Brain structure in children with congenital visual disorders and visual impairment

AIM: To examine if congenital visual impairment is associated with differences in brain anatomy in children. METHOD: Ten children (8-12y) with congenital disorders of the peripheral visual system with severe visual impairment (SVI; >0.8 logMAR) or mild-to-moderate visual impairment (MVI; 0.6-0.8 logMAR) were compared to 21 typically sighted comparison (TSC) children. Thalamus volume, grey matter density, white matter microstructure, and integrity of visual tracts were investigated in SVI, MVI, and TSC groups with anatomical and diffusion-weighted magnetic resonance imaging. RESULTS: Compared to the TSC group, the SVI group had lower white matter integrity in tracts of the visual system (optic radiations: SVI 0.35±0.015, TSC 0.39±0.007 [p=0.022]; posterior corpus callosum: SVI 0.37±0.019; TSC 0.42±0.009 [p=0.033]) and lower left thalamus volume (SVI 4.37±0.087; TSC 4.99±0.339 [p=0.015]). Neuroanatomical differences were greater in the SVI group, while no consistent differences between the MVI and TSC group were observed. INTERPRETATION: Posterior tracts of the visual system are compromised in children with congenital visual impairment versus those who are typically sighted. The severity of visual input appears to have affected neuroanatomical development as significant reductions were only found in the SVI group. WHAT THIS PAPER ADDS: Severe visual impairment in mid-childhood is associated with reduced integrity of visual pathways and reduced thalamus volume

Impaired antibody-mediated protection and defective IgA B cell memory in experimental infection of adults with respiratory syncytial virus

Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) re-infects throughout life. After >40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. Objectives: Characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B cell frequencies and antibody longevity. Measurements and Main Results: Despite moderately high levels of pre-existing serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from PCR-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects, but correlated with plasmablasts that peaked around day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, where virus-specific IgA memory B cells were readily recovered. Conclusions: This observed specific defect in IgA memory may partly explain RSV's ability to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone

Impaired antibody-mediated protection and defective IgA B cell memory in experimental infection of adults with respiratory syncytial virus

Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) re-infects throughout life. After >40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. Objectives: Characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B cell frequencies and antibody longevity. Measurements and Main Results: Despite moderately high levels of pre-existing serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from PCR-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects, but correlated with plasmablasts that peaked around day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, where virus-specific IgA memory B cells were readily recovered. Conclusions: This observed specific defect in IgA memory may partly explain RSV's ability to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone

Mechanisms controlling anaemia in Trypanosoma congolense infected mice.

Trypanosoma congolense are extracellular protozoan parasites of the blood stream of artiodactyls and are one of the main constraints on cattle production in Africa. In cattle, anaemia is the key feature of disease and persists after parasitaemia has declined to low or undetectable levels, but treatment to clear the parasites usually resolves the anaemia. The progress of anaemia after Trypanosoma congolense infection was followed in three mouse strains. Anaemia developed rapidly in all three strains until the peak of the first wave of parasitaemia. This was followed by a second phase, characterized by slower progress to severe anaemia in C57BL/6, by slow recovery in surviving A/J and a rapid recovery in BALB/c. There was no association between parasitaemia and severity of anaemia. Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia. Expression of genes involved in erythropoiesis and iron metabolism was followed in spleen, liver and kidney tissues in the three strains of mice using microarrays. There was no evidence for a response to erythropoietin, consistent with anaemia of chronic disease, which is erythropoietin insensitive. However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng. The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect. Several transcription factors regulating haematopoiesis, Tal1, Gata1, Zfpm1 and Klf1 were expressed at consistently lower levels in C57BL/6 mice suggesting that these mice have a lower haematopoietic capacity and therefore less ability to recover from haemolysis induced anaemia after infection

Concurrent Detection of Circulating Minor Histocompatibility Antigen-Specific CD8+ T Cells in SCT Recipients by Combinatorial Encoding MHC Multimers

Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for patients with hematologic malignancies. Its therapeutic effect is largely dependent on recognition of minor histocompatibility antigens (MiHA) by donor-derived CD8+ T cells. Therefore, monitoring of multiple MiHA-specific CD8+ T cell responses may prove to be valuable for evaluating the efficacy of allogeneic SCT. In this study, we investigated the use of the combinatorial encoding MHC multimer technique to simultaneously detect MiHA-specific CD8+ T cells in peripheral blood of SCT recipients. Feasibility of this approach was demonstrated by applying dual-color encoding MHC multimers for a set of 10 known MiHA. Interestingly, single staining using a fluorochrome- and Qdot-based five-color combination showed comparable results to dual-color staining for most MiHA-specific CD8+ T cell responses. In addition, we determined the potential value of combinatorial encoding MHC multimers in MiHA identification. Therefore, a set of 75 candidate MiHA peptides was predicted from polymorphic genes with a hematopoietic expression profile and further selected for high and intermediate binding affinity for HLA-A2. Screening of a large cohort of SCT recipients resulted in the detection of dual-color encoded CD8+ T cells following MHC multimer-based T cell enrichment and short ex vivo expansion. Interestingly, candidate MiHA-specific CD8+ T cell responses for LAG3 and TLR10 derived polymorphic peptides could be confirmed by genotyping of the respective SNPs. These findings demonstrate the potency of the combinatorial MHC multimer approach in the monitoring of CD8+ T cell responses to known and potential MiHA in limited amounts of peripheral blood from allogeneic SCT recipients

Long-term evidence for ecological intensification as a pathway to sustainable agriculture

Ecological intensification (EI) could help return agriculture into a 'safe operating space' for humanity. Using a novel application of meta-analysis to data from 30 long-term experiments from Europe and Africa (comprising 25,565 yield records), we investigated how field-scale EI practices interact with each other, and with N fertilizer and tillage, in their effects on long-term crop yields. Here we confirmed that EI practices (specifically, increasing crop diversity and adding fertility crops and organic matter) have generally positive effects on the yield of staple crops. However, we show that EI practices have a largely substitutive interaction with N fertilizer, so that EI practices substantially increase yield at low N fertilizer doses but have minimal or no effect on yield at high N fertilizer doses. EI practices had comparable effects across different tillage intensities, and reducing tillage did not strongly affect yields.Intensifying food production sustainably is critical given growing demand and agriculture's environmental footprint. This meta-analysis finds that practices such as adding organic matter and increasing crop diversity can partly substitute for nitrogen fertilizer to sustain or increase yields

Statistical modeling of ground motion relations for seismic hazard analysis

We introduce a new approach for ground motion relations (GMR) in the probabilistic seismic hazard analysis (PSHA), being influenced by the extreme value theory of mathematical statistics. Therein, we understand a GMR as a random function. We derive mathematically the principle of area-equivalence; wherein two alternative GMRs have an equivalent influence on the hazard if these GMRs have equivalent area functions. This includes local biases. An interpretation of the difference between these GMRs (an actual and a modeled one) as a random component leads to a general overestimation of residual variance and hazard. Beside this, we discuss important aspects of classical approaches and discover discrepancies with the state of the art of stochastics and statistics (model selection and significance, test of distribution assumptions, extreme value statistics). We criticize especially the assumption of logarithmic normally distributed residuals of maxima like the peak ground acceleration (PGA). The natural distribution of its individual random component (equivalent to exp(epsilon_0) of Joyner and Boore 1993) is the generalized extreme value. We show by numerical researches that the actual distribution can be hidden and a wrong distribution assumption can influence the PSHA negatively as the negligence of area equivalence does. Finally, we suggest an estimation concept for GMRs of PSHA with a regression-free variance estimation of the individual random component. We demonstrate the advantages of event-specific GMRs by analyzing data sets from the PEER strong motion database and estimate event-specific GMRs. Therein, the majority of the best models base on an anisotropic point source approach. The residual variance of logarithmized PGA is significantly smaller than in previous models. We validate the estimations for the event with the largest sample by empirical area functions. etc

Movement of environmental threats modifies the relevance of the defensive eye-blink in a spatially-tuned manner.

Subcortical reflexive motor responses are under continuous cortical control to produce the most effective behaviour. For example, the excitability of brainstem circuitry subserving the defensive hand-blink reflex (HBR), a response elicited by intense somatosensory stimuli to the wrist, depends on a number of properties of the eliciting stimulus. These include face-hand proximity, which has allowed the description of an HBR response field around the face (commonly referred to as a defensive peripersonal space, DPPS), as well as stimulus movement and probability of stimulus occurrence. However, the effect of stimulus-independent movements of objects in the environment has not been explored. Here we used virtual reality to test whether and how the HBR-derived DPPS is affected by the presence and movement of threatening objects in the environment. In two experiments conducted on 40 healthy volunteers, we observed that threatening arrows flying towards the participant result in DPPS expansion, an effect directionally-tuned towards the source of the arrows. These results indicate that the excitability of brainstem circuitry subserving the HBR is continuously adjusted, taking into account the movement of environmental objects. Such adjustments fit in a framework where the relevance of defensive actions is continually evaluated, to maximise their survival value