Ritanserin as an adjunct to lithium and haloperidol for the treatment of medication-naive patients with acute mania: a double blind and placebo controlled trial

BACKGROUND: Bipolar disorder is a lifelong episodic condition characterized by mood swings between mania and depression. Several lines of evidence suggest that serotonin is likely to play a pivotal role in the pathophysiology of bipolar disorder. Ritanserin, a 5-HT(2 )receptor antagonist, has been reported to have antipsychotic activity. In this 6-week double blind, placebo controlled study involving moderate to severe manic patients, we assessed the effects of ritanserin plus haloperidol in combination with lithium. METHODS: 45 patients aged between 21–43 were eligible to participate as they met the DSM-IV criteria for a current manic episode, on the basis of a clinical interview by an academician psychiatrist. In addition, a score of at least 20 points on the Young Mania rating Scale was required representing moderate to severe mania. Patients were randomly allocated lithium (1–1.2 mEq/L) + haloperidol (10 mg/day)+ ritanserin (10 mg/day) (Group A) or lithium (1–1.2 mEq/L)+ haloperidol (10 mg/day) + placebo (Group B) for a 6-week, double-blind, placebo-controlled study. Patients were assessed by a third year psychiatry resident at baseline and 3, 7, 14, 21, 28 and 42 days after the medication started. All patients entered the hospital were not previously under any medication. The mean decrease in the Young Mania Rating Scale score from baseline was used as the main outcome measure of response of mania to treatment. The extrapyramidal symptoms were assessed using the Extrapyramidal Symptoms Rating Scale. Side effects were systematically recorded throughout the study and were assessed using a checklist. RESULTS: Young Mania Rating Scale total scores improved with ritanserin. The difference between the two protocols was significant as indicated by the effect of group and the between-subjects factor (F = 5.02, d.f. = 1, P = 0.03). The means Extrapyramidal Symptoms Rating Scale scores for the placebo group were higher than the ritanserin group and the difference was significant in day 42. The difference between the two groups in the frequency of side effects was not significant CONCLUSIONS: The efficacy of ritanserin to obtain a better improvement in patients with mania seems to support the 5-HT hypothesis of bipolar disorder

Properties of Graphene: A Theoretical Perspective

In this review, we provide an in-depth description of the physics of monolayer and bilayer graphene from a theorist's perspective. We discuss the physical properties of graphene in an external magnetic field, reflecting the chiral nature of the quasiparticles near the Dirac point with a Landau level at zero energy. We address the unique integer quantum Hall effects, the role of electron correlations, and the recent observation of the fractional quantum Hall effect in the monolayer graphene. The quantum Hall effect in bilayer graphene is fundamentally different from that of a monolayer, reflecting the unique band structure of this system. The theory of transport in the absence of an external magnetic field is discussed in detail, along with the role of disorder studied in various theoretical models. We highlight the differences and similarities between monolayer and bilayer graphene, and focus on thermodynamic properties such as the compressibility, the plasmon spectra, the weak localization correction, quantum Hall effect, and optical properties. Confinement of electrons in graphene is nontrivial due to Klein tunneling. We review various theoretical and experimental studies of quantum confined structures made from graphene. The band structure of graphene nanoribbons and the role of the sublattice symmetry, edge geometry and the size of the nanoribbon on the electronic and magnetic properties are very active areas of research, and a detailed review of these topics is presented. Also, the effects of substrate interactions, adsorbed atoms, lattice defects and doping on the band structure of finite-sized graphene systems are discussed. We also include a brief description of graphane -- gapped material obtained from graphene by attaching hydrogen atoms to each carbon atom in the lattice.Comment: 189 pages. submitted in Advances in Physic

Quantum Resistance Standard Based on Epitaxial Graphene

We report development of a quantum Hall resistance standard accurate to a few parts in a billion at 300 mK and based on large area epitaxial graphene. The remarkable precision constitutes an improvement of four orders of magnitude over the best results obtained in exfoliated graphene and is similar to the accuracy achieved in well-established semiconductor standards. Unlike the traditional resistance standards the novel graphene device is still accurately quantized at 4.2 K, vastly simplifying practical metrology. This breakthrough was made possible by exceptional graphene quality achieved with scalable silicon carbide technology on a wafer scale and shows great promise for future large scale applications in electronics.Comment: Submitte

Complex morphology and functional dynamics of vital murine intestinal mucosa revealed by autofluorescence 2-photon microscopy

The mucosa of the gastrointestinal tract is a dynamic tissue composed of numerous cell types with complex cellular functions. Study of the vital intestinal mucosa has been hampered by lack of suitable model systems. We here present a novel animal model that enables highly resolved three-dimensional imaging of the vital murine intestine in anaesthetized mice. Using intravital autofluorescence 2-photon (A2P) microscopy we studied the choreographed interactions of enterocytes, goblet cells, enteroendocrine cells and brush cells with other cellular constituents of the small intestinal mucosa over several hours at a subcellular resolution and in three dimensions. Vigorously moving lymphoid cells and their interaction with constituent parts of the lamina propria were examined and quantitatively analyzed. Nuclear and lectin staining permitted simultaneous characterization of autofluorescence and admitted dyes and yielded additional spectral information that is crucial to the interpretation of the complex intestinal mucosa. This novel intravital approach provides detailed insights into the physiology of the small intestine and especially opens a new window for investigating cellular dynamics under nearly physiological conditions

The present and future of serum diagnostic tests for testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability

Human ZIC1 (zinc finger protein of cerebellum 1), one of five homologs of the Drosophila pair-rule gene odd-paired, encodes a transcription factor previously implicated in vertebrate brain development. Heterozygous deletions of ZIC1 and its nearby paralog ZIC4 on chromosome 3q25.1 are associated with Dandy-Walker malformation of the cerebellum, and loss of the orthologous Zic1 gene in the mouse causes cerebellar hypoplasia and vertebral defects. We describe individuals from five families with heterozygous mutations located in the final (third) exon of ZIC1 (encoding four nonsense and one missense change) who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. The location of the nonsense mutations predicts escape of mutant ZIC1 transcripts from nonsense-mediated decay, which was confirmed in a cell line from an affected individual. Both nonsense and missense mutations are associated with altered and/or enhanced expression of a target gene, engrailed-2, in a Xenopus embryo assay. Analysis of mouse embryos revealed a localized domain of Zic1 expression at embryonic days 11.5–12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture. We conclude that the human mutations uncover a previously unsuspected role for Zic1 in early cranial suture development, potentially by regulating engrailed 1, which was previously shown to be critical for positioning of the murine coronal suture. The diagnosis of a ZIC1 mutation has significant implications for prognosis and we recommend genetic testing when common causes of coronal synostosis have been excluded

Perturbation Centrality and Turbine: A Novel Centrality Measure Obtained Using a Versatile Network Dynamics Tool

Analysis of network dynamics became a focal point to understand and predict changes of complex systems. Here we introduce Turbine, a generic framework enabling fast simulation of any algorithmically definable dynamics on very large networks. Using a perturbation transmission model inspired by communicating vessels, we define a novel centrality measure: perturbation centrality. Hubs and inter-modular nodes proved to be highly efficient in perturbation propagation. High perturbation centrality nodes of the Met-tRNA synthetase protein structure network were identified as amino acids involved in intra-protein communication by earlier studies. Changes in perturbation centralities of yeast interactome nodes upon various stresses well recapitulated the functional changes of stressed yeast cells. The novelty and usefulness of perturbation centrality was validated in several other model, biological and social networks. The Turbine software and the perturbation centrality measure may provide a large variety of novel options to assess signaling, drug action, environmental and social interventions. The Turbine algorithm is available at: http://www.turbine.linkgroup.huComment: 21 pages, 4 figues, 1 table, 58 references + a Supplement of 52 pages, 10 figures, 9 tables and 39 references; Turbine algorithm is available at: http://www.turbine.linkgroup.h

Drug use and nightlife: more than just dance music

<p>Abstract</p> <p>Background</p> <p>Research over the last decade has focused almost exclusively on the association between electronic music and MDMA (3,4-Methylenedioxymethamphetamine or "ecstasy") or other stimulant drug use in clubs. Less attention has been given to other nightlife venues and music preferences, such as rock music or southern/funky music. This study aims to examine a broader spectrum of nightlife, beyond dance music. It looks at whether certain factors influence the frequency of illegal drug and alcohol use: the frequency of going to certain nightlife venues in the previous month (such as, pubs, clubs or goa parties); listening to rock music, dance music or southern and funky music; or sampling venues (such as, clubs, dance events or rock festivals). The question of how these nightlife variables influence the use of popular drugs like alcohol, MDMA, cannabis, cocaine and amphetamines is addressed.</p> <p>Methods</p> <p>The study sample consisted of 775 visitors of dance events, clubs and rock festivals in Belgium. Study participants answered a survey on patterns of going out, music preferences and drug use. Odds ratios were used to determine whether the odds of being an illegal substance user are higher for certain nightlife-related variables. Furthermore, five separate ordinal regression analyses were used to investigate drug use in relation to music preference, venues visited during the last month and sampling venue.</p> <p>Results</p> <p>Respondents who used illegal drugs were 2.5 times more likely to report that they prefer dance music. Goa party visitors were nearly 5 times more likely to use illegal drugs. For those who reported visiting clubs, the odds of using illegal drugs were nearly 2 times higher. Having gone to a pub in the last month was associated with both more frequent alcohol use and more frequent illegal substance use. People who reported liking rock music and attendees of rock festivals used drugs less frequently.</p> <p>Conclusions</p> <p>It was concluded that a more extended recreational environment, beyond dance clubs, is associated with frequent drug use. This stresses the importance of targeted prevention in various recreational venues tailored to the specific needs of the setting and its visitors.</p