Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis.

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.

Family physician practice visits arising from the Alberta Physician Achievement Review.

BACKGROUND: Licensed physicians in Alberta are required to participate in the Physician Achievement Review (PAR) program every 5 years, comprising multi-source feedback questionnaires with confidential feedback, and practice visits for a minority of physicians. We wished to identify and classify issues requiring change or improvement from the family practice visits, and the responses to advice. METHODS: Retrospective analysis of narrative practice visit reports data using a mixed methods design to study records of visits to 51 family physicians and general practitioners who participated in PAR during the period 2010 to 2011, and whose ratings in one or more major assessment domains were significantly lower than their peer group. RESULTS: Reports from visits to the practices of family physicians and general practitioners confirmed opportunities for change and improvement, with two main groupings - practice environment and physician performance. For 40/51 physicians (78%) suggested actions were discussed with physicians and changes were confirmed. Areas of particular concern included problems arising from practice isolation and diagnostic conclusions being reached with incomplete clinical evidence. CONCLUSION: This study provides additional evidence for the construct validity of a regulatory authority educational program in which multi-source performance feedback identifies areas for practice quality improvement, and change is encouraged by supplementary contact for selected physicians.

Patient rights and medical education: clinical principles.

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.

Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity.

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.

The functional relationships of medical schools and health services.

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.