Theiler’s murine encephalomyelitis virus as an experimental model system to study the mechanism of blood–brain barrier disruption

Theiler’s murine encephalomyelitis virus is a widely used model to study the initiation and progression of multiple sclerosis. Many researchers have used this model to investigate how the immune system and genetic factors contribute to the disease process. Current research has highlighted the importance of cytotoxic CD8 T cells and specific major histocompatibility complex (MHC) class I alleles. Our lab has adopted this concept to create a novel mouse model to study the mechanism of blood–brain barrier (BBB) disruption, an integral feature of numerous neurological disorders. We have demonstrated that epitope-specific CD8 T cells cause disruption of the tight junction architecture and ensuing CNS vascular permeability in the absence of neutrophil support. This CD8 T cell-initiated BBB disruption is dependent on perforin expression. We have also elucidated a potential role for hematopoietic factors in this process. Despite having identical MHC class I molecules, similar inflammation in the CNS, and equivalent ability to utilize perforin, C57BL/6 mice are highly susceptible to this condition, while 129 SvIm mice are resistant. This susceptibility is transferable with the bone marrow compartment. These findings led us to conduct a comprehensive genetic analysis which has revealed a list of candidate genes implicated in regulating traits associated with BBB disruption. Future studies will continue to define the underlying molecular mechanism of CD8 T cell-initiated BBB disruption and may assist in the development of potential therapeutic approaches to ameliorate pathology associated with BBB disruption in neurological disorders.     

The Duboisia Genus,Australian Aborigines and Suggestibility

Abstract

Plant hallucinogens, such as those of the Duboisia genus called pituri, have been used by tribal elders in Australian aboriginal populations to create managed states of consciousness, to provide their youth with a fast-paced educational experience, and to inculcate values, beliefs and religious tenets. Use of the suggestible states created by such substances (particularly in pubertal initiatory rituals marking the transition to manhood) are part of this process, which contributes to cultural cohesiveness and survival; their effectiveness is due to the unique ability of the biochemical properties of the plant to evoke suggestibility in those who ingest them. This article draws on research about suggestibility as a psychological characteristic of altered states of consciousness as well as a normal human psychological phenomenon, and examines in great detail the use of the pituri plant, deriving data from a 100-item bibliography generated by the Australian Institute of Aboriginal and Torres Strait Islander Studies in Canberra. Botanical/chemical data on use of the Duboisia genus up to the end of the nineteenth century is examined, as well as the way in which this hallucinogen was utilized as a “psychotechnology.”     

Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.     

An Educational Intervention to Increase Internists’ Confidence With and Provision of Preventive Services to Adolescents and Young Adults

Background: Internal medicine (IM) physicians report inadequate preparation to care for adolescents and young adults. Purpose: The aim is to (a) improve IM residents’ comfort and confidence caring for adolescents/young adults and (b) increase the percentage of adolescent/young adult patients receiving preventive healthcare. Methods: Fifty-two PGY1 IM residents were assigned to treatment or control groups. Residents in the treatment group interviewed and received feedback from adolescent instructors. We developed a survey to measure residents’ comfort and confidence caring for adolescents/young adults and evaluated their adherence to screening guidelines for patients ages 16 to 26. Results: Significantly more residents in the intervention group felt confident identifying sexually transmitted infections (STIs) and substance abuse and treating STIs, substance abuse, and depression compared to residents in the control group. Residents in the intervention group were no more likely to screen adolescents/young adults for Chlamydia, HIV, alcohol misuse, or depression in the 6 months following the intervention. Conclusions: An educational intervention utilizing adolescent instructors improves resident confidence but does not increase adherence to screening guidelines.