Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection

Bovine African Trypanosomosis is an infectious parasitic disease affecting livestock productivity and thereby impairing the economic development of Sub-Saharan Africa. The most important trypanosome species implicated is T. congolense, causing anemia as most important pathological feature. Using murine models, it was shown that due to the parasite's efficient immune evasion mechanisms, including (i) antigenic variation of the variable surface glycoprotein (VSG) coat, (ii) induction of polyclonal B cell activation, (iii) loss of B cell memory and (iv) T cell mediated immunosuppression, disease prevention through vaccination has so far been impossible. In trypanotolerant models a strong, early pro-inflammatory immune response involving IFN-gamma, TNF and NO, combined with a strong humoral anti-VSG response, ensures early parasitemia control. This potent protective inflammatory response is counterbalanced by the production of the anti-inflammatory cytokine IL-10, which in turn prevents early death of the host from uncontrolled hyper-inflammation-mediated immunopathologies. Though at this stage different hematopoietic cells, such as NK cells, T cells and B cells as well as myeloid cells (i.e. alternatively activated myeloid cells (M2) or Ly6c(-) monocytes), were found to produce IL-10, the contribution of non-hematopoietic cells as potential IL-10 source during experimental T. congolense infection has not been addressed. Here, we report for the first time that during the chronic stage of T. congolense infection non-hematopoietic cells constitute an important source of IL-10. Our data shows that hepatocyte-derived IL-10 is mandatory for host survival and is crucial for the control of trypanosomosis-induced inflammation and associated immunopathologies such as anemia, hepatosplenomegaly and excessive tissue injury. Author summary Bovine African Trypanosomosis is a parasitic disease of veterinary importance that adversely affects the public health and economic development of sub-Saharan Africa. The most important trypanosome species implicated is T. congolense, causing anemia as most important pathological feature and major cause of death. Using murine models, it was shown that the disease is characterized by a well-timed and balanced production of pro-inflammatory cytokine promoting factors followed by an anti-inflammatory response, involving IL-10. The latter is required to attenuate infection-associated pathogenicity and to prevent early host death from uncontrolled hyper-inflammation mediated immunopathologies. However, the cellular source of IL-10 in vivo and the window within which these cells exert their function during the course of African trypanosomiasis remain poorly understood, which hampers the design of effective therapeutic strategies. Using a T. congolense infection mouse model, relevant for bovine trypanosomosis, we demonstrate that during the chronic stage of infection hepatocyte-derived IL-10, but not myeloid cell-derived IL-10, regulates the main infection-associated immunopathologies and ultimately mediates host survival. Hence, strategies that tilt the balance of hepatocyte cytokine production in favor of IL-10 could majorly impact the wellbeing and survival of T. congolense-infected animals. Given the unmet medical need for this parasite infection, our findings offer promise for improved treatment protocols in the field

Trypanosoma brucei brucei infection impairs MHC class II antigen presentation capacity of macrophages

During African trypanosomiasis, macrophages play a central role in T cell hyporesponsiveness to parasite-related and unrelated antigens. In this study, the ability of macrophages from Trypanosoma b. brucei-infected mice to present exogenous antigens to a major histocompatibility complex (MHC) class II-restricted CD4(+) T cell hybridoma was analysed. We demonstrate that the antigen presentation capacity of macrophages from infected mice is markedly reduced as a result of a lower expression of [MHC class II-peptide] complexes on their plasma membrane. This defect did not result from a decreased antigen uptake/catabolism, a reduced MHC class II and intercellular adhesion molecule 1 expression on the surface of macrophages, a decreased affinity of MHC class II molecules for antigenic peptides, a competition between exogenous and parasite antigens, or the generation of inhibitory peptides. Our data indicate that the step resulting in coexpression of processed antigens and MHC class II molecules is affected in T. b. brucei-infected mice. Additionally, macrophages from infected mice secreted IL-10 that in turn contributes to the impairment of T cell activation

Neutron-induced Fission Cross Section of240,242Pu

A sensitivity analysis for the new generation of fast reactors [Salvatores (2008)] has shown the importance of improved cross section data for several actinides. Among them, the240,242Pu(n,f) cross sections require an accuracy improvement to 1-3% and 3-5%, respectively, from the current level of 6% and 20%. At the Van de Graaff facility of the Institute for Reference Materials and Measurements (JRC-IRMM) the fission cross section of the two isotopes was measured relative to two secondary standard reactions,237Np(n,f) and238U(n,f), using a twin Frisch-grid ionization chamber. The secondary standard reactions were benchmarked through measurements against the primary standard reaction235U(n,f) in the same geometry. Sample masses were determined by means of low-geometry alpha counting or/and a 2p Frisch-grid ionization chamber, with an uncertainty lower than 2%. The neutron flux and the impact of scattering from material between source and target was examined, the largest effect having been found in cross section ratio measurements between a fissile and a fertile isotope. Our240,242Pu(n,f) cross sections are in agreement with previous experimental results and slightly lower than present evaluations. In case of the242Pu(n,f) reaction no evidence for a resonance at En=1.1 MeV was found.Postprint (published version

MIF contributes to Trypanosoma brucei associated immunopathogenicity development

African trypanosomiasis is a chronic debilitating disease affecting the health and economic well-being of many people in developing countries. The pathogenicity associated with this disease involves a persistent inflammatory response, whereby M1-type myeloid cells, including Ly6C(high) inflammatory monocytes, are centrally implicated. A comparative gene analysis between trypanosusceptible and trypanotolerant animals identified MIF (macrophage migrating inhibitory factor) as an important pathogenic candidate molecule. Using MIF-deficient mice and anti-MIF antibody treated mice, we show that MIF mediates the pathogenic inflammatory immune response and increases the recruitment of inflammatory monocytes and neutrophils to contribute to liver injury in Trypanosoma brucei infected mice. Moreover, neutrophil-derived MIF contributed more significantly than monocyte-derived MIF to increased pathogenic liver TNF production and liver injury during trypanosome infection. MIF deficient animals also featured limited anemia, coinciding with increased iron bio-availability, improved erythropoiesis and reduced RBC clearance during the chronic phase of infection. Our data suggest that MIF promotes the most prominent pathological features of experimental trypanosome infections (i.e. anemia and liver injury), and prompt considering MIF as a novel target for treatment of trypanosomiasis-associated immunopathogenicity

Effects of low carbohydrate diets high in red meats or poultry, fish and shellfish on plasma lipids and weight loss

<p>Abstract</p> <p>Background</p> <p>Low carbohydrate diets (LCDs) have been demonstrated to be effective tools for promoting weight loss and an improved plasma lipid profile. Such diets are often associated with increased meat consumption, either poultry, fish, and shellfish (PFS), which are generally high in polyunsaturated fat (PUFA) or red meats (RM), generally high in saturated fat (SFA). The fatty acid profile and content of a diet may influence the plasma lipid profile of humans. This study examined whether the type of meat consumed could influence the outcome of an LCD.</p> <p>Methods</p> <p>Moderately obese subjects consumed two different LCDs as part of a weight loss regimen: 1) a diet high in foods of mammalian origin (RM) intended to contain more SFA, or 2) a diet high in PFS intended to contain more PUFA. Diet dependent changes in body weight, nutritional intake, and plasma lipids were evaluated during a 28 day study period.</p> <p>Results</p> <p>Both diets were associated with significant weight loss after 28 days, -5.26 ± 0.84 kg and -5.74 ± 0.63 kg for RM and PFS groups, respectively. The PFS diet was associated with a significantly higher intake of PUFA and cholesterol. Despite high cholesterol and fat intakes, neither diet was associated with significant changes in plasma cholesterol or the plasma lipoprotein cholesterol profile. While plasma triglycerides were reduced in both groups, the effect was only statistically significant for the PFS diet.</p

MIF-mediated hemodilution promotes pathogenic anemia in experimental African trypanosomosis

Animal African trypanosomosis is a major threat to the economic development and human health in sub-Saharan Africa. Trypanosoma congolense infections represent the major constraint in livestock production, with anemia as the major pathogenic lethal feature. The mechanisms underlying anemia development are ill defined, which hampers the development of an effective therapy. Here, the contribution of the erythropoietic and erythrophagocytic potential as well as of hemodilution to the development of T. congolense-induced anemia were addressed in a mouse model of low virulence relevant for bovine trypanosomosis. We show that in infected mice, splenic extramedullary erythropoiesis could compensate for the chronic low-grade type I inflammation-induced phagocytosis of senescent red blood cells ( RBCs) in spleen and liver myeloid cells, as well as for the impaired maturation of RBCs occurring in the bone marrow and spleen. Rather, anemia resulted from hemodilution. Our data also suggest that the heme catabolism subsequent to sustained erythrophagocytosis resulted in iron accumulation in tissue and hyperbilirubinemia. Moreover, hypoalbuminemia, potentially resulting from hemodilution and liver injury in infected mice, impaired the elimination of toxic circulating molecules like bilirubin. Hemodilutional thrombocytopenia also coincided with impaired coagulation. Combined, these effects could elicit multiple organ failure and uncontrolled bleeding thus reduce the survival of infected mice. MIF ( macrophage migrating inhibitory factor), a potential pathogenic molecule in African trypanosomosis, was found herein to promote erythrophagocytosis, to block extramedullary erythropoiesis and RBC maturation, and to trigger hemodilution. Hence, these data prompt considering MIF as a potential target for treatment of natural bovine trypanosomosis

Evolutie in actie. Behoud van de zeldzame Duinwespenorchis in de kustduinen-

Ecological speciation is the process by which one species diverges intotwo distinct phylogenetic lineages that gradually become reproductivelyisolated from each other after they have colonized a new habitat. Because ecological speciation typically occurs across a continuum of time and several intermediate stages, often called ecological races or ecotypes, can be discerned during the speciation process, it may result in a complex of taxa among which species limits are difficult to define. A typical example of a species group among which species limits are difficult to define is the genus Epipactis. It contains a complex of autogamous and non-autogamous taxa that may have arisen after the colonization of new habitats, followed by rapid adaptation and evolutionary changes in key traits that allow establishment and survival in these newly colonized habitats. However, the taxonomic status of these species is problematic and different authors have treated the taxonomy of Epipactis in different ways, some recognizing the different taxa as distinct species, others considering them only as minor intraspecific variants or ecological races. Here we present the results of genomic, meta-genomic and morphological analyses aimed at investigating the taxonomic status of coastal dune populations of the widespread terrestrial orchid Epipactis helleborine. Investigations of the mycorrhizal fungi associating with coastal dune populations and typical forest populations has shown that they associate with significantly different fungal communities. Crossing experiments show that both taxa easily cross and produce viable seeds. However, germination of seeds of dune populations in forest habitat andvice versa was always lower than that of seeds of coastal populations indune habitats or of forest populations in forest habitat, leading to strong reproductive isolation as a result of immigrant inviability. Genomic analyses using SNP markers further revealed that coastal dune populations diverged only about 50 generations ago from inland populations, went through a significant bottleneck and were most likely the result of a single colonization event. The sampled dune populations also showed very little genetic differentiation and no apparent spatial genetic structure was observed. Overall these results are consistent with a process of genetic divergence after a single very recent colonization event followed by extensive gene flow among populations. From a taxonomic point of view coastal dune populations of E. helleborine should not be treated as a separate species, but rather as an ecotype

Cutting errors in total knee replacement: Assessment by computer assisted surgery

The observed errors in the position of the implanted prosthesis can be due to a number of potential causes. One of these is the potential error during execution of the bone cuts. However, there is only minimal information on this in the current literature. The amount of cutting errors in 40 consecutive total knee replacements was reported. All the operations were done by the same surgeon. The amount of cutting error was measured by the use of computer navigation system. It was hypothesized that there was no difference in the amount of error between bone cut through the cutting slot (slotted cutting) and bone cut done on the surface of the cutting guide (open cutting). It was found that the average absolute cutting error was 1° in the coronal plane and 1.4° in the sagittal plane. Significantly more outlier (more than 3°) was observed in the errors in the sagittal plane (P = 0.014, chi square test). Open cutting resulted in less error in the sagittal plane of the tibial cut when compared with slotted cutting (P = 0.031, Mann-Whitney U Test). This was attributed by the use of a thicker saw blade with higher stiffness in the open cutting method. © 2008 Springer-Verlag.postprin