Microstructural Imaging in Temporal Lobe Epilepsy: Diffusion Imaging Changes Relate to Reduced Neurite Density

Purpose: Previous imaging studies in patients with refractory temporal lobe epilepsy (TLE) have examined the spatial distribution of changes in imaging parameters such as diffusion tensor imaging (DTI) metrics and cortical thickness. Multi-compartment models offer greater specificity with parameters more directly related to known changes in TLE such as altered neuronal density and myelination. We studied the spatial distribution of conventional and novel metrics including neurite density derived from NODDI (Neurite Orientation Dispersion and Density Imaging) and myelin water fraction (MWF) derived from mcDESPOT (Multi-Compartment Driven Equilibrium Single Pulse Observation of T1/T2)] to infer the underlying neurobiology of changes in conventional metrics. / Methods: 20 patients with TLE and 20 matched controls underwent magnetic resonance imaging including a volumetric T1-weighted sequence, multi-shell diffusion from which DTI and NODDI metrics were derived and a protocol suitable for mcDESPOT fitting. Models of the grey matter-white matter and grey matter-CSF surfaces were automatically generated from the T1-weighted MRI. Conventional diffusion and novel metrics of neurite density and MWF were sampled from intracortical grey matter and subcortical white matter surfaces and cortical thickness was measured. / Results: In intracortical grey matter, diffusivity was increased in the ipsilateral temporal and frontopolar cortices with more restricted areas of reduced neurite density. Diffusivity increases were largely related to reductions in neurite density, and to a lesser extent CSF partial volume effects, but not MWF. In subcortical white matter, widespread bilateral reductions in fractional anisotropy and increases in radial diffusivity were seen. These were primarily related to reduced neurite density, with an additional relationship to reduced MWF in the temporal pole and anterolateral temporal neocortex. Changes were greater with increasing epilepsy duration. Bilaterally reduced cortical thickness in the mesial temporal lobe and centroparietal cortices was unrelated to neurite density and MWF. / Conclusions: Diffusivity changes in grey and white matter are primarily related to reduced neurite density with an additional relationship to reduced MWF in the temporal pole. Neurite density may represent a more sensitive and specific biomarker of progressive neuronal damage in refractory TLE that deserves further study

A Comparison of Initial Antiretroviral Therapy in the Swiss HIV Cohort Study and the Recommendations of the International AIDS Society-USA

BACKGROUND: In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS). METHODS: Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS-USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year. RESULTS: Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients (adjusted odds ratio aOR 1.83, 95%CI 1.28-2.62), those with a high education level (aOR 1.49, 95%CI 1.07-2.06) or a high CD4 count (aOR 1.53, 95%CI 1.02-2.30) were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens (aOR 0.54, 95% CI 0.37-0.80) whereas CD4 count increase after one year of treatment was similar in both groups. CONCLUSIONS: Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations

TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression

BACKGROUND: During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. METHODS: This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out. RESULTS: No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates. CONCLUSION: By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals

Noise and Robustness in Phyllotaxis

A striking feature of vascular plants is the regular arrangement of lateral organs on the stem, known as phyllotaxis. The most common phyllotactic patterns can be described using spirals, numbers from the Fibonacci sequence and the golden angle. This rich mathematical structure, along with the experimental reproduction of phyllotactic spirals in physical systems, has led to a view of phyllotaxis focusing on regularity. However all organisms are affected by natural stochastic variability, raising questions about the effect of this variability on phyllotaxis and the achievement of such regular patterns. Here we address these questions theoretically using a dynamical system of interacting sources of inhibitory field. Previous work has shown that phyllotaxis can emerge deterministically from the self-organization of such sources and that inhibition is primarily mediated by the depletion of the plant hormone auxin through polarized transport. We incorporated stochasticity in the model and found three main classes of defects in spiral phyllotaxis – the reversal of the handedness of spirals, the concomitant initiation of organs and the occurrence of distichous angles – and we investigated whether a secondary inhibitory field filters out defects. Our results are consistent with available experimental data and yield a prediction of the main source of stochasticity during organogenesis. Our model can be related to cellular parameters and thus provides a framework for the analysis of phyllotactic mutants at both cellular and tissular levels. We propose that secondary fields associated with organogenesis, such as other biochemical signals or mechanical forces, are important for the robustness of phyllotaxis. More generally, our work sheds light on how a target pattern can be achieved within a noisy background

Distinct Kinetics of Memory B-Cell and Plasma-Cell Responses in Peripheral Blood Following a Blood-Stage Plasmodium chabaudi Infection in Mice

B cell and plasma cell responses take place in lymphoid organs, but because of the inaccessibility of these organs, analyses of human responses are largely performed using peripheral blood mononuclear cells (PBMC). To determine whether PBMC are a useful source of memory B cells and plasma cells in malaria, and whether they reflect Plasmodium-specific B cell responses in spleen or bone marrow, we have investigated these components of the humoral response in PBMC using a model of Plasmodium chabaudi blood-stage infections in C57BL/6 mice. We detected memory B cells, defined as isotype-switched IgD− IgM− CD19+ B cells, and low numbers of Plasmodium chabaudi Merozoite Surface Protein-1 (MSP1)-specific memory B cells, in PBMC at all time points sampled for up to 90 days following primary or secondary infection. By contrast, we only detected CD138+ plasma cells and MSP1-specific antibody-secreting cells within a narrow time frame following primary (days 10 to 25) or secondary (day 10) infection. CD138+ plasma cells in PBMC at these times expressed CD19, B220 and MHC class II, suggesting that they were not dislodged bone-marrow long-lived plasma cells, but newly differentiated migratory plasmablasts migrating to the bone marrow; thus reflective of an ongoing or developing immune response. Our data indicates that PBMC can be a useful source for malaria-specific memory B cells and plasma cells, but extrapolation of the results to human malaria infections suggests that timing of sampling, particularly for plasma cells, may be critical. Studies should therefore include multiple sampling points, and at times of infection/immunisation when the B-cell phenotypes of interest are likely to be found in peripheral blood