fork, desmose and centrosome double and migrate, while the divided kinetosomes stay in the same place. Later, the centrosomes organize the extranuclear spindle, which is connected to the kinetosome region by the microtubular desmose. The convergent end of the three-pronged fork seems to be in contact with the centrosome region. In early and mid-prophase, thick microtubular bundles pass through the nucleus in cytoplasmic channels and converge towards the two poles. Asters were never seen at the spindle poles. The channels and microtubular bundles in the spindle double in number during late prophase and lengthen in early anaphase. The spindle bundles diverge in late anaphase, extend to very near the plasma membrane and depolymerize during telophase. The cleavage furrow in which tubulin and actin are characterized appears in anaphase, formed by invagination of plasma membrane in the kinetosome region. The structure and rearrangements of the Crypthecodinium cohnii microtubular system are compared with those of other dinoflagellates and protists and of higher eukaryotes.

In order to determine if a mitotic spindle organizing center is present in dinoflagellate cells, we used a library of 12 monoclonal antibodies obtained by immunizing mice with isolated human centrosomes. When tested by immunofluorescence on cryosections of the dinoflaggelate Crypthecodinium cohnii B., a positive labeling was obtained with three of these antibodies. In interphase cells, the anti-centrosome antibodies labeled structures located either in the cell periphery, corresponding probably to both basal bodies (i.e. kinetosomes) and in the perinuclear area. In the latter case, two punctate structures were observed near the nuclear envelope. They have never been described, either in light, or in electron microscopic studies of dinoflagellates. We have designated them as centrosome-like structures. A microtubular desmose reacting positively with anti-tubulin Ab was also visible, linking kinetosomes and centrosome-like structures. During mitosis, the double punctate structures were observed at the poles of the nucleus. Double immunolabeling with tubulin and anti-centrosome Ab was also carried out and strongly suggested that in mitotic cells, centrosome-like structures, located at the poles of the mitotic spindle, were associated with microtubular bundles and probably organize and polarize them. These data indicate the existence of centrosome-like structures in C. cohnii cells and the strong conservation of some centrosomal epitopes from dinoflagellates to human. One of the antibodies (CTR 210) recognized by immunoblotting, a single protein band at 72 kDa from a total protein extract. The direct demonstration that this protein is located at the centrosome-like structures and at the kinetosomes deserves further study.

1. 1. Steady-state plasma level samples of sixty-five schizophrenic patients from two psychiatric hospitals assigned to three treatment groups (amitriptyline 150 mg/day, perphenazine 20 mg/day and a combination of amitriptyline and perphenmazine at 150 mg and 20 mg/day) were assayed for amitriptyline (AT), endogenous nortriptyline (NT) and perphenazine (PPZ) using gas-liquid chromatography. 2. 2. Results reveal that AT and NT levels are independent of sex and hospital environment. 3. 3. PPZ significantly increased the steady-state NT plasma levels, probably through inhibition of the hydroxylation biotransformation pathway, but had no effect on AT levels, thus indicating that PPZ has no influence on the desmethylation pathway, or alternatively, the hydroxylation of AT.

Twenty-two hospitalized schizophrenic patients, participating in a large-scale phase II double-blind dose-effect study (30, 60, and 120 mg weekly) of penfluridol, a new diphenylbutylpiperidine neuroleptic, were maintained on a regular dosage regimen for 13 wk. Several blood samples were taken during the last dosage interval. Results show that the peak concentration develops within 12 hr after the last dose. A rapid decline, probably due to tissue re-equilibration, then occurs and is followed by a much slower falloff. Detectable concentrations 168 hr after administration are consistent with the long duration of action of penfluridol. Statistically significant differences between doses were found in the analysis of variance of plasma concentrations at all sampling times and in mean steady-state plasm concentrations. Wide differences in plasma concentrations were noted in patients receiving the same absolute dose, but a good relationship was defined between mean steady-state concentration and the dose expressed as mg per either kg of body weight or square meter of body surface area.

A comparative study of fluphénazine enanthate, a long-acting neuroleptic, fluphénazine bichlorhydrate and placebo was made on 28 chronic schizophrenics. The double-blind technique was possible by giving to the patients one of the three following treatments: the long-acting neuroleptic by injection every fortnight and placebo tablets daily, the standard neuroleptic (tablets) daily and regular injection of sesame oil or the two inactive substances in a similar way. Dosage of fluphénazine enanthate was 25, 50 or 75 mg every fortnight and of bichlorhydrate 10, 20 or 30 mg. daily after a fixed schedule. Antipsychotic action of the drugs was evaluated according to three types of measures: 1) IMPS; 2) NOSIE and 3) need for chlorpromazine given p.r.n. (indirect measure). Results of this study indicate that both fluphénazine salts are superior to placebo and possess significant antipsychotic properties as demonstrated by the indirect measure. No significant difference was found between enanthate and bichlorhydrate of fluphénazine. Some methodological aspects of psychopharmacological research are also discussed.

The Technical Committee 7 of the European Workshop on Industrial Computer Systems (EWICS TC7) is very active in the field of Programmed Electronic Systems safety and reliability. It has been supported by the Commission of the European Communities to develop standards in this domain. A set of Position Papers was produced between 1981 and 1985. These have been used as references for some international standards. EWICS TC7 is currently working under a contract with the Commission to develop a set of documents dealing with metrics, design for safety, and reliability and safety assessment. It is also proposing a set of related projects under the EUREKA framework.

Behavioral pharmacology has generally focused upon one aspect of drug action, the unconditioned effect. This usually describes the influence of administered substanced upon either physiological (e.g., heart rate, temperature), behavioral (e.g., latency, discrimination ability), or psychological (e. g., mood, personality) measures (Efron, 1968). It is possible, however, to examine other drug properties. For example, the ability of compounds to function as reinforcers has been demonstrated in studies in which organisms will emit specified behaviors to obtain drugs (Schuster and Thompson, 1969; Brecher, 1972). In addition, there is now widespread evidence derived from the animal laboratory that ingested substances can act as stimulus events (Thompson and Pickens, 1971) controlling behavior in the