Everolimus induced mood changes in breast cancer patients: a case-control study.

Introduction The PI3K/Akt/mTOR pathway plays a critical role in cancer cell growth, proliferation and angiogenesis, but also in brain homeostasis and the pathophysiology of mood disorders. The impact of the mTOR inhibitor everolimus on the mood of breast cancer patients is unknown. Materials and methods Consecutive, post-menopausal metastatic breast cancer patients receiving hormone therapy +/- everolimus were prospectively followed-up using the Beck Depression Inventory (BDI) and the MADRS (Montgomery and Asberg Depression Rating Scale) questionnaires. Results Post hoc tests comparing everolimus + hormonotherapy to hormonotherapy alone demonstrated a significant effect of everolimus after 6 weeks of treatment on BDI scores (t(1,38) = -2.0716, p < 0.05), and after 3 weeks (t(1,38) = -3.9165, p < 0.001) and 6 weeks of treatment (t(1,38) = -2.0373, p < 0.05) on MADRS scores. Analysis within each treatment group showed that the effect of time since treatment initiation on BDI and MADRS scores was specifically observed in the everolimus + hormonotherapy group (F(2,34) = 11.875, p < 0.001 and F(2,34) = 7.820, p < 0.01 respectively), but not in the hormonotherapy alone group (F(2,34) = 1.671, p > 0.2 and F(2,34) = 0.830, p > 0.2 respectively). Conclusions The mTOR inhibitor everolimus induces significant mood alterations in breast cancer patients. The evaluation of psychiatric symptoms is not only mandatory in the context of phase 1, dose-finding studies of PI3K/Akt/mTOR inhibitors, but is also clinically relevant in daily practice.

Enhanced habit formation in Gilles de la Tourette syndrome.

Tics are sometimes described as voluntary movements performed in an automatic or habitual way. Here, we addressed the question of balance between goal-directed and habitual behavioural control in Gilles de la Tourette syndrome and formally tested the hypothesis of enhanced habit formation in these patients. To this aim, we administered a three-stage instrumental learning paradigm to 17 unmedicated and 17 antipsychotic-medicated patients with Gilles de la Tourette syndrome and matched controls. In the first stage of the task, participants learned stimulus-response-outcome associations. The subsequent outcome devaluation and 'slip-of-action' tests allowed evaluation of the participants' capacity to flexibly adjust their behaviour to changes in action outcome value. In this task, unmedicated patients relied predominantly on habitual, outcome-insensitive behavioural control. Moreover, in these patients, the engagement in habitual responses correlated with more severe tics. Medicated patients performed at an intermediate level between unmedicated patients and controls. Using diffusion tensor imaging on a subset of patients, we also addressed whether the engagement in habitual responding was related to structural connectivity within cortico-striatal networks. We showed that engagement in habitual behaviour in patients with Gilles de la Tourette syndrome correlated with greater structural connectivity within the right motor cortico-striatal network. In unmedicated patients, stronger structural connectivity of the supplementary motor cortex with the sensorimotor putamen predicted more severe tics. Overall, our results indicate enhanced habit formation in unmedicated patients with Gilles de la Tourette syndrome. Aberrant reinforcement signals to the sensorimotor striatum may be fundamental for the formation of stimulus-response associations and may contribute to the habitual behaviour and tics of this syndrome.

Determination of chitin content in fungal cell wall: an alternative flow cytometric method.

The conventional methods used to evaluate chitin content in fungi, such as biochemical assessment of glucosamine release after acid hydrolysis or epifluorescence microscopy, are low throughput, laborious, time-consuming, and cannot evaluate a large number of cells. We developed a flow cytometric assay, efficient, and fast, based on Calcofluor White staining to measure chitin content in yeast cells. A staining index was defined, its value was directly related to chitin amount and taking into consideration the different levels of autofluorecence. Twenty-two Candida spp. and four Cryptococcus neoformans clinical isolates with distinct susceptibility profiles to caspofungin were evaluated. Candida albicans clinical isolate SC5314, and isogenic strains with deletions in chitin synthase 3 (chs3Δ/chs3Δ) and genes encoding predicted GlycosylPhosphatidylInositol (GPI)-anchored proteins (pga31Δ/Δ and pga62Δ/Δ), were used as controls. As expected, the wild-type strain displayed a significant higher chitin content (P < 0.001) than chs3Δ/chs3Δ and pga31Δ/Δ especially in the presence of caspofungin. Ca. parapsilosis, Ca. tropicalis, and Ca. albicans showed higher cell wall chitin content. Although no relationship between chitin content and antifungal drug susceptibility phenotype was found, an association was established between the paradoxical growth effect in the presence of high caspofungin concentrations and the chitin content. This novel flow cytometry protocol revealed to be a simple and reliable assay to estimate cell wall chitin content of fungi.

Premature commitment to uncertain decisions during human NMDA receptor hypofunction.

Making accurate decisions based on unreliable sensory evidence requires cognitive inference. Dysfunction of n-methyl-d-aspartate (NMDA) receptors impairs the integration of noisy input in theoretical models of neural circuits, but whether and how this synaptic alteration impairs human inference and confidence during uncertain decisions remains unknown. Here we use placebo-controlled infusions of ketamine to characterize the causal effect of human NMDA receptor hypofunction on cognitive inference and its neural correlates. At the behavioral level, ketamine triggers inference errors and elevated decision uncertainty. At the neural level, ketamine is associated with imbalanced coding of evidence and premature response preparation in electroencephalographic (EEG) activity. Through computational modeling of inference and confidence, we propose that this specific pattern of behavioral and neural impairments reflects an early commitment to inaccurate decisions, which aims at resolving the abnormal uncertainty generated by NMDA receptor hypofunction.

Work-related psychosocial risk factors and psychiatric disorders: A cross-sectional study in the French working population.

PURPOSE: The study estimates the prevalence of probable psychiatric disorder in the working population, determines the proportion of people presenting a probable psychiatric disorder among people exposed to work-related psychosocial risk factors (PSRFs), and identifies which PSRF has the strongest association with having a probable psychiatric disorder. METHODS: A cross-sectional study conducted in March 2018 involved a representative sample of the French working population. The General Health Questionnaire 28 (GHQ-28) was used to estimate the prevalence of probable psychiatric disorder and 44 items were gathered from theoretical models of PSRFs. We used multiple logistic regression to estimate the association of each PSRF with having a probable psychiatric disorder, adjusted on individual, health, and job confounders. RESULTS: This study involved 3200 French participants. The proportion of probable psychiatric disorder was 22.2% [20.6; 24.0]. Ten PSRFs were significantly associated with it. The strongest association was for having problems handling professional and personal responsibilities (reported by 15% of the study population) (OR = 1.97 [1.52; 2.54]), with 45% pathological GHQ-28 scores (potential psychiatric cases) for people exposed to this PSRF versus 18% non-exposed. The next strongest association was lack of support of colleagues (reported by 28%) (OR = 1.63 [1.29; 2.06]). The third strongest association was feeling sometimes afraid when doing the job (reported by 63%) (OR = 1.53, [1.21; 1.93]). CONCLUSIONS: Our study identified 10 PSRFs associated with psychiatric disorder, with substantial exposure rate among the population. The results of our research could help develop recommendations to improve work environment.

Unconscious memory suppression.

Recent evidence suggests that high-level executive control can occur unconsciously. In this study, we tested whether unconscious executive control extends to memory retrieval and forgetting. In a first experiment, participants learned word-word associations and were trained to either actively recall or forget theses associations in response to conscious visual cues (Think/No-Think paradigm). Then, the very same cues were subliminally presented while participants were performing a grammatical gender categorization task on distinct word pairs. Memory retrieval tested a few minutes later was significantly influenced by conscious and masked cues, suggesting that memory recall could be manipulated unbeknownst to the participants. In a second experiment, we replicated these findings and added a baseline condition in which some words were not preceded by masked cues. Memory recall was significantly reduced both when words were preceded by an unconscious instruction to forget compared to the baseline condition (i.e. no cue), and to the unconscious instructions to recall. Overall, our results suggest that executive control can occur unconsciously and suppress a specific memory outside of one's awareness.

Specific effect of a dopamine partial agonist on counterfactual learning: evidence from Gilles de la Tourette syndrome.

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Previously, we showed that aripiprazole may protect motivational function by preserving reinforcement-related signals used to sustain reward-maximization. However, the effect of aripiprazole on more cognitive facets of human reinforcement learning, such as learning from the forgone outcomes of alternative courses of action (i.e., counterfactual learning), is unknown. To test the influence of aripiprazole on counterfactual learning, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette (GTS) patients, one consisting of patients who were completely unmedicated and the other consisting of patients who were receiving aripiprazole monotherapy, and to healthy subjects. We found that whereas learning performance improved in the presence of counterfactual feedback in both healthy controls and unmedicated GTS patients, this was not the case in aripiprazole-medicated GTS patients. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication.

Illusion of agency in patients with Gilles de la Tourette Syndrome.

The sense of agency refers to the conscious experience of authorship and control over actions. The voluntary or involuntary nature of tics, which are the hallmark of Gilles de la Tourette Syndrome (GTS), is unclear. Here, we studied metacognitive processing of agency in an explicit agency task on non-medicated and medicated GTS patients compared to matched controls. In this task, the participants made judgements of control and performance after completion of a computerized game where they had to catch targets with a cursor by moving the computer mouse. The task included several conditions, where the objective control over the cursor could be normal, disrupted or artificially enhanced. We show that GTS patients, independently of medication status, based their judgments of agency predominantly on the matching between their intention and the outcome, i.e., had an illusion of agency in the task condition where their performance was artificially enhanced. Nevertheless, they recognized not to be fully in control in conditions of disrupted control. The propensity to illusions of agency was negatively correlated with global disease severity. Our findings suggest alterations of metacognition of agency in GTS patients. This illusion of agency could reflect a compensatory mechanism related to tic control, but is more likely to be related to deviant brain maturation in GTS.

Anxiety, depression and school absenteeism in youth with chronic or episodic headache.

BACKGROUND: Chronic daily headache (CDH) in children has been documented in general and clinical populations. Comorbid psychological conditions, risk factors and functional outcomes of CDH in children are not well understood. OBJECTIVES: To examine anxiety and depression, associated risk factors and school outcomes in a clinical population of youth with CDH compared with youth with episodic headache (EH). METHODS: Data regarding headache characteristics, anxiety, depression and missed school days were collected from 368 consecutive patients eight to 17 years of age, who presented with primary headache at a specialized pediatric headache centre. RESULTS: A total of 297 patients (81%) were diagnosed with EH and 71 were diagnosed with CDH. Among those with CDH, 78.9% presented with chronic tension-type headache and 21.1% with chronic migraine (CM). Children with CDH had a higher depression score than the standardized reference population. No difference was observed for anxiety or depression scores between children with CDH and those with EH. However, children with CM were more anxious and more depressed than those with chronic tension-type headache. Youth experiencing migraine with aura were three times as likely to have clinically significant anxiety scores. Headache frequency and history were not associated with psychopathological symptoms. Children with CDH missed school more often and for longer periods of time. CONCLUSIONS: These findings document the prevalence of anxiety, depression and school absenteeism in youth with CDH or EH. The present research also extends recent studies examining the impact of aura on psychiatric comorbidity and the debate on CM criteria.

Reading impairment in schizophrenia: dysconnectivity within the visual system.

Patients with schizophrenia suffer from perceptual visual deficits. It remains unclear whether those deficits result from an isolated impairment of a localized brain process or from a more diffuse long-range dysconnectivity within the visual system. We aimed to explore, with a reading paradigm, the functioning of both ventral and dorsal visual pathways and their interaction in schizophrenia. Patients with schizophrenia and control subjects were studied using event-related functional MRI (fMRI) while reading words that were progressively degraded through word rotation or letter spacing. Reading intact or minimally degraded single words involves mainly the ventral visual pathway. Conversely, reading in non-optimal conditions involves both the ventral and the dorsal pathway. The reading paradigm thus allowed us to study the functioning of both pathways and their interaction. Behaviourally, patients with schizophrenia were selectively impaired at reading highly degraded words. While fMRI activation level was not different between patients and controls, functional connectivity between the ventral and dorsal visual pathways increased with word degradation in control subjects, but not in patients. Moreover, there was a negative correlation between the patients' behavioural sensitivity to stimulus degradation and dorso-ventral connectivity. This study suggests that perceptual visual deficits in schizophrenia could be related to dysconnectivity between dorsal and ventral visual pathways.

In vivo and in vitro effects of RAD001 on bladder cancer.

OBJECTIVE: To evaluate the influence of Everolimus (RAD001) on chemically induced urothelial lesions in mice and its influence on in vitro human bladder cancer cell lines. METHODS: ICR male mice were given N-butyl-N-(4-hydroxybutyl) nitrosamine in drinking water for a period of 12 weeks. Subsequently, RAD001 was administered via oral gavage, for 6 weeks. At the end of the experiment, all the animals were sacrificed and tumor development was determined by means of histopathologic evaluation; mammalian target of rapamycin (mTOR) expressivity was evaluated by immunohistochemistry. Three human bladder cancer cell lines (T24, HT1376, and 5637) were treated using a range of RAD001 concentrations. MTT assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cytometry were used to assess cell proliferation, apoptosis index, and cell cycle analysis, respectively. Immunoblotting analysis of 3 cell line extracts using mTOR and Akt antibodies was performed in order to study the expression of Akt and mTOR proteins and their phosphorylated forms. RESULTS: The incidence of urothelial lesions in animals treated with RAD001 was similar to those animals not treated. RAD001 did not block T24 and HT1376 cell proliferation or induce apoptosis. A reduction in cell proliferation rate and therefore G0/G1 phase arrest, as well as a statistically significant induction of apoptosis (P = 0.001), was only observed in the 5637 cell line. CONCLUSION: RAD001 seems not to have a significant effect on chemically induced murine bladder tumors. The effect of RAD001 on tumor proliferation and apoptosis was achieved only in superficial derived bladder cancer cell line, no effect was observed in invasive cell lines.

Novel method using a laser scanning cytometer for detection of mycobacteria in clinical samples.

In order to evaluate the capacity of laser scanning cytometry (LSC) to detect acid-fast bacilli directly on clinical samples, a comparison between Kinyoun-stained smears analyzed under light microscopy and propidium iodide-auramine-stained smears analyzed by LSC was performed. The results were compared with those for culture on BACTEC MGIT 960. LSC is a new, reliable methodology to detect MYCOBACTERIA: