Olanzapine-associated neuroleptic malignant syndrome: Is there an overlap with the serotonin syndrome?

BACKGROUND: The neuroleptic malignant syndrome is a rare but serious condition mainly associated with antipsychotic medication. There are controversies as to whether "classical" forms of neuroleptic malignant syndrome can occur in patients given atypical antipsychotics. The serotonin syndrome is caused by drug-induced excess of intrasynaptic 5-hydroxytryptamine. The possible relationship between neuroleptic malignant syndrome and serotonin syndrome is at present in the focus of scientific interest. METHODS: This retrospective phenomenological study aims to examine the seventeen reported olanzapine – induced neuroleptic malignant syndrome cases under the light of possible overlap between neuroleptic malignant syndrome and serotonin syndrome clinical features. RESULTS: The serotonin syndrome clinical features most often reported in cases initially diagnosed as neuroleptic malignant syndrome are: fever (82%), mental status changes (82%) and diaphoresis (47%). Three out of the ten classical serotonin syndrome clinical features were concurrently observed in eleven (65%) patients and four clinical features were observed in seven (41%) patients. CONCLUSION: The results of this study show that the clinical symptoms of olanzapine-induced neuroleptic malignant syndrome and serotonin syndrome are overlapping suggesting similarities in underlying pathophysiological mechanisms

Treatment of severe neuroleptic-induced tardive torticollis

BACKGROUND: The aim of this paper is to describe a case of severe neuroleptic-induced tardive torticollis successfully treated with a combination of clozapine, clonazepam and botulinum toxin-A. CASE REPORT: The patient, a 30-year old man with a seven-year history of delusional disorder experienced severe right torticollis with painful tightness of the neck and elevation of the shoulder. At this time he was receiving haloperidol 20 mg, trifluoperazine 5 mg, zuclopenthixol 20 mg and biperidine 4 mg daily. The combination therapy with clozapine and clonazepam and the long-term use of botulinum toxin-A resulted in a complete remission of dystonic movements. CONCLUSIONS: The present observations provide evidence indicating that this combination therapy may be of benefit in patients with severe neuroleptic-induced tardive torticollis

Physical anhedonia in the acute phase of schizophrenia

BACKGROUND: The aim of the current study is to investigate the relationship between physical anhedonia and psychopathological parameters, pharmacological parameters or motor side-effects in a sample of inpatients with schizophrenia in an acute episode of their illness. METHOD: Eighty one patients with schizophrenia, consecutively admitted, with an acute episode of their illness, at the Eginition Hospital, Department of Psychiatry, University of Athens, during a one-year period were investigated regarding possible relationships between physical anhedonia, social-demographic data and clinical parameters as well as motor side-effects, induced by antipsychotic agents. All patients were assessed using the Chapman Revised Physical Anhedonia Scale (RPAS), the Positive and Negative Syndrome Scale (PANSS), the Rating Scale for Extrapyramidal Side-Effects (EPSE), the Barnes Akathisia Rating Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). Simple cross tabulations were initially employed. Subsequently, multiple regression analysis was performed. RESULTS: Both positive and negative symptoms were associated with physical anhedonia. A positive association between physical anhedonia and the non-paranoid sub-category of schizophrenia was also proved. CONCLUSION: According to these results, it seems that in the acute phase of schizophrenia, physical anhedonia may be a contributing factor to patient's psychopathology

Group classification of the Sachs equations for a radiating axisymmetric, non-rotating, vacuum space-time

We carry out a Lie group analysis of the Sachs equations for a time-dependent axisymmetric non-rotating space-time in which the Ricci tensor vanishes. These equations, which are the first two members of the set of Newman-Penrose equations, define the characteristic initial-value problem for the space-time. We find a particular form for the initial data such that these equations admit a Lie symmetry, and so defines a geometrically special class of such spacetimes. These should additionally be of particular physical interest because of this special geometric feature.Comment: 18 Pages. Submitted to Classical and Quantum Gravit

The Pareto Frontier of Inefficiency in Mechanism Design

We study the trade-off between the Price of Anarchy (PoA) and the Price of Stability (PoS) in mechanism design, in the prototypical problem of unrelated machine scheduling. We give bounds on the space of feasible mechanisms with respect to the above metrics, and observe that two fundamental mechanisms, namely the First-Price (FP) and the Second-Price (SP), lie on the two opposite extrema of this boundary. Furthermore, for the natural class of anonymous task-independent mechanisms, we completely characterize the PoA/PoS Pareto frontier; we design a class of optimal mechanisms (formula presented) that lie exactly on this frontier. In particular, these mechanisms range smoothly, with respect to parameter (formula presented) across the frontier, between the First-Price (formula presented) and Second-Price (formula presented) mechanisms. En route to these results, we also provide a definitive answer to an important question related to the scheduling problem, namely whether non-truthful mechanisms can provide better makespan guarantees in the equilibrium, compared to truthful ones. We answer this question in the negative, by proving that the Price of Anarchy of all scheduling mechanisms is at least n, where n is the number of machines

Widespread translational control of fibrosis in the human heart by RNA-binding proteins

BACKGROUND: Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. METHODS: Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used an RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these post-transcriptional mechanisms are also active in the diseased fibrotic human heart. RESULTS: We generated nucleotide-resolution translatome data during the TGFβ1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in post-transcriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same post-transcriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as PUM2 and QKI that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward pro-fibrotic myofibroblasts in response to TGFβ1. CONCLUSIONS: We reveal widespread translational effects of TGFβ1 and define novel post-transcriptional regulatory networks that control the fibroblast-to-myofibroblast transition. These networks are active in human heart disease and silencing of hub genes limits fibroblast activation. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.Fil: Ng, Bobby G.. Sanford Burnham Prebys Medical Discovery Institute; Estados UnidosFil: Eklund, Erik A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos. Lund University; SueciaFil: Shiryaev, Sergey A.. Sanford Burnham Prebys Medical Discovery Institute; Estados UnidosFil: Dong, Yin Y.. University of Oxford; Reino UnidoFil: Abbott, Mary Alice. University of Massachusetts Medical School; Estados UnidosFil: Asteggiano, Carla Gabriela. Universidad Católica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Bamshad, Michael J.. University of Washington; Estados UnidosFil: Barr, Eileen. University of Emory; Estados UnidosFil: Bernstein, Jonathan A.. University of Stanford; Estados UnidosFil: Chelakkadan, Shabeed. Monash Children's Hospital; AustraliaFil: Christodoulou, John. Sydney Medical School; Australia. University of Melbourne; AustraliaFil: Chung, Wendy K.. Columbia University; Estados UnidosFil: Ciliberto, Michael A.. University of Iowa; Estados UnidosFil: Cousin, Janice. National Human Genome Research Institute ; Estados UnidosFil: Gardiner, Fiona. University of Melbourne; AustraliaFil: Ghosh, Suman. University of Florida; Estados UnidosFil: Graf, William D.. University of Connecticut; Estados UnidosFil: Grunewald, Stephanie. University College London; Estados UnidosFil: Hammond, Katherine. University of Alabama at Birmingahm; Estados UnidosFil: Hauser, Natalie S.. Inova, Fairfax Hospital Falls Church; Estados UnidosFil: Hoganson, George E.. University Of Illinois At Chicago; Estados UnidosFil: Houck, Kimberly M.. Baylor College of Medicine; Estados UnidosFil: Kohler, Jennefer N.. University of Stanford; Estados UnidosFil: Morava, Eva. Mayo Clinic; Estados UnidosFil: Larson, Austin A.. University Of Colorado Anschutz Medical Campus.; Estados UnidosFil: Liu, Pengfei. Baylor Genetics; Estados Unidos. Baylor College Of Medicine; Estados UnidosFil: Madathil, Sujana. University of Iowa; Estados UnidosFil: McCormack, Colleen. University of Stanford; Estados UnidosFil: Meeks, Naomi J.L.. University Of Colorado Anschutz Medical Campus.; Estados UnidosFil: Papazoglu, Gabriela Magali. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentin

Prediction of Human Disease Genes by Human-Mouse Conserved Coexpression Analysis

One of the most limiting aspects of biological research in the post-genomic era is the capability to integrate massive datasets on gene structure and function for producing useful biological knowledge. In this report we have applied an integrative approach to address the problem of identifying likely candidate genes within loci associated with human genetic diseases. Despite the recent progress in sequencing technologies, approaching this problem from an experimental perspective still represents a very demanding task, because the critical region may typically contain hundreds of positional candidates. We found that by concentrating only on genes sharing similar expression profiles in both human and mouse, massive microarray datasets can be used to reliably identify disease-relevant relationships among genes. Moreover, we found that integrating the coexpression criterion with systematic phenome analysis allows efficient identification of disease genes in large genomic regions. Using this approach on 850 OMIM loci characterized by unknown molecular basis, we propose high-probability candidates for 81 genetic diseases