Envelope Determinants of Equine Lentiviral Vaccine Protection

Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection. © 2013 Craigo et al

Mutations in Polymerase Genes Enhanced the Virulence of 2009 Pandemic H1N1 Influenza Virus in Mice

Influenza A virus can infect a wide variety of animal species with illness ranging from mild to severe, and is a continual cause for concern. Genetic mutations that occur either naturally or during viral adaptation in a poorly susceptible host are key mechanisms underlying the evolution and virulence of influenza A virus. Here, the variants containing PA-A36T or PB2-H357N observed in the mouse-adapted descendants of 2009 pandemic H1N1 virus (pH1N1), A/Sichuan/1/2009 (SC), were characterized. Both mutations enhanced polymerase activity in mammalian cells. These effects were confirmed using recombinant SC virus containing polymerase genes with wild type (WT) or mutant PA or PB2. The PA-A36T mutant showed enhanced growth property compared to the WT in both human A549 cells and porcine PK15 cells in vitro, without significant effect on viral propagation in murine LA-4 cells and pathogenicity in mice; however, it did enhance the lung virus titer. PB2-H357N variant demonstrated growth ability comparable to the WT in A549 cells, but replicated well in PK15, LA-4 cells and in mice with an enhanced pathogenic phenotype. Despite such mutations are rare in nature, they could be observed in avian H5 and H7 subtype viruses which were currently recognized to pose potential threat to human. Our findings indicated that pH1N1 may adapt well in mammals when acquiring these mutations. Therefore, future molecular epidemiological surveillance should include scrutiny of both markers because of their potential impact on pathogenesis

Clinical and biological progress over 50 years in Rett syndrome

In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families

The relation of joint laxity and trunk rotation

A study was designed to evaluate the joint laxity during scoliosis screening, and to show if there is a relation of joint laxity values to the trunk rotation. One thousand, two hundred and seventy-three children (598 females, 675 males) with an average age of 10.4 years were screened with a scoliometer and forward bending for trunk rotations. Scapular and shoulder elevations, flexible pes planus were recorded and joint laxity was evaluated with the Beighton score. There was high inter-observer and intra-observer reliability for both scoliometer and Beighton scores. In 41 children (3.2%) with Beighton score 7 or higher, trunk rotation measurements were higher than for the rest of the children. Trunk rotation measurements of 7 degrees or higher were found in 30 children, who were more lax than the rest of the group and were invited for radiography, with a detection of curves between 11 and 18 degrees in 10 of them. The Beighton score is a practical and reliable method for defining joint laxity. Although the number of patients with scoliosis was limited, there are findings supporting the relation between joint laxity and scoliosis. Moreover, there was increased laxity in children with increased trunk rotations. Ligamentous laxity may be one of the causes changing the contour of the back. (c) 2005 Lippincott Williams & Wilkins.C1 Pamukkale Univ, Sch Med, Dept Orthoped, Denizli, Turkey

The relation of joint laxity and trunk rotation.

A study was designed to evaluate the joint laxity during scoliosis screening, and to show if there is a relation of joint laxity values to the trunk rotation. One thousand, two hundred and seventy-three children (598 females, 675 males) with an average age of 10.4 years were screened with a scoliometer and forward bending for trunk rotations. Scapular and shoulder elevations, flexible pes planus were recorded and joint laxity was evaluated with the Beighton score. There was high inter-observer and intra-observer reliability for both scoliometer and Beighton scores. In 41 children (3.2%) with Beighton score 7 or higher, trunk rotation measurements were higher than for the rest of the children. Trunk rotation measurements of 7 degrees or higher were found in 30 children, who were more lax than the rest of the group and were invited for radiography, with a detection of curves between 11 and 18 degrees in 10 of them. The Beighton score is a practical and reliable method for defining joint laxity. Although the number of patients with scoliosis was limited, there are findings supporting the relation between joint laxity and scoliosis. Moreover, there was increased laxity in children with increased trunk rotations. Ligamentous laxity may be one of the causes changing the contour of the back