Safety and tolerance of combination of monoamine oxidase inhibitors and direct dopamine agonists in adults and older adults with highly resistant depression.

INTRODUCTION: Dopamine (DA) is likely to be involved in some depressive dimensions, such as anhedonia and amotivation, which account for a part of treatment-resistant forms. Monoamine oxidase inhibitors (MAOI) and direct D2 and D3 receptors agonists (D2/3r-dAG) are known to help, but we lack safety data about their combined usage. We report on safety and tolerance of the MAOI+D2r-dAG combination in a clinical series. METHOD: All patients referred to our recourse center for depression between 2013 and 2021 were screened to select those who did receive the combo. Data were extracted from clinical files. RESULTS: Sixteen patients of 60±17 years of age (8 women, 7 with age>65years, all suffered from treatment resistant depression, 7 with bipolar disorder) received the combo. There were no life-threatening adverse effects (AE). However, AE were reported by 14 patients (88%) most of which were mild and consisted of insomnia, nausea, nervousness, confusion, impulse control disorder and/or "sleep attacks". One patient presented a serious AE requiring a short hospitalization for confusion. Intolerance led to failure to introduce treatment in two patients (13%). The retrospective non-interventional design, the variety of molecules, and the modest sample size limited the scope of these results. CONCLUSION: There was no life-threatening safety issue in combining MAOI and D2/3r-dAG, especially regarding cardiovascular side effects. The systematic screening of AE might account for their frequency, but these precluded the treatment in only two patients. Comparative studies are needed to assess the efficacy of this new combination.

Olfaction evaluation and correlation with brain atrophy in Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a well-recognized ciliopathy characterized by cardinal features namely: early onset retinitis pigmentosa, polydactyly, obesity, hypogonadism, renal and cognitive impairment. Recently, disorders of olfaction (anosmia, hyposmia) have been also described in BBS patients. Moreover, morphological brain anomalies have been reported and prompt for further investigations to determine whether they are primary or secondary to peripheral organ involvement (i.e. visual or olfactory neuronal tissue). The objective of this article is to evaluate olfactory disorders in BBS patients and to investigate putative correlation with morphological cerebral anomalies. To this end, 20 BBS patients were recruited and evaluated for olfaction using the University of Pennsylvania Smell Identification Test (UPSIT). All of them underwent a structural magnetic resonance imaging (MRI) scan. We first investigated brain morphological differences between BBS subjects and 14 healthy volunteers. Then, we showed objective olfaction disorders in BBS patients and highlight correlation between gray matter volume reduction and olfaction dysfunction in several brain areas.

FibroScan used in street-based outreach for drug users is useful for hepatitis C virus screening and management: a prospective study.

Although hepatitis C virus (HCV) infection prevalence is high among drug users, they do not commonly receive regular care in academic centres. The aim of this prospective study was to assess the influence of FibroScan use on HCV screening and management in street-based outreach. From January 2006 to January 2007, all consecutive drug users were offered noninvasive evaluation of liver fibrosis with FibroScan. After FibroScan, parameters were recorded with a structured, face-to-face questionnaire by outreach workers. All 298 subjects accepted FibroScan evaluation drug use was--ever injected heroin (69%), ever snorted or injected cocaine (89%), current chronic alcohol abuse (44%). The median FibroScan score was 5.3 kPa. Before blood sampling, 34% of subjects reported HCV positivity. HCV positivity was found in 83 cases. All these subjects had positive HCV-RNA. Forty-five subjects agreed to meet a hepatologist. By multivariate analysis, never snorted cocaine, consumed alcohol < 21 drinks per week, duration of injected heroin > 7 years, and FibroScan > 7.1 kPa were significantly associated with HCV positivity. Thus in a street-based outreach service for drug users, the acceptance of FibroScan is excellent. FibroScan with a hospital-based physician may facilitate screening and management of drug users for HCV infection.

Changes of non-invasive markers and FibroScan values during HCV treatment.

The recent advent of non-invasive methods for assessment of fibrosis allows serial assessments in all patients with hepatitis C. The aim of this prospective study was to evaluate changes in liver fibrosis, as measured with non-invasive methods, in a large cohort of HCV-infected patients with and without treatment. From May 2003 through March 2006, all previously untreated HCV-infected patients were enrolled in this study. Liver fibrosis was staged with FibroScan and Fibrotest at inclusion, then every year in untreated patients, and at the end of treatment and 6 months later in treated patients. The study population consisted of 416 patients, of whom 112 started treatment after enrolment. In the treatment group, FibroScan and Fibrotest values were significantly higher before and after treatment than in untreated patients at baseline and after 1 year. However, there was no significant difference between treated and untreated patients at the end of follow-up. FibroScan and Fibrotest values fell in all treated patients, whatever their virological response. In multivariate analysis, treatment was the only factor independently associated with a fall in the FibroScan value. In conclusion, whatever the virological response, treatment for HCV infection is associated with an improvement of FibroScan and Fibrotest values. Further studies are needed to compare these non-invasive methods with liver biopsy. These non-invasive methods, and especially FibroScan, should be useful for assessing treatment efficacy in clinical trials of new drugs.

Liver fibrosis in patients with chronic hepatitis C and persistently normal liver enzymes: influence of HIV infection.

Liver fibrosis progress slowly in patients with chronic hepatitis C and persistently normal alanine aminotransferase (PNALT) compared to subjects with elevated aminotransferases. Differences in liver fibrosis according to human immunodeficiency virus (HIV) status in this population have not been examined. All patients with serum hepatitis C virus (HCV)-RNA and PNALT who underwent liver fibrosis assessment using elastometry since 2004 at three different European hospitals were evaluated. Patients previously treated with interferon were excluded. PNALT was defined as ALT below the upper limit of normality in at least three consecutive determinations within the last 12 months. Fibrosis stage was defined as mild (Metavir F0-F1) if stiffness < or =7.1 kPa; moderate (F2) if 7.2-9.4 kPa; severe (F3) if 9.5-14 kPa, and cirrhosis (F4) if >14 kPa. A total of 449 HIV-negative and 133 HIV-positive patients were evaluated. HIV-negative patients were older (mean age 51.8 vs 43.5 years) and more frequently females (63%vs 37%) than the HIV counterparts. Mean serum HCV-RNA was similar in both the groups (5.9 vs 5.8 log IU/mL). Overall, 78.8% of the HIV patients were on HAART and their mean CD4 count was 525 (+/-278) cells/microL. In HIV-negatives, liver fibrosis was mild in 84.6%; moderate in 8.7%, severe in 3.3% and cirrhosis was found in 3.3%. In HIV patients, these figures were 70.7%, 18.8%, 6%, and 4.5%, respectively. In the multivariate logistic regression analysis, older age (odds ratio or OR: 1.04; 95% confidence interval or CI: 1.02-1.07; P < 0.001) and being HIV+ (OR: 2.6; 95% CI: 1.21-5.85; P < 0.01) were associated with severe liver fibrosis or cirrhosis (F3-F4). Thus, severe liver fibrosis and cirrhosis are seen in 6.6% of the HCV-monoinfected and in 10.5% of HCV-HIV co-infected patients with PNALT. Some degree of liver fibrosis that justifies treatment is seen in 15% of the HCV-monoinfected but doubles to nearly 30% in HIV-HCV co-infected patients with PNALT.

Non-invasive evaluation of liver fibrosis by transient elastography and biochemical markers in elderly inpatients.

AIM: The objective of this study was to evaluate liver fibrosis using non-invasive methods in elderly patients. METHODS: In a prospective two-day study, all consecutive patients of geriatric units were examined using transient elastography (FibroScan) and biochemical markers (Hepascore, Aspartate Transaminase (AST) to platelet ratio index [APRI], Forns score, FibroTest). Three groups of patients were included: elderly patients without liver disease (group A, 85.2+/-7.3 years); healthy younger control subjects without liver fibrosis (group B, 46.4+/-15.2 years); and elderly patients with confirmed liver disease (group C, 82.4+/-2.3 years). RESULTS: FibroScan) results in the elderly patients correlated well with fibrosis surrogates, but were more difficult to obtain than in the younger subjects. Mean liver stiffness was 6.1 kPa (group A) versus 4.9 kPa (group B) and versus 10.2 kPa (group C) (P<0.0001). FibroTest results were 0.5 in group A versus 0.2 in group B, and versus 0.6 in group C (P<0.0001). In group A, statistical analysis showed that diabetes was associated with advanced liver fibrosis (FibroScan) > or = 9.5 kPa). A body mass index greater than 26kg/m2, age greater than 85 years, comorbidity score and polymedication were not associated with fibrosis. CONCLUSION: Although liver stiffness may be more difficult to assess in the elderly, FibroScan may nevertheless serve as a new, non-invasive method for detecting liver fibrosis in this population.

[Eradication of hepatitis C virus after a 5-week treatment]. / Eradication du virus de l'hépatite C après un traitement de cinq semaines.

The standard regimen for the treatment of chronic hepatitis C virus (HCV) is peginterferon alpha-2a or -2b associated with ribavirine. The recommended duration of treatment for genotype 2 HCV infection is 24 weeks. However, the relatively poor drug tolerance often leads to a reduction or a discontinuation of the treatment. Here, we report two female patients who discontinued antiviral therapy after less than 6 weeks for intolerance and who experienced a sustained virological response. A treatment of 3 to 5 weeks may be enough for genotype 2 HCV eradication. However, there is not sufficient evidence in 2009 to recommend a reduced treatment duration.

Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy.

The recent availability of non-invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)-coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV-monoinfected and 287 (30.4%) HIV/HCV-coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/muL and 88% were under HAART (mean time, 4.2 +/- 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients (P < 0.005). A good correlation was found between FibroScan) and biochemical indexes [AST to platelet ratio index (r = 0.405, P < 0.0001), FIB-4 (r = 0.393, P < 0.0001) and Forns (r = 0.407, P < 0.0001)], regardless of the HIV status. In the multivariate analysis, age >45 years, body mass index (BMI) >25 kg/m(2), and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV-coinfected patients have more advanced liver fibrosis than HCV-monoinfected patients despite the immunologic benefit of HAART.

Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: a prospective study.

BACKGROUND: The role of hepatic iron overload in the development of hepatic fibrosis in patients with hemochromatosis is well-established. Transient elastography (FibroScan) is a new noninvasive, rapid, reproducible bedside method, allowing assessment of liver fibrosis by measuring liver rigidity. OBJECTIVES: The aim of this prospective study was to evaluate liver fibrosis with FibroScan and other noninvasive biochemical methods in patients with hemochromatosis (C282Y homozygosity) compared with control patients. PATIENTS AND METHODS: From January 2004 through October 2006, all consecutive patients with hemochromatosis were evaluated for liver fibrosis using noninvasive methods (FibroScan and biochemical markers). These patients were compared with patients who had chronic cytolysis and no fibrosis on liver biopsy. RESULTS: One hundred and three consecutive patients (57 cases and 46 controls) were fully investigated. Median FibroScan values were similar in both groups, 5.20 kPa versus 4.9 kPa, respectively. No differences were observed between cases and controls for all biochemical markers. A strong correlation was observed between FibroScan and many biochemical markers, although ferritin levels did not correlate with FibroScan values. The prevalence of patients with FibroScan values greater than 7.1 kPa (cut-off level for significant fibrosis) was 22.8% in patients with hemochromatosis and 0% in the controls (P<0.0001). CONCLUSION: FibroScan and biochemical markers could be reliable noninvasive methods for detecting liver fibrosis in patients with hemochromatosis. Such patients have high FibroScan values more often than do control patients. Further longitudinal and prospective studies are necessary to confirm these preliminary data.

[Illicit drugs, medications and traffic accidents]. / Drogues, médicaments et accidentologie.

The European Union (EU) has 25 member-states and 455 million inhabitants. Statistics on traffic accidents in the EU show that more than 45,000 people are killed annually, including 5200 in France. At the same time, nearly two million persons in the EU require medical treatment for traffic-accident-related injuries, including 109,000 in France. In addition, traffic accidents are the major cause of death of those individuals aged 15 to 24 years. One third of the EU inhabitants will be hospitalized during their life due to a traffic accident with a cost over 160 billion euro (2-3% of the Gross Domestic Product). An important contributing factor to crashes is the use of alcohol and/or illicit drugs or medication when driving, as they exert negative effects on cognition and psychomotor functions. For illicit drugs, abuse of cannabis with or without alcohol is a major concern for the EU. In fact, three million Europeans use cannabis daily and 80% of them drive after use. A number of French studies since 1999 have underlined the high prevalence of cannabis found in the blood of injured or killed drivers. From medical or judicial observations, it is clear that cannabis use increases the risk of traffic accidents. Many groups outside Europe have also shown the association between drug abuse and crashes. The number of casualties related to certain medicines, especially benzodiazepines remains at a high level, particularly in the elderly. In many countries the prevalence of medicinal drugs associated with car accidents is higher than with cannabis. Annex III of the European Union Council Directive of July the 29th 1991 in fact states that a driving license should not be issued to or renewed for applicants or drivers who are dependent on psychotropic substances or use them regularly. Recently, France has categorized the medicinal drugs available in the country by using three pictograms: level one yellow, "be careful"; level two orange, "be very careful"; level three red, "don't drive". It is an important campaign that increases awareness among the public and the medical professionals about the potential dangerous effects of medicinal drugs when driving. The EU objective of reducing the number of fatalities to 25,000 by 2010 will require strengthening measures against the use of alcohol, illicit and medicinal drugs by not well-informed drivers. It is not only a really great challenge, but also a significant investment towards improving public health in France as well as in Europe.

Low time resolution in schizophrenia Lengthened windows of simultaneity for visual, auditory and bimodal stimuli.

The guarantee of perceptual coherence for events through everyday life situations depends upon the capacity to correctly integrate series of multi-sensory experiences. Patients with schizophrenia have been shown to reveal a deficit in integrating, i.e., "binding", perceptual information together. However, results in the literature have also suggested the reverse effect. Indeed, in certain paradigms patients have revealed more binding phenomenon than healthy controls and reported experiencing two distinct events as occurring "together". This finding suggests that patients may require longer time intervals between two distinct events before being able to perceive them as "one-after-the-other". The question here was to test whether this perceptual binding abnormality in schizophrenia is confined to events within the same modality or whether it is also present across sensory modalities. Thirty patients with schizophrenia were compared with 33 normal controls using a simultaneity judgement paradigm. There were two uni-modal conditions in which stimuli were presented in the same modality (visual or auditory) and one bimodal condition (audio-visual). Participants were presented with stimuli varying across a range of inter-stimulus intervals (ISI). They were required to judge whether they experienced two stimuli as occurring "together" or "one-after-the-other". Compared to controls and in all conditions, patients needed larger ISI to experience two stimuli as "one-after-the-other" (all ISI x Group interactions p<5 x 10(-5)). These abnormalities correlated with the disorganization dimension but not with the dosage of chlorpromazine equivalent. The increase of the time interval needed to perceive two stimuli as "one-after-the-other", reflect an abnormally low time resolution in patients with schizophrenia. We discuss the possible involvement of anatomical disconnectivity in schizophrenia which would specifically affect the time integration properties of neural assemblies.

Optimisation of a post-processing method to remove the pulse artifact from EEG data recorded during fMRI: an application to P300 recordings during e-fMRI.

In functional cerebral studies, it has been established that co-registered electroencephalography (EEG) measurements and functional magnetic resonance imaging (fMRI) were complementary. However, EEG data recorded inside an MRI scanner are heavily distorted, mainly by the most prominent artifact, the cardiac pulse artifact (PA). We describe an original algorithm which yields a high-quality PA filter and demonstrates how this tool can be used to improve the quality of P300 ERP measurements during event-related fMRI (e-fMRI) experiments. EEG data were acquired in interleaved mode during e-fMRI while six healthy volunteers performed a visual odd-ball task, involving Distractors, Target and Novel stimuli, to elicit P300 components. The PA was corrected with the original algorithm. The temporal variations in the PA were evidenced using a principal component analysis (PCA), on each EEG channel. The procedure yielded several PA templates, which were regressed from the EEG data. The PA removal procedure was optimised, and then implemented to improve the measured P300 components. Regressing the most adequate PA template resulted in a high-quality reduction in spectral power at frequencies associated with the cardiac PA. More reliable P300 component measurements were obtained, evidencing higher amplitudes for Novels (9.76-11.20 microV) than for to Targets (6.3-9.09 microV) in centro-parietal and prefrontal areas. The improvement of the processing of EEG data acquired simultaneously with fMRI data provides a new tool and casts perspectives to study the functional organisation of the brain.

[What is needed for rTMS to become a treatment?]. / Que manque-t-il à la rTMS pour devenir une thérapie?

Repetitive trans-cranial magnetic stimulation (rTMS) can modulate cortical excitability. Consequently, it appears appealing for the treatment of some affections such as depression or hallucinations. There is already some proof that the concept is valid, but rTMS is slow in progressing in the therapeutic field as a true armamentum. Indeed its effects are of short duration and even inconstant from one patient to the next. These drawbacks depend on certain factors that we will discuss. Until now, there has been inadequate control of the stimulation site. It is possible that this site could vary on an individual basis. It seems logical to propose the use of functional imaging for such a purpose, but its use should be adapted to the symptom. Even after localizing the site, the coil has to be placed accurately. This could be facilitated by a neuronavigator. Stimulation protocols are currently defined by three parameters: the frequency modulating the cortical action either as a stimulation (>5 Hz) or an inhibition (<1 Hz), the intensity and the number of stimuli influencing, notably, the amplitude and duration of the effect. Unfortunately, the effect is inconstant in a given patient and paradoxical reactions have been observed in more than 15% of normal individuals. Improved reliability and amplification of the effect rely on the better control of other parameters: pattern of stimulation, pre and post-conditioning, state of the cortex during stimulation, associated medications, endogenous idiosyncratic factors and related pathology. We will review the current physiological literature to discuss the possible options that would constitute a rational basis for setting up more efficient protocols.

Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate.

BACKGROUND: Methotrexate is an effective treatment in Crohn's disease, which may induce liver fibrosis with high cumulative doses. Transient elastography (FibroScan, Echosens, Paris, France) is a new non-invasive rapid, allowing assessment of liver fibrosis by measurement of liver stiffness. AIM: A prospective study to evaluate liver fibrosis with FibroScan and non-invasive biochemical methods in Crohn's disease patients treated with methotrexate. METHODS: Consecutive Crohn's disease patients had evaluation of liver fibrosis with non-invasive methods. Two subgroups of patients were compared: cumulative dose of methotrexate of more than 1500 mg (group 1) and naive for methotrexate (group 2). Liver biopsy was performed in patients with persistent liver enzyme abnormalities or FibroScan value >8.7 kPa. RESULTS: Fifty-four consecutive Crohn's disease patients were fully investigated (45 females, mean age 41 +/- 14 years). Median FibroScan values were similar in group 1 (n = 21) and in group 2 (n = 33), 5.5 and 4.5 kPa, respectively. FibroScan values were not correlated with the cumulative dose of methotrexate. CONCLUSION: In Crohn's disease patients treated with a high dose of methotrexate, significant liver fibrosis is rare and not accurately detected with liver enzymes abnormalities. FibroScan could be recommended and liver biopsy could be performed only with patients with high values and/or with chronic liver enzymes abnormalities.

[Impact of a new parasitologic laboratory for malaria diagnosis on diagnosis and cost of malaria in a company setting: experience from Angola]. / Impact de la création d'un laboratoire de diagnostic parasitologique du paludisme sur le diagnostic et le cout du paludisme dans une entreprise: une expérience Angolaise.

In malaria endemic areas treating every fever episode as a malaria onset would result in overdiagnosis with a margin of the error varying in function of epidemiological factors. When further compounded by overestimation related to errors in parasitologic diagnosis, clinical misdiagnosis leads to unwarranted hospitalization and inappropriate treatment. In a company setting this would mean unnecessary loss of employee work time. False positive diagnosis causes overestimation of chemoresistance, overconsumption of antimalarial drugs and underestimation of other infectious diseases. Judging from these high costs, it can be assumed that improving the reliability of parasitologic diagnosis would have a positive impact on the quality of clinical management, efficiency of antimalarial use and accuracy of epidemiological surveys. This assumption was confirmed by analysis of data following start-up of a parasitologic laboratory for malaria diagnosis in the health care clinic at Sonamet's fabrication yard in Lobito, Angola. Laboratory personnel receives expert training and audit findings demonstrate consistently reliable diagnosis. This experience underscores the need for reliable parasitologic diagnosis as a prerequisite for any large-scale malaria control program.

Sexual quality of life is impaired in patients with chronic hepatitis C.

Chronic hepatitis C (CHC) patients often have altered quality of life. Few data are available about sexual impairment (SI) in CHC. From 2011 to 2013, we included consecutive CHC outpatients. Exclusion criteria were: antiviral therapy, co-infection, age <18 or >75, transplantation, alcohol consumption, Eastern Cooperative Oncology Group >1. Non-CHC subjects were healthy blood donors. Sexual questionnaires for men and women were adapted from the International Index of Erectile Function and Female Sexual Function Index, respectively, and concerned the past 30 days. Two hundred eighty-one patients were compared with 1086 blood donors. SI was more frequent in CHC patients. Men with CHC had worse desire, confidence, erections, climax and satisfaction (P<0.001). Women with CHC had worse desire, arousal, climax, satisfaction, lubrication and comfort (P<0.001). In multivariate analysis, factors associated with SI in men were CHC (odds ratio (OR)=4.45, 95% confidence interval (CI) 2.46-8.06), age (OR=1.06, 95% CI 1.03-1.09), no intercourse (OR=8.74, 95% CI 4.65-16.04) and unemployment (OR=2.14, 95% CI 1.16-3.95). Factors associated with a worse global sexual life in women were CHC (OR=7.96, 95% CI 4.07-15.58) and no intercourse (OR=21.39, 95% CI 11.03-41.48). The study results were corroborated by propensity score-matching analysis. Sexual life is impaired in men and women with CHC. In clinical practice, sexual quality of life should be evaluated and treated.

P300 recordings during event-related fMRI: a feasibility study.

Analysis of combined event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) can provide a high temporal and high spatial resolution to study functional cerebral processes. However, EEG data recorded inside an MR scanner is heavily distorted by artifacts. It is important in cognitive studies to ensure that recorded data reflect the same brain activity, and this is achieved through interleaved electroencephalographic (EEG) and fMRI measurements. Here, we demonstrate the feasibility of recording P300 ERPs during fMRI using a three-stimulus visual oddball task and involving a small number of trials for each stimulus. Ten EEG channels were acquired interleaved with fMRI images in five healthy subjects. The stimuli, including rare targets "X," frequent repetitive distractors "O," and rare distractors referred to as novels, were randomly presented every 2 +/- 1 s. The post hoc filter presented here was designed and applied to EEG data to remove the cardiac pulse artifact. Interleaved EEG/fMRI acquisition evidenced two P300 ERPs evoked at Fz, Cz, and Pz by targets and novels. Novel-related ERPs were of higher amplitude than their target-related counterparts. The fMRI maps acquired concurrently showed stronger BOLD response for target condition. We have shown that interleaved acquisition allows to obtain reliable P300 data and fMRI results, likely to shed light on the anatomical location of brain regions involved in cognitive ERPs relevant to many disorders affecting CNS functions. These noninvasive multimodal neuroimaging techniques can be used to explore and better understand processes underlying the functional brain organization.

Neural correlates of implicit object identification.

The present study sought to assess neural correlates of implicit identification of objects by means of fMRI, using tasks that require matching of the physical properties of objects. Behavioural data suggests that there is automatic access to object identity when observers attend to a physical property of the form of an object (e.g. the object's orientation) and no evidence for semantic processing when subjects attend to colour. We evaluated whether, in addition to neural areas associated with decisions to specific perceptual properties, areas associated with access to semantic information were activated when tasks demanded processing of the global configuration of pictures. We used two perceptual matching tasks based on the global orientation or on the colour of line drawings. Our results confirmed behavioural data. Activations in the inferior occipital cortex, fusiform and inferior temporal gyri in both tasks (orientation and colour) account for perceptual and structural processing involved in each task. In contrast, activations in the posterior and medial parts of the fusiform gyrus, shown to be involved in explicit semantic judgements, were more pronounced in the orientation-matching task, suggesting that semantic information from the pictures is processed in an implicit way even when not required by the task. Thus, this study suggests that cortical regions usually involved in explicit semantic processing are also activated when implicit processing of objects occurs.

In vivo and in vitro studies on sex steroid binding protein (SBP) regulation in rainbow trout (Oncorhynchus mykiss): influence of sex steroid hormones and of factors linked to growth and metabolism.

The respective roles of sex steroids and hormones related to growth and metabolism, on SBP regulation have been studied in rainbow trout. In vivo, oestradiol (E2) supplementation induces a slow but significant increase of plasma SBP concentration. Testosterone or cortisol injections have no effect. In vitro, the steroid binding protein that accumulates in incubation medium of hepatic cell primary cultures has been characterized and found to be similar to blood SBP. Its production is increased by addition of E2 (maximum: +300%). This effect develops slowly over several days of culture and is dose dependent; as little as 1-10 nM E2 is effective. Recombinant rainbow trout GH (rtGH)--0.01 to 1 microgram/ml--also increases SBP accumulation as compared to control cells and seems to maintain SBP production over culture duration. In preliminary experiments, (1) insulin-like growth factor (IGF) and SBP concentrations were found to change inversely after a 4 days stimulation with increasing concentrations of GH; (2) recombinant human IGF1 (250 ng/ml) tended to be inhibitory when SBP production was expressed per mg of total cellular protein, and a micromolar concentration of bovine insulin was clearly inhibitory. Other hormones tested in vitro: triiodothyronine (10-1000 nM), thyroxine (100 nM), 17 alpha, 20 beta-dihydroprogesterone (10-2000 nM), and testosterone (1-1000 nM) did not influence SBP concentration in hepatic cells culture media.

Vitellogenin synthesis in cultured hepatocytes; an in vitro test for the estrogenic potency of chemicals.

We describe here an in vitro technique to assess the estrogenic activity of chemicals. This technique is based on rainbow trout hepatocytes incubated in a basic medium free of any additional growth factors or estrogenic chemicals and uses the production of vitellogenin (VTG) as a marker for the estrogenic potency of the compounds tested. The system allows at least some of the metabolic transformations which are undertaken by the liver cells in vivo and could therefore be used for xenobiotic compounds which exhibit estrogenic activities after liver metabolic transformation. A dose-response curve was always consistently obtained using estradiol-17 beta (E2), with a mid point at around 100 nM E2 and a maximum response at around 1000 nM. Established estrogens such as 17 a 1 ethynylestradiol (EE2) or diethylstilboestrol (DES) were also tested. EE2 appeared to be equipotent with E2 and DES slightly less potent. E2 conjugates were, perhaps surprisingly, also very potent. Estradiol-3-sulfate was equipotent with E2 and estradiol-17 beta-glucuronide approx. 10% as potent. Other steroids such as androgens and progesterone, though active in the bioassay, were 3 orders of magnitude less potent than E2. Of the various steroids tested, only cortisol, at concentrations up to 50 microM, was completely inactive. Six different phytoestrogens were tested in the assay. All were weakly estrogenic, possessing approximately one thousandth the potency of E2 (they were as potent as the androgens and progesterone). All six phytoestrogens, as well as the androgens and progesterone, were tested in the presence of tamoxifen. In all cases tamoxifen reduced the production of VTG significantly, demonstrating that the estrogenic action of all of these compounds was most likely mediated by the E2 receptor. The potencies determined here may not reflect the situation in vivo but can provide complementary results about the activity of chemicals which need an hepatic metabolization to be estrogenic. Hepatocyte cultures would profitably be developed in other species to sustain these results.