Transgenic primates as research tools: now a reality

To see full article - click here

Article

Nature 459, 523-527 (28 May 2009) | doi:10.1038/nature08090; Received 27 September 2008; Accepted 30 April 2009

Generation of transgenic non-human primates with germline transmission

Erika Sasaki¹, Hiroshi Suemizu¹, Akiko Shimada¹, Kisaburo Hanazawa², Ryo Oiwa¹, Michiko Kamioka¹, Ikuo Tomioka^1,3, Yusuke Sotomaru⁵, Reiko Hirakawa^1,3, Tomoo Eto¹, Seiji Shiozawa^1,4, Takuji Maeda^1,4, Mamoru Ito¹, Ryoji Ito¹, Chika Kito¹, Chie Yagihashi¹, Kenji Kawai¹, Hiroyuki Miyoshi⁶, Yoshikuni Tanioka¹, Norikazu Tamaoki¹, Sonoko Habu⁷, Hideyuki Okano⁴ & Tatsuji Nomura¹

1. Central Institute for Experimental Animals, 1430 Nogawa, Miyamae-ku, Kawasaki, Kanagawa 216-0001, Japan
2. Department of Urology, Juntendo University Nerima Hospital 3-1-10 Takanodai, Nerima-ku, Tokyo 177-8521, Japan
3. Center for Integrated Medical Research,
4. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
5. Natural Science Centre for Basic Research and Development, Hiroshima University 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan
6. Subteam for Manipulation of Cell Fate, RIKEN BioResource Centre, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
7. Department of Immunology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan

Correspondence to: Erika Sasaki¹Hideyuki Okano⁴ Correspondence and requests for materials should be addressed to E.S. (Email: esasaki@ciea.or.jp) or H.O. (Email: hidokano@sc.itc.keio.ac.jp).

Top of page

Abstract

The common marmoset (Callithrix jacchus) is increasingly attractive for use as a non-human primate animal model in biomedical research. It has a relatively high reproduction rate for a primate, making it potentially suitable for transgenic modification. Although several attempts have been made to produce non-human transgenic primates, transgene expression in the somatic tissues of live infants has not been demonstrated by objective analyses such as polymerase chain reaction with reverse transcription or western blots. Here we show that the injection of a self-inactivating lentiviral vector in sucrose solution into marmoset embryos results in transgenic common marmosets that expressed the transgene in several organs. Notably, we achieved germline transmission of the transgene, and the transgenic offspring developed normally. The successful creation of transgenic marmosets provides a new animal model for human disease that has the great advantage of a close genetic relationship with humans. This model will be valuable to many fields of biomedical research.

Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder

To see article click here

Original Article

Molecular Psychiatry advance online publication 26 May 2009; doi: 10.1038/mp.2009.50

Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder

M H Bloch¹, J McGuire¹, A Landeros-Weisenberger¹, J F Leckman¹ and C Pittenger²

1. ¹Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA
2. ²Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Correspondence: Dr MH Bloch, Child Study Center, Yale University School of Medicine, PO Box 20709, New Haven, CT 06520, USA. E-mail: Michael.bloch@yale.edu

Received 22 January 2009; Accepted 13 April 2009; Published online 26 May 2009.

Top of page

Abstract

We sought to determine differences in efficacy and tolerability between different doses of selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) using meta-analysis. We identified 9 studies involving 2268 subjects that were randomized, double-blind placebo-controlled clinical trials that compared multiple, fixed-doses of selective serotonin reuptake inhibitors (SSRIs) to each other and to placebo in the treatment of adults with OCD. Change in Y-BOCS score, proportion of treatment responders, and dropouts (all-cause and due to side-effects) were determined for each included study. Weighted mean difference was used to examine mean change in Y-BOCS score. Pooled absolute risk difference was used to examine dichotomous outcomes. Meta-analysis was performed using a fixed effects model in RevMan 4.2.8. We found that compared with either low or medium doses, higher doses of SSRIs were associated with improved treatment efficacy, using either Y-BOCS score or proportion of treatment responders as an outcome. Dose of SSRIs was not associated with the number of all-cause dropouts. Higher doses of SSRIs were associated with significantly higher proportion of dropouts due to side-effects. These results suggests that higher doses of SSRIs are associated with greater efficacy in the treatment of OCD. This SSRI efficacy pattern stands in contrast to other psychiatric disorders like Major Depressive Disorder. This greater treatment efficacy is somewhat counterbalanced by the greater side-effect burden with higher doses of SSRIs. At present, there are insufficient data to generalize these findings to children or adolescents with OCD.

Chromosome 8p: A Review

See article here

Feature Review

Molecular Psychiatry (2009) 14, 563–589; doi:10.1038/mp.2009.2; published online 10 February 2009

Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer

R Tabarés-Seisdedos¹ and J L R Rubenstein²

1. Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, CIBER-SAM, University of Valencia, Valencia, Spain
2. Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA, USA. E-mail: Rafael.Tabares@uv.es

Correspondence: Professor Dr R Tabarés-Seisdedos, Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, University of Valencia, CIBER-SAM, Blasco-Ibáñez 17, 46010 Valencia, Spain; Professor Dr John LR Rubenstein, Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA 94143, USA. E-mail: John.Rubenstein@ucsf.edu

Received 1 August 2008; Revised 19 December 2008; Accepted 7 January 2009; Published online 10 February 2009.

Top of page

Abstract

Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.

The Best on Translational Science

Academic Health Science Centres: a revolution in healthcare?

6 March 2009

King’s Health Partners hosted an international conference on 6 March 2009, discussing ‘Academic Health Science Centres: a revolution in healthcare?’

Presentations followed by question and answer sessions were given from a variety of healthcare and research experts from across the globe, within both public and private sector organisations.

The conference saw over 300 attendees from the UK and further afield, and was opened by Sir Alan Langlands, Principal and Chancellor for the University of Dundee. Other speakers throughout the day included representatives from US healthcare organisations and pharmaceutical companies as well as our own internal specialists in both research and clinical delivery.

The day ended on a positive, with a closing note from Ruth Carnall, Chief Executive for NHS London, whereby she gave her support to all the AHSC applicants, in what will be a positive change for the benefit of patients.

Check this conference on the web and download the presentations. They are really outstanding. Click here.

To see an outstanding Translational Science Center application from the Imperial College of Science, Technology and Medicine, click here.