Drug-induced cholestasis

Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug-induced cholestasis. This review summarizes their variable clinical presentations, examines the role of transport proteins in hepatic drug clearance and toxicity, and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management.     

Investigating synapse formation and function using human pluripotent stem cell-derived neurons

A major goal of stem-cell research is to identify conditions that reliably regulate their differentiation into specific cell types. This goal is particularly important for human stem cells if they are to be used for in vivo transplantation or as a platform for drug development. Here we describe the establishment of procedures to direct the differentiation of human embryonic stem cells and human induced pluripotent stem cells into forebrain neurons that are capable of forming synaptic connections. In addition, HEK293T cells expressing Neuroligin (NLGN) 3 and NLGN4, but not those containing autism-associated mutations, are able to induce presynaptic differentiation in human induced pluripotent stem cell-derived neurons. We show that a mutant NLGN4 containing an in-frame deletion is unable to localize correctly to the cell surface when overexpressed and fails to enhance synapse formation in human induced pluripotent stem cell-derived neurons. These findings establish human pluripotent stem cell-derived neurons as a viable model for the study of synaptic differentiation and function under normal and disorder-associated conditions.     

A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

Deregulation of apoptosis is a common occurrence in cancer, for which emerging oncology therapeutic agents designed to engage this pathway are undergoing clinical trials. With the aim of uncovering strategies to activate apoptosis in cancer cells, we used a pooled shRNA screen to interrogate death receptor signaling. This screening approach identified 16 genes that modulate the sensitivity to ligand induced apoptosis, with several genes exhibiting frequent overexpression and/or copy number gain in cancer. Interestingly, two of the top hits, EDD1 and GRHL2, are found 50 kb apart on chromosome 8q22, a region that is frequently amplified in many cancers. By using a series of silencing and overexpression studies, we show that EDD1 and GRHL2 suppress death-receptor expression, and that EDD1 expression is elevated in breast, pancreas, and lung cancer cell lines resistant to death receptor-mediated apoptosis. Supporting the relevance of EDD1 and GRHL2 as therapeutic candidates to engage apoptosis in cancer cells, silencing the expression of either gene sensitizes 8q22-amplified breast cancer cell lines to death receptor induced apoptosis. Our findings highlight a mechanism by which cancer cells may evade apoptosis, and therefore provide insight in the search for new targets and functional biomarkers for this pathway.     

Prognostic value of the Geneva prediction rule in patients in whom pulmonary embolism is ruled out

Abstract. Bertoletti L, Le Gal G, Aujesky D, Roy P‐M, Sanchez O, Verschuren F, Bounameaux H, Perrier A, Righini M. (University of Geneva, Geneva, Switzerland; Université De Saint‐Etienne, Jean Monnet, Saint‐Etienne; Brest University Hospital, Brest, France; Bern University Hospital, Bern, Switzerland; Angers University Hospital, Angers; Paris Descartes University, Paris, France; Saint‐Luc University Hospital, Bruxelles, Belgium; and University of Geneva, Geneva, Switzerland). Prognostic value of the Geneva prediction rule in patients in whom pulmonary embolism is ruled out. J Intern Med 2011; 269 : 433–440. Objectives. The prognosis of patients in whom pulmonary embolism (PE) is suspected but ruled out is poorly understood. We evaluated whether the initial assessment of clinical probability of PE could help to predict the prognosis for these patients. Design. Retrospective analysis of data obtained during a prospective multicentre management study. Setting. Six general and teaching hospitals in Belgium, France and Switzerland. Subjects. In 1334 patients in whom PE was ruled out, 3‐month mortality data were available (hospital readmission status was unknown for three patients) and clinical probability was evaluated with the revised Geneva score (RGS). Main outcome measures. Three‐month mortality and readmission rates. Results. Three‐month mortality and readmissions rates were 3% and 19%, respectively and differed significantly depending on the RGS‐determined PE probability group (P < 0.001). When compared with patients presenting with a low probability, the risk of death after 3 months was higher in cases of intermediate or high RGS‐based probability {odds ratio: 8.7 [95% confidence interval (CI): 2.7–28.5] and 22.6 (95%CI: 2.1–241.2), respectively}. The readmission risk increased with PE probability group (P < 0.001). The main causes of death were cancer, respiratory failure and cardiovascular failure. In total, 86% of patients with low RGS‐based probability were alive and had not been readmitted to hospital, whereas other patients had a twofold increased risk of death or readmission during the 3‐month follow‐up. The simplified Geneva score, calculated a posteriori, gave similar results. Conclusions. Initial assessment of clinical probability may help to stratify prognosis of patients in whom PE has been ruled out. Patients with a low probability of PE have a good prognosis. Whether patients with higher probability might benefit from more vigilant care should be evaluated.     

Oligodendrocyte responses to buprenorphine uncover novel and opposing roles of μ-opioid- and nociceptin/orphanin FQ receptors in cell development: implications for drug addiction treatment during pregnancy

Although the classical function of myelin is the facilitation of saltatory conduction, this membrane and the oligodendrocytes, the cells that make myelin in the central nervous system (CNS), are now recognized as important regulators of plasticity and remodeling in the developing brain. As such, oligodendrocyte maturation and myelination are among the most vulnerable processes along CNS development. We have shown previously that rat brain myelination is significantly altered by buprenorphine, an opioid analogue currently used in clinical trials for managing pregnant opioid addicts. Perinatal exposure to low levels of this drug induced accelerated and increased expression of myelin basic proteins (MBPs), cellular and myelin components that are markers of mature oligodendrocytes. In contrast, supra-therapeutic drug doses delayed MBP brain expression and resulted in a decreased number of myelinated axons. We have now found that this biphasic-dose response to buprenorphine can be attributed to the participation of both the μ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOP receptor) in the oligodendrocytes. This is particularly intriguing because the NOP receptor/nociceptin system has been primarily linked to behavior and pain regulation, but a role in CNS development or myelination has not been described before. Our findings suggest that balance between signaling mediated by (a) MOR activation and (b) a novel, yet unidentified pathway that includes the NOP receptor, plays a crucial role in the timing of oligodendrocyte maturation and myelin synthesis. Moreover, exposure to opioids could disrupt the normal interplay between these two systems altering the developmental pattern of brain myelination.     

Chronic electrical stimulation of transected peripheral nerves preserves anatomy and function in the primary somatosensory cortex

The structure and function of the central nervous system strongly depend on the organization and efficacy of the incoming sensory input. A disruption of somesthetic input severely alters the metabolic activity, electrophysiological properties and even gross anatomical features of the primary somatosensory cortex. Here we examined, in the rat somatosensory cortex, the neuroprotective and therapeutic effects of artificial sensory stimulation after irreversible unilateral transection of a peripheral sensory nerve (the infraorbital branch of the trigeminal nerve). The proximal stump of the nerve was inserted into a silicon tube with stimulating electrodes, through which continuous electrical stimulation was applied for 12 h/day (square pulses of 100 μs, 3.0 V, at 20 Hz) for 4 weeks. Deafferented animals showed significant decreases in cortical evoked potentials, cytochrome oxidase staining intensity (layers II–IV), cortical volume (layer IV) and number of parvalbumin‐expressing (layers II–IV) and calbindin‐D28k‐expressing (layers II/III) interneurons. These deafferentation‐dependent effects were largely absent in the nerve‐stimulated animals. Together, these results provide evidence that chronic electrical stimulation has a neuroprotective and preservative effect on the sensory cortex, and raise the possibility that, by controlling the physical parameters of an artificial sensory input to a sectioned peripheral nerve, chronically deafferented brain regions could be maintained at near‐‘normal’ conditions. Our findings could be important for the design of sensory neuroprostheses and for therapeutic purposes in brain lesions or neural degenerative processes.     

Psychometric properties of the Spanish version of the Body Weight,Image and Self-Esteem Evaluation questionnaire in patients with severe mental disorders

Objective

Clinicians need brief and valid instruments to monitor the psychosocial impact of weight gain in persons with psychiatric disorders. We examined the psychometric properties of the Spanish version of the Body Weight, Image and Self-Esteem Evaluation (B-WISE) questionnaire in patients with severe mental disorders.

Method

The data come from a naturalistic, cross-sectional, validation study conducted at 6 centres in Spain. A total of 211 outpatients with severe mental disorders, 118 with schizophrenia and 93 with bipolar disorder, were evaluated using the B-WISE, the Visual Analogue Scale for Weight and Body Image, and the Clinical Global Impression–Severity (CGI-S). The body mass index was also obtained.

Results

The principal component analysis confirms 3 components explaining 50.93% of the variance. The Cronbach α values for B-WISE scales ranged between .55 and .73. Significant Pearson correlations were found between B-WISE total score and CGI-S (r = − 0.25; P < .001) and Visual Analogue Scale for Weight and Body Image (r = 0.47; P < .001). The B-WISE discriminates among patients with mild, moderate, and severe mental disorders according to CGI-S scores (F = 6.52; P < .005). Body mass index categorization significantly influenced total B-WISE scores (F = 3.586, P < .050). The B-WISE score corresponding to the 5th and 10th percentiles was 22.

Conclusions

We were able to demonstrate that the Spanish version of the B-WISE is a valid instrument for assessing psychosocial impact of weight gain in patients with severe mental disorders in daily clinical practice.     

Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion

The hallucinogenic brew Ayahuasca, a rich source of serotonergic agonists and reuptake inhibitors, has been used for ages by Amazonian populations during religious ceremonies. Among all perceptual changes induced by Ayahuasca, the most remarkable are vivid “seeings.” During such seeings, users report potent imagery. Using functional magnetic resonance imaging during a closed‐eyes imagery task, we found that Ayahuasca produces a robust increase in the activation of several occipital, temporal, and frontal areas. In the primary visual area, the effect was comparable in magnitude to the activation levels of natural image with the eyes open. Importantly, this effect was specifically correlated with the occurrence of individual perceptual changes measured by psychiatric scales. The activity of cortical areas BA30 and BA37, known to be involved with episodic memory and the processing of contextual associations, was also potentiated by Ayahuasca intake during imagery. Finally, we detected a positive modulation by Ayahuasca of BA 10, a frontal area involved with intentional prospective imagination, working memory and the processing of information from internal sources. Therefore, our results indicate that Ayahuasca seeings stem from the activation of an extensive network generally involved with vision, memory, and intention. By boosting the intensity of recalled images to the same level of natural image, Ayahuasca lends a status of reality to inner experiences. It is therefore understandable why Ayahuasca was culturally selected over many centuries by rain forest shamans to facilitate mystical revelations of visual nature. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.