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Background Microglial activation is thought to be a key pathophysiological mechanism underlying disease activity in all forms of MS. Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory properties that is widely used in the treatment of rheumatological diseases. In this series of experiments, we explore the effect of HCQ on human microglial activation in vitro and on the development of experimental autoimmune encephalitis (EAE) in vivo. Methods We activated human microglia with lipopolysaccharide (LPS), and measured concentrations of several pro- and anti-inflammatory cytokines in untreated and HCQ pretreated cultures. We investigated the effect of HCQ pretreatment at two doses on the development of EAE and spinal cord histology. Results HCQ pretreatment reduced the production of pro-inflammatory (TNF-alpha, IL-6, and IL-12) and anti-inflammatory (IL-10 and IL-1 receptor antagonist) cytokines in LPS-stimulated human microglia. HCQ pretreatment delayed the onset of EAE, and reduced the number of Iba-1 positive microglia/macrophages and signs of demyelination in the spinal cords of HCQ treated animals. Conclusion HCQ treatment reduces the activation of human microglia in vitro, delays the onset of EAE, and decreases the representation of activated macrophages/microglia and demyelination in the spinal cord of treated mice. HCQ is a plausible candidate for further clinical studies in MS.

Frontometaphyseal dysplasia is an X-linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X-linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin-binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X-inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.

Medical schools need good functional relationships with the health systems in which their students, graduates and staff will learn and work. With increasing complexity and rising costs of health delivery the 2 types of organisation have become more interdependent but not always as collaborating partners. Recent changes in the organisation of undergraduate medical education have been reactive to re-structuring of health services. For example, traditional teaching hospitals have become more specialised and less suitable for general medical education. While this has helped to decentralise medical education into appropriate clinical environments, these and other changes have generally been adaptive to the health systems rather than being instigated by the medical schools for educational reasons. This discussion paper examines the nature of the relationships and their contributory elements. A taxonomy of functional relationships is proposed with primary categories of (i) autonomy (ii) contiguity (iii) interdependence (iv) collaboration, and (v) obligation. It is suggested that medical schools should become more assertive in application of their creative talents and educational resources throughout the environment in which their graduates will use their medical skills, and in which they will work with other health care professionals.

The rights of patients may be considered within three broad categories: (i) health as a fundamental human right, (ii) equitable healthcare provision by governments and institutions, and (iii) professional relationships with individual health practitioners. Doctors should be well prepared in medical schools to understand and uphold patient rights. A simplified framework for learning and for teaching medical students about patient rights is proposed with the acronym DROIT – dignity, respect, obligation, information and trust.

Medical schools need good functional relationships with the health systems in which their students, graduates and staff will learn and work. With increasing complexity and rising costs of health delivery the 2 types of organisation have become more interdependent but not always as collaborating partners. Recent changes in the organisation of undergraduate medical education have been reactive to re-structuring of health services. For example, traditional teaching hospitals have become more specialised and less suitable for general medical education. While this has helped to decentralise medical education into appropriate clinical environments, these and other changes have generally been adaptive to the health systems rather than being instigated by the medical schools for educational reasons. This discussion paper examines the nature of the relationships and their contributory elements. A taxonomy of functional relationships is proposed with primary categories of (i) autonomy (ii) contiguity (iii) interdependence (iv) collaboration, and (v) obligation. It is suggested that medical schools should become more assertive in application of their creative talents and educational resources throughout the environment in which their graduates will use their medical skills, and in which they will work with other health care professionals.

Stephen P. Robertson,* Zandra A. Jenkins, Timothy Morgan, Lesley Ades, Salim Aftimos, Odile Boute, Torunn Fiskerstrand, Sixto Garcia-Minaur, Arthur Grix, Andrew Green, Vazken Der Kaloustian, Ray Lewkonia, Brenda McInnes, Mieke M. van Haelst, Grazia Macini, Tamas Illes, Geert Mortier, Ruth Newbury-Ecob, Linda Nicholson, Charles I. Scott, Karolina Ochman, Izabela Brozek, Deborah J. Shears, Andrea Superti-Furga, Mohnish Suri, Margo Whiteford, Andrew O.M. Wilkie, and Deborah Krakow Department of Paediatrics and Child Health, Dunedin School of Medicine, Dunedin, New Zealand Department of Medical Genetics, The Children’s Hospital at Westmead, Sydney, Australia Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia Northern Regional Genetics Service, Auckland, New Zealand Genetics Service, Jeanne de Flandre Hospital, Lille, France Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway Genetics Service, Western General Hospital, Edinburgh, United Kingdom Permanente Medical Group, Sacramento, California Department of Medical Genetics, Our Lady’s Hospital for Sick Children, Dublin, Ireland Division of Medical Genetics, McGill University, Montreal Children’s Hospital, Montreal, Canada Department of Medical Genetics, Alberta Children’s Hospital, Calgary, Canada Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Orthopedic Surgery, University of Pecs, Pecs, Hungary Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium Clinical Genetics Service, United Bristol Hospitals Trust, Bristol, United Kingdom Division of Medical Genetics, DuPont Hospital for Children, Wilmington, Delaware Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland Clinical and Molecular Genetics Unit, Institute for Child Health, London, United Kingdom Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany Clinical Genetics Service, City Hospital, Nottingham, United Kingdom Ferguson-Smith Centre for Medical Genetics, Glasgow, United Kingdom Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, United Kingdom Cedars Sinai Medical Research Institute, Los Angeles, California

Mission statements and role documents of medical schools in the United Kingdom, United States, Canada and Australia have been examined on their Internet Web sites and categorised in purpose, content and presentation. The format and content are highly variable, but there is a common vision of three integral roles, namely, education, advancement of knowledge and service to society. Other frequent themes include tradition and historical perspective, service for designated communities, and benchmarking to accreditation standards. Differences in content reflect variable interpretation of the notion of "mission", and local or national characteristics such as institutional affiliations, the types, levels and organisation of medical education, relationships with health systems, and extent of multi-professional education. Outcomes data and measures of medical school performance referenced to the institution's stated missions are rarely encountered. Mission documents placed on the Internet are in the public domain. These Web sites and documents and linked information constitute a valuable new resource for international exchange of approaches and ideas in medical education and generally in academic medicine. Routine inclusion of outcome or performance data could help to demonstrate the community roles and social accountability of medical schools This paper proposes that partial standardisation of these Web documents could enhance their value both internally and for external readers. A generic descriptive statement template is offered.