Prostate-specific antigen bounce in patients treated before 60 years old by iodine 125 brachytherapy for prostate cancer is frequent and not a prognostic factor.

PURPOSE: The only prognostic factor of prostate-specific antigen (PSA) bounce in prostate cancer found in several studies is young age but has never been specifically studied in this subset of patients for long-term results. Bounce characteristics, histological, clinical, and dosimetric data in young patients were analyzed, as well as their impact on toxicity and survival. MATERIAL AND METHODS: This retrospective study included patients aged ≤60 years treated with exclusive iodine 125 brachytherapy with low or intermediary prostate adenocarcinoma during 1999-2014. Exclusion criteria were a follow-up of ≤24 months. PSA bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. RESULTS: This study analyzed 179 patients. Median age was 56 years (46-59 years). The median follow-up was 79 months (54; 123). The bounce incidence was 56.8% (49.6%; 64.2%) at 5 years, inversely proportional to positive/total biopsies ratio (HR 0.98, 95% CI [0.97, 0.99]). Incidence of biochemical failure was 1.2%, 95% CI (0.3%; 4.7%), at 5 years with no difference between the bounce and no-bounce group (HR 0.96, 95% CI [0.25; 3.58]). Bounce is an unfavorable prognostic factor for grade two and three urinary toxicities 6.67 (4.14; 10.76) (p < 0.001). CONCLUSIONS: PSA bounce is common in young people after brachytherapy. It should be monitored without starting an inadequate and sometimes invasive relapse checkup or a relapse treatment.

[Evaluation of the French practices in brachytherapy using surveys]. / Évaluation par questionnaire des pratiques de la curiethérapie de prostate en France.

INTRODUCTION: Prostate cancer brachytherapy can be used as an alternative to the radical prostatectomy and radiotherapy. In the low-risk group, specific survivals are up to 95% after 10years. The aim of the study is to describe the practices in brachytherapy in France. MATERIALS AND METHODS: A survey made by AFU (French Urologic Association) and SFRO (French Society Of Oncological Radiotherapy) assessing the practices in brachytherapy in France was sent to all the urologists and radiotherapists even if they did not practice it. RESULTS: In total, 1417 surveys were sent, 285 were received coming from 211 urologists (74%) and 74 radiotherapists (26%). Sixty (21%) practiced brachytherapy (31 urologists, 29 radiotherapists). Low dose rate with permanent implants was used in 83,3%. Brachytherapy was advised for low-risk group by 90% who responded the survey, 73% used it in intermediate risk and only 13% in high risk. CONCLUSION: Brachytherapy is hardly used in low risk prostate cancer. It probably needs a reconsideration of recommendations due to the good results in association with a good picking. The urologist-radiotherapist couple is essential in the overall care of the patient. LEVEL OF EVIDENCE: 4.

Notch1 endocytosis is induced by ligand and is required for signal transduction.

The Notch signalling pathway is widely utilised during embryogenesis in situations where cell-cell interactions are important for cell fate specification and differentiation. DSL ligand endocytosis into the ligand-expressing cell is an important aspect of Notch signalling because it is thought to supply the force needed to separate the Notch heterodimer to initiate signal transduction. A functional role for receptor endocytosis during Notch signal transduction is more controversial. Here we have used live-cell imaging to examine trafficking of the Notch1 receptor in response to ligand binding. Contact with cells expressing ligands induced internalisation and intracellular trafficking of Notch1. Notch1 endocytosis was accompanied by transendocytosis of ligand into the Notch1-expressing signal-receiving cell. Ligand caused Notch1 endocytosis into SARA-positive endosomes in a manner dependent on clathrin and dynamin function. Moreover, inhibition of endocytosis in the receptor-expressing cell impaired ligand-induced Notch1 signalling. Our findings resolve conflicting observations from mammalian and Drosophila studies by demonstrating that ligand-dependent activation of Notch1 signalling requires receptor endocytosis. Endocytosis of Notch1 may provide a force on the ligand:receptor complex that is important for potent signal transduction.

Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress.

Traumatic stress in early-life increases the risk for cognitive and neuropsychiatric disorders later in life. Such early stress can also impact the progeny even if not directly exposed, likely through epigenetic mechanisms. Here, we report in mice that the offspring of males subjected to postnatal traumatic stress have decreased gene expression in molecular pathways necessary for neuronal signaling, and altered synaptic plasticity when adult. Long-term potentiation is abolished and long-term depression is enhanced in the hippocampus, and these defects are associated with impaired long-term memory in both the exposed fathers and their offspring. The brain-specific gamma isoform of protein kinase C (Prkcc) is one of the affected signaling components in the hippocampus. Its expression is reduced in the offspring, and DNA methylation at its promoter is altered both in the hippocampus of the offspring and the sperm of fathers. These results suggest that postnatal traumatic stress in males can affect brain plasticity and cognitive functions in the adult progeny, possibly through epigenetic alterations in the male germline.

High-frequency stimulation of the hippocampus blocks fear learning sensitization and return of extinguished fear.

Patients with post-traumatic stress disorder (PTSD) present hippocampal (HPC) dysfunction, which may facilitate fear-related phenomena such as fear learning sensitization (i.e. potentiation of fear acquisition by initial fear conditioning (FC1)) and fear return (i.e. reactivation of extinguished fear). Fear return is sensitive to HPC high-frequency stimulation (HFS) in rats. The goal of the present study was to examine whether fear learning sensitization is also sensitive to HPC HFS in rats. We found in control conditions that, after FC1 (with 15 shock administrations) and extinction, conditioning in a different context with one shock administration was potentiated (proactive effect) and associated with fear return in the initial context (retroactive effect). Both phenomena were prevented by HPC HFS applied before the second conditioning. We also found that the effect of HPC HFS on fear learning sensitization required initial extinction. These findings suggest a pivotal role of the HPC in preventing proactive and retroactive effects of successive fear conditionings. These data also support the concept that HPC deactivation may be involved in fear learning sensitization and fear return in PTSD patients.

A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

[Diagnosis and management of adverse events occuring during BCG therapy for non-muscle invasive bladder cancer (NMIBC): review of the Cancer Committee of the French Association of Urology]. / Diagnostic et prise en charge des événements indésirables survenant au décours des instillations endovésicales de BCG pour le traitement des tumeurs de vessie n'infiltrant pas le muscle (TVNIM) : revue du comité de cancérologie de l'Association française d'urologie.

INTRODUCTION: Intravesical BCG immuno-therapy with maintenance therapy is considered as the standard treatment for non-muscle invasive bladder cancer with high risk of recurrence and progression. In practice, adverse events (AEs) of BCG therapy could restrict its prescription by urologists. The aim of this article was to present a review of these AEs and of their management. MATERIALS AND METHODS: A bibliographic research in French and English using Medline(®) and Embase(®) with the keywords "BCG", "bladder", "complication", "toxicity", "adverse reaction", "prevention" and "treatment" was performed. RESULTS: The main mechanism of AEs of BCG are infectious (cystitis, fever), immuno-allergic (granulomatous prostatitis, epididymo-orchitis, and granulomatous reactions) and auto-immune (arthralgies, rash). Management of AEs is based on their pathophysiological mechanisms. Classifications of BCG therapy AEs based on clinical features allow to adapt their treatments. CONCLUSION: The combination of antibiotics directed against BCG, steroid or non-steroidal anti-inflammatory medication and symptomatic treatment is currently the triad on which is set up the appropriate treatment of severe AEs. Reductions of BCG doses and ofloxacin medication after instillation decrease the frequency and severity of minor and moderate AEs. Severe or more than 7 days long infectious AEs, immuno-allergic AEs or auto-immune during more than 7 days impose cessation of BCG immuno-therapy.

[Metabolic impact of androgen deprivation therapy for prostate cancer]. / Impact métabolique de la suppression androgénique dans le cancer de la prostate.

Because of the low mortality rates associated with prostate cancer, treatments long-term adverse effects constitute an important parameter in the management of patients. In particular, androgen deprivation has been shown to be linked to several metabolic disorders which are already frequent in men after age 60, such as weight and fat gain, insulin resistance likely to evolve into diabetes, and dyslipidemia. So far no consensus guidelines have been published regarding the screening and treatment of metabolic disorders in men with prostate cancer. It is essential to detect and manage these metabolic disorders, all the more so as they seem to be associated with an increased aggressiveness of prostate cancer. Here we report the development of a new questionnaire, which might contribute to the systematic management, and potentially the screening and treatment or the prevention of these metabolic disorders in patients with prostate cancer. In accordance with recent reviews and on the basis of experience, our French board of experts also recommends systematic screening and selective treatment for diabetes, regular follow-up of fasting glucose rates, lipid profile and blood pressure in all patients under long-term androgen deprivation treatment, as well as lifestyle changes (practice of exercise, nutritional habits).

[CAPURO survey on quality of life of urologists in 2009]. / Enquête CAPURO sur la qualité de vie des urologues en 2009.

BACKGROUND: The physician's well-being at work is more and more evaluated, but so far few studies have concerned the specialty of urology. The objective of this survey CAPURO was to explore the quality of the professional life of French urologists, to get their position about on going reforms and information about their extra professional activities. METHODS: The duration of this survey conducted in 2009 was one month with a questionnaire of 25 questions available at the AFU congress and on the Internet site www.cap-uro.com. RESULTS: Two hundred and ninety-six urologists have answered the questionnaire. More than two of three urologists declared being satisfied of their work, especially private urologists. The mean duration of weekly work was 57hours with much time spent for activities not directly related to the care of patients, but judged useful to develop quality of care and evaluation of practices. Ninety percent of urologists declared not to have an easy access to the new techniques and 60% of them were interested by clinical research, but most of them didn't have the necessary resources. They declared to be satisfied by the continuous medical training, but they affirmed lacking of help to get accreditation. Oncology, benign hyperplasias of prostate, lithiasis and endourology were the main urological specialities exercised by urologists. A majority of French urologists seemed to be very anxious about the future, mainly because of on going reforms. A few numbers of urologists had extra professional activities. CONCLUSION: In 2009, French urologists who participated in the survey CAPURO were mostly satisfied or very satisfied with their conditions of practice, but with some dissatisfaction justifying a real dialogue between health authorities and professionals.

[A survey from the French Urology Association about sick leave prescriptions by 145 surgeons]. / Enquête de l'Association française d'urologie sur les pratiques de prescriptions d'arrêt de travail auprès de 145 chirurgiens urologues.

OBJECTIVES: To describe and evaluate prescriptions of sick leave by urology surgeons for different kinds of interventions. METHODS: Between January and April 2006, a web-based survey was completed by urology surgeons on a voluntary basis. The analyzed data pertained to personal characteristics of the surgeons, mean duration of sick leave for 15 interventions and the type of job of the patient (strenuous or not). Analyses were performed with software SAS™ version 9.2. Descriptive analyses were performed and Kruskal-Wallis test was used to search for statistically significant differences between variables (p<0,05). RESULTS: One hundred and forty-eight surgeons were involved and 145 answers could be analyzed. Mean age of the surgeons was 46,3±9,4years. Urology surgeons were in the public sector (n=73/140; 52%), in private practice (n=43/140; 31%) or both (n=24/140; 17%). Kruskal-Wallis test showed that all patients who had a job considered as strenuous had significantly longer sick leave prescriptions. Younger surgeons (under 40) used to prescribe shorter sick leaves than their older counterparts. CONCLUSION: Sick leave prescriptions of the urology surgeons were globally homogeneous in this survey. Only a few interventions were the occasion of discordant prescriptions depending upon the age or practice (public/private) of the surgeons. Several hypotheses could be further explored as regard the source of variation in sick leave prescriptions. These results are usable for those stakeholders who are interested in continuous medical education and evaluation.

Dimorphic effects of leptin on the circadian and hypocretinergic systems of mice.

The hormone leptin controls food intake and body weight through its receptor in the hypothalamus, and may modulate physiological functions such as reproduction, sleep or circadian timing. In the present study, the effects of leptin on the resetting of the circadian clock, the hypothalamic suprachiasmatic nucleus (SCN) and on the activity of the hypocretinergic system were examined in vivo, with comparative analysis between male and female mice. A single leptin injection (5 mg/kg) at both the onset and offset of the activity period did not alter locomotion of mice housed under a 12 : 12 h light/dark cycle and did not shift the circadian behavioral rhythm of mice housed in constant darkness. By contrast, leptin potentiated the phase-shifting effect of a 30-min light-pulse on behavioural rhythms during the late subjective night, although only in females. This was accompanied by a higher induction of the clock genes Per1 and Per2 in the SCN. A 2-week chronic exposure to a physiological dose of leptin (100 µg/kg per day) decreased locomotor activity, expression of hypocretin receptor 1 and 2, as well as the number of hypocretin-immunoreactive neurones only in female mice, whereas the number of c-fos-positive hypocretinergic neurones was reduced in both genders. These results highlight a dimorphic effect of leptin on the hypocretinergic system and on the response of the circadian clock to light. Leptin may thus modulate the sleep/wake cycle and circadian system beside its well-established action on food intake and regulation of body weight.

Low-frequency stimulation of the hippocampus following fear extinction impairs both restoration of rapid eye movement sleep and retrieval of extinction memory.

Post-learning rapid eye movement (REM) sleep deprivation has often been shown to impair hippocampal functioning, which results in deficit in retrieval of some types of memory. However, it remains to be determined whether post-learning alteration of hippocampal functioning affects, in turn, REM sleep. Recent studies have shown that both post-extinction REM sleep deprivation and post-extinction application of hippocampal low-frequency stimulation (LFS) impair memory of fear extinction, indicating possible bidirectional interactions between hippocampal functioning and REM sleep. To analyze the potential effect of post-extinction alteration of hippocampal functioning on REM sleep, rats were implanted with stimulating electrodes in the dorsal hippocampus for post-extinction LFS. Sleep was recorded before (two sessions, 1 day apart) and after conditioning (five tone and eyelid-shock pairings), and following extinction training (25 tone-alone presentations) for 6 h per session. Fear conditioning reduced time spent in REM sleep, which was restored with fear extinction. Hippocampal LFS, applied immediately following extinction training, abolished the restorative effect of fear extinction on REM sleep and impaired extinction retrieval. These data extend previous findings and suggest bidirectional interactions between hippocampal functioning and REM sleep for successful extinction retrieval.

Novel CaF(2) nanocomposite with high strength and fluoride ion release.

Secondary caries and restoration fracture remain common problems in dentistry. This study tested the hypothesis that combining nano-CaF(2) and glass fillers would yield nanocomposites with high mechanical properties and F release. Novel CaF(2) nanoparticles (56-nm) were synthesized via spray-drying and incorporated into resin. F release increased with increasing the nano-CaF(2) content, or with decreasing pH (p < 0.05). F-release rates at 70-84 days were 1.13 microg/(cm(2) x day) and 0.50 microg/(cm(2) x day) for nanocomposites containing 30% and 20% nano-CaF(2), respectively. They matched the 0.65 microg/(cm(2) x day) of resin-modified glass ionomer (p > 0.1). The nanocomposites had flexural strengths of 70-120 MPa, after 84-day immersion at pH 4, pH 5.5, and pH 7. These strengths were nearly three-fold that of resin-modified glass ionomer, and matched/exceeded a composite with little F release. In summary, novel CaF(2) nanoparticles produced high F release at low filler levels, thereby making room in resin for reinforcement glass. This yielded nanocomposites with high F-release and stress-bearing properties, which may help reduce secondary caries and restoration fracture.

Strong nanocomposites with Ca, PO(4), and F release for caries inhibition.

This article reviews recent studies on: (1) the synthesis of novel calcium phosphate and calcium fluoride nanoparticles and their incorporation into dental resins to develop nanocomposites; (2) the effects of key microstructural parameters on Ca, PO(4), and F ion release from nanocomposites, including the effects of nanofiller volume fraction, particle size, and silanization; and (3) mechanical properties of nanocomposites, including water-aging effects, flexural strength, fracture toughness, and three-body wear. This article demonstrates that a major advantage of using the new nanoparticles is that high levels of Ca, PO(4), and F release can be achieved at low filler levels in the resin, because of the high surface areas of the nanoparticles. This leaves room in the resin for substantial reinforcement fillers. The combination of releasing nanofillers with stable and strong reinforcing fillers is promising to yield a nanocomposite with both stress-bearing and caries-inhibiting capabilities, a combination not yet available in current materials.

[Recommendations for the treatment of prostate cancer in the elderly man: A study by the oncology committee of the French association of urology]. / Recommandations pour la prise en charge du cancer de la prostate chez l'homme âgé : un travail du comité de cancérologie de l'association française d'urologie.

The increase in life expectancy combined with the increase in the global incidence of cancers will probably results in an increase in the number of cancers observed in the elderly. The increase in the incidence of prostate cancers in geriatric patients (45% of prostate cancers are diagnosed after 75 years old) is in sharp contrast with the lack of strong scientific data on the topic. By the meantime, oncogeriatrics has been developing for some years now under the guidance of the International Society of Oncogeriatrics. Such an approach aims at palliating the low quality of care of cancers in geriatric patients. The reasons for the low quality of care come from the characteristics of these patients and from the training of the care providers. The authors recall the principles of oncogeriatric evaluation and the classification of patients as it is actually proposed. They describe the main treatments and their results in the geriatric population and they describe the decision process concerning the choice of the treatment. They also suggest some guidelines on the diagnosis of prostate cancer, evaluation of the patients and the treatments of the disease in the elderly. Prostate cancer is almost the perfect model for oncogeriatrics. Urologists should remain the corner stone of its management, whatever the age of their patient.

Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor.

BACKGROUND AND PURPOSE: The OX(2) receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX(2) receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). EXPERIMENTAL APPROACH: The affinity of [(3)H]EMPA was assessed in membranes from HEK293-hOX(2)-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A- or orexin-B-induced accumulation of [(3)H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX(2) receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala(11),D-Leu(15)]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats. KEY RESULTS: [(3)H]EMPA bound to human and rat OX(2)-HEK293 membranes with K(D) values of 1.1 and 1.4 nmol x L(-1) respectively. EMPA competitively antagonized orexin-A- and orexin-B-evoked accumulation of [(3)H]IP at hOX(2) receptors with pA(2) values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [(3)H]EMPA for OX(2) receptors. EMPA significantly reversed [Ala(11),D-Leu(15)]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure. CONCLUSIONS AND IMPLICATIONS: EMPA is a high-affinity, reversible and selective OX(2) receptor antagonist, active in vivo, which should prove useful for analysis of OX(2) receptor function.

[PSA and follow-up after treatment of prostate cancer]. / PSA et suivi après traitement du cancer de la prostate.

A first serum total PSA assay is recommended during the first three months after treatment. When PSA is detectable, PSA assay should be repeated three months later to confirm this elevation and to estimate the PSA doubling time (PSADT). In the absence of residual cancer, PSA becomes undetectable by the first month after total prostatectomy: less than 0.1 ng/ml (or less than 0.07 ng/ml) for the ultrasensitive assay method and less than 0.2 ng/ml for the other methods. In the presence of residual cancer, PSA either does not become undetectable or increases after an initial undetectable period. A consensus has been reached to define recurrence as PSA greater than 0.2 ng/ml confirmed on two successive assays. After external beam radiotherapy, PSA can decrease after a mean interval of one to two years to a value less than 1 ng/ml (predictive of recurrence-free survival). Biochemical recurrence after radiotherapy is defined by an increase of PSA by 2 ng or more above the PSA nadir, whether or not it is associated with endocrine therapy. After endocrine therapy, the PSA nadir is correlated with recurrence-free survival. PSA is decreased for a mean of 18 to 24 months followed by a rise in PSA, corresponding to hormone-independence. The time to recurrence or the time to reach the nadir and the PSA doubling time after local therapy with surgery or radiotherapy have a diagnostic value in terms of the site of recurrence, local or metastatic and a prognostic value for survival and response to complementary radiotherapy or endocrine therapy. A PSADT less than eight to 12 months is correlated with a high risk of metastatic recurrence and 10-year mortality. The histological and biochemical characteristics in favour of local recurrence are Gleason score less or equal to seven (3+4), elevation of PSA after a period greater than 12 months and PSADT greater than 10 months. In other cases, recurrence is predominantly metastatic. The risk of demonstrating metastasis in the case of biochemical recurrence after total prostatectomy and before endocrine therapy depends on the PSA level and the PSADT. No consensus has been reached concerning the indication for complementary investigations by bone scan and abdominopelvic CT in patients with biochemical recurrence after treatment of localized cancer without endocrine therapy. However, when PSADT greater than six months, the risk of metastasis is less than 3% even for PSA greater than 30 ng/ml. When PSADT less than six months and PSA greater than 10 ng/ml, the risk of metastasis is close to 50%.

Effects of aripiprazole/OPC-14597 on motor activity, pharmacological models of psychosis, and brain activity in rats.

Aripiprazole (OPC-14597) is an antipsychotic with a unique pharmacology as a dopamine D2 receptor partial agonist, which has been demonstrated to reduce symptoms of schizophrenia. To further profile this compound in preclinical models, we examined aripiprazole-induced activity changes as measured by pharmacological magnetic resonance imaging (MRI) and characterized the drug in several rodent models of motor behaviors and of psychosis. Continuous arterial spin labeling MRI measuring blood perfusion (as an indirect measure of activity) reveals that aripiprazole dose-dependently decreased brain activity in the entorhinal piriform cortex, perirhinal cortex, nucleus accumbens shell, and basolateral amygdala. While no deficits were observed in the rotarod test for motor coordination in the simpler (8 RPM) version, in the more challenging condition (16 RPM) doses of 10 and 30mg/kg i.p. produced deficits. Catalepsy was seen only at the highest dose tested (30mg/kg i.p.) and only at the 3 and 6h time points, not at the 1h time point. In pharmacological models of psychosis, 1-30mg/kg aripiprazole i.p. effectively reduced locomotor activity induced by dopamine agonists (amphetamine and apomorphine), NMDA antagonists (MK-801 and phencyclidine (PCP)), and a serotonin agonist (2,5-dimethoxy-4-iodoamphetamine (DOI)). However, aripiprazole reversed prepulse inhibition deficits induced by amphetamine, but not by any of the other agents tested. Aripiprazole alters brain activity in regions relevant to schizophrenia, and furthermore, has a pharmacological profile that differs for the two psychosis models tested and does not match the typical or atypical psychotics. Thus, D2 partial agonists may constitute a new group of antipsychotics.

Challenging the model for induction of metallothionein gene expression.

Metallothioneins (MTs) are low-molecular-weight, cysteine-rich metal-binding proteins found in a wide variety of organisms including bacteria, fungi and all eukaryotic plant and animal species. MTs bind essential and non-essential heavy metals. In mammalian cells MT genes are highly inducible by many heavy metals including Zn, Cd, Hg, and Cu. Aquatic systems are contaminated by different pollutants, including metals, as a result of man's activities. Bivalve molluscs are known to accumulate high concentrations of heavy metals in their tissue and are widely used as bioindicators for pollution in marine and freshwater environments, with MTs frequently used as a valuable marker of metal contamination. We here describe the MT isoform gene expression patterns of marine and freshwater molluscs and fish species after Cd or Zn contamination. Contamination was carried out at a river site polluted by a zinc ore extraction plant or in the laboratory at low, environmentally relevant metal concentrations. A comparison for each species based on the accumulated MT protein levels often shows discrepancies between gene expression and protein level. In addition, several differences observed in the pattern of MT gene expression between mollusc and mammalian species enable us to discuss and challenge a model for the induction of MT gene expression.