Trypanosoma cruzi infection induces a massive extrafollicular and follicular splenic B-cell response which is a high source of non-parasite-specific antibodies

Acute infection with Trypanosoma cruzi, the aetiological agent of Chagas’ disease, results in parasitaemia and polyclonal lymphocyte activation. It has been reported that polyclonal B‐cell activation is associated with hypergammaglobulinaemia and delayed parasite‐specific antibody response. In the present study we analysed the development of a B‐cell response within the different microenvironments of the spleen during acute T. cruzi infection. We observed massive germinal centre (GC) and extrafollicular (EF) responses at the peak of infection. However, the EF foci were evident since day 3 post‐infection (p.i.), and, early in the infection, they mainly provided IgM. The EF foci response reached its peak at 11 days p.i. and extended from the red pulp into the periarteriolar lymphatic sheath. The GCs were detected from day 8 p.i. At the peak of parasitaemia, CD138⁺ B220⁺ plasma cells in EF foci, red pulp and T‐cell zone expressed IgM and all the IgG isotypes. Instead of the substantial B‐cell response, most of the antibodies produced by splenic cells did not target the parasite, and parasite‐specific IgG isotypes could be detected in sera only after 18 days p.i. We also observed that the bone marrow of infected mice presented a strong reduction in CD138⁺ B220⁺ cells compared with that of normal mice. Hence, in acute infection with T. cruzi, the spleen appears to be the most important lymphoid organ that lodges plasma cells and the main producer of antibodies. The development of a B‐cell response during T. cruzi infection shows features that are particular to T. cruzi and other protozoan infection but different to other infections or immunization with model antigens.     

Peripheral blood cells chimerism after unrelated cord blood transplantation in children: kinetics,predictive factors and impact on post‐transplant outcome

This study aimed to describe kinetics of complete donor chimerism occurrence (cDC, >99·9% donor) after unrelated cord blood transplantation (UCBT), to identify its predictive factors and its impact on post‐transplant outcome. Ninety‐four children who received single UCBT after a myeloablative conditioning regimen had blood chimerism evaluation at predefined post‐transplant dates, using a real‐time polymerase chain reaction method with 0·1% sensitivity. Cumulative incidence of cDC at 1 year post‐transplantation was 61·8%. Three predictive factors were identified in multivariate analysis: history of malignant disease (P = 0·03), older age (above 2·16 years, the first quartile of age, P = 0·0055) and higher level of cord/recipient human leucocyte antigen mismatch (4/6 vs. 5‐6/6, P < 0·001) increased the probability of post‐transplant cDC. Although graft cell dose had a strong impact on haematological recovery, it did not apparently influence cDC occurrence. Early cDC (i.e. more than 99·9% donor chimerism on days 15–30 post‐transplant) appeared useful to predict engraftment (P = 0·003) as well as acute and chronic graft‐versus‐host disease (GvHD). Severe acute or chronic GvHD never occurred in patients with DC ≤99·9%, suggesting than even minimal residual host haematopoiesis is associated with a very low risk of GvHD after UCBT.     

Temporally structured metapopulation dynamics and persistence of influenza A H3N2 virus in humans

Populations of seasonal influenza virus experience strong annual bottlenecks that pose a considerable extinction risk. It has been suggested that an influenza source population located in tropical Southeast or East Asia seeds annual temperate epidemics. Here we investigate the seasonal dynamics and migration patterns of influenza A H3N2 virus by analysis of virus samples obtained from 2003 to 2006 from Australia, Europe, Japan, New York, New Zealand, Southeast Asia, and newly sequenced viruses from Hong Kong. In contrast to annual temperate epidemics, relatively low levels of relative genetic diversity and no seasonal fluctuations characterized virus populations in tropical Southeast Asia and Hong Kong. Bayesian phylogeographic analysis using discrete temporal and spatial characters reveal high rates of viral migration between urban centers tested. Although the virus population that migrated between Southeast Asia and Hong Kong persisted through time, this was dependent on virus input from temperate regions and these tropical regions did not maintain a source for annual H3N2 influenza epidemics. We further show that multiple lineages may seed annual influenza epidemics, and that each region may function as a potential source population. We therefore propose that the global persistence of H3N2 influenza A virus is the result of a migrating metapopulation in which multiple different localities may seed seasonal epidemics in temperate regions in a given year. Such complex global migration dynamics may confound control efforts and contribute to the emergence and spread of antigenic variants and drug-resistant viruses.     

Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling

Intestinal barrier function requires intricate cooperation between intestinal epithelial cells and immune cells. Enteropathogens are able to invade the intestinal lymphoid tissue known as Peyer's patches (PPs) and disrupt the integrity of the intestinal barrier. However, the underlying molecular mechanisms of this process are poorly understood. In mice infected with Yersinia pseudotuberculosis, we found that PP barrier dysfunction is dependent on the Yersinia virulence plasmid and the expression of TLR-2 by hematopoietic cells, but not by intestinal epithelial cells. Upon TLR-2 stimulation, Y. pseudotuberculosis-infected monocytes activated caspase-1 and produced IL-1β. In turn, IL-1β increased NF-κB and myosin light chain kinase activation in intestinal epithelial cells, thus disrupting the intestinal barrier by opening the tight junctions. Therefore, Y. pseudotuberculosis subverts intestinal barrier function by altering the interplay between immune and epithelial cells during infection.     

Use of non-invasive cardiac investigations to predict clinical endpoints after coronary bypass graft surgery in coronary artery disease patients: results from the prognosis and evaluation of risk in the coronary operated patient (PERISCOP) study.

AIMS: Little is known about which patients who have undergone coronary bypass surgery are at risk of future clinical cardiovascular events and may benefit from further medical treatment. We sought to determine if routine non-invasive cardiac investigations performed early after surgery were able to stratify the risk of cardiovascular events in this population. METHODS: Two thousand and sixty-five consecutive patients were enrolled in a prospective multicenter study (PERISCOP). Exercise testing, echocardiography, and 24-h ambulatory ECG monitoring were performed at day 20+/-10 after coronary bypass surgery. Follow-up was performed 1 year after coronary bypass surgery. Causes of all hospitalisation and death occurring within 1 year were documented and classified by an End-point Committee. The principal endpoint was the combination of all-cause deaths and cardiovascular events requiring hospitalisation (myocardial infarction, unstable or severe angina, stroke, congestive heart failure). RESULTS: The 1-year frequency of first events was 155 (8%). In multivariate analysis, exercise duration <420s (RR=1.68; 95% CI: 1.13-2.49), exercise induced ST segment depression >1mm (RR=1.90; 95% CI: 1.18-3.05), and left ventricular (LV) dysfunction (wall motion index <1.15) (RR=1.97; 95% CI: 1.10-3.51) were independent predictors of cardiovascular events and deaths. Ambulatory ECG monitoring had no predictive value. CONCLUSIONS: Exercise testing and echocardiography performed early after coronary bypass surgery are able to identify high-risk patients who may benefit from intensive secondary prevention.     

Respiratory muscle metabolic activity on PET/CT correlates with obstructive ventilatory defect severity and prognosis in patients undergoing lung cancer surgery

Background and Objective

Respiratory muscle activity is increased in patients with chronic respiratory disease. ¹⁸F-FDG-PET/CT can assess respiratory muscle activity. We hypothesized that respiratory muscles metabolism was correlated to lung function impairment and was associated to prognosis in patients undergoing lung cancer surgery based on the research question whether respiratory muscle metabolism quantitatively correlates with the severity of lung function impairment in patients? Does respiratory muscle hypermetabolism have prognostic value?

Methods

Patients undergoing ¹⁸F-FDG-PET/CT and pulmonary function tests prior to lung cancer surgery were identified. Maximum Standardized Uptake Value (SUVm) were measured in each respiratory muscle group (sternocleidomastoid, scalene, intercostal, diaphragm), normalized against deltoid SUVm. Respiratory muscle hypermetabolism was defined as SUVm >90th centile in any respiratory muscle group. Clinical outcomes were collected from a prospective cohort.

Results

One hundred fifty-six patients were included, mostly male [110 (71%)], 53 (34%) with previous diagnosis of COPD. Respiratory muscle SUVm were: scalene: 1.84 [1.51–2.25], sternocleidomastoid 1.64 [1.34–1.95], intercostal 1.01 [0.84–1.16], diaphragm 1.79 [1.41–2.27]. Tracer uptake was inversely correlated to FEV1 for the scalene (r = −0.29, p < 0.001) and SCM (r = −0.17, p = 0.03) respiratory muscle groups and positively correlated to TLC for the scalene (r = 0.17, p = 0.04). Respiratory muscle hypermetabolism was found in 45 patients (28.8%), who had a lower VO₂ max (15.4 [14.2–17.5] vs. 17.2 mL/kg/min [15.2–21.1], p = 0.07) and poorer overall survival when adjusting to FEV1% (p < 0.01).

Conclusion

Our findings show respiratory muscle hypermetabolism is associated with lung function impairment and has prognostic significance. ¹⁸F-FDG/PET-CT should be considered as a tool for assessing respiratory muscle activity and to identify high-risk patients.     

Nociceptive and sympathetic innervations in the abaxial part of the cranial horn of the equine medial meniscus: an immunohistochemical approach

In athletic horses, diseases leading to lameness are of great importance due to the loss of performance and the resultant economic concerns. Although stifle lesions are frequent in the hindlimb, due to the large size and complexity of the joint, and although meniscal tears have been identified as the most common soft tissue injuries in this joint, little is known about the mechanism that causes the painful sensation and thus the lameness. The aim of our study was to highlight any peripheral fibres involved in meniscal nociception in five macroscopically sound cranial horns of the equine medial meniscus, which has been one of the most common sites reported for equine meniscal injuries. Immunohistochemical stainings were performed using antibodies against Substance P in order to identify nociceptive fibres; against tyrosine hydroxylase for detecting postganglionic sympathetic fibres; and against glial fibrillary acidic proteins in order to identify Schwann cells. Our work highlights for the first time the presence of nociceptive and sympathetic fibres in equine menisci. They were found in the abaxial part of the cranial horn of the equine medial meniscus. This study suggests that when the abaxial part is injured, the meniscus itself could be the source of pain. These findings could provide a better understanding of the clinical presentation of horses with meniscal injury and contribute towards improving therapeutic strategies to alleviate pain in cases of equine meniscal injury.     

Primary infection of C57BL/6 mice with Plasmodium yoelii induces a heterogeneous response of NKT cells

NKT cells are a population of innate-like lymphocytes that display effector functions and immunoregulatory properties. We characterized the NKT cell response induced in C57BL/6 mice during a primary infection with Plasmodium yoelii sporozoites. We observed a heterogeneous NKT cell response that differed between liver and spleen. Hepatic NKT cells found in infected livers consisted mainly of CD1d-dependent CD4+ and double-negative (DN) NKT cells, whereas CD1d-independent NKT cells exhibiting a TCR(high) CD4(high) phenotype were prominent among splenic NKT cells during the infection. Hepatic and splenic NKT cells isolated from infected mice were activated and secreted mainly gamma interferon and tumor necrosis factor alpha in response to stimulation. Finally, P. yoelii-activated hepatic DN NKT cells inhibited the parasite's liver stage in a CD1d-dependent manner in vitro. However, experiments using B6.CD1d-deficient mice showed that CD1d and CD1d-restricted NKT cells are not necessary to control the parasite's development in vivo during neither the preerythrocytic stage nor the erythrocytic stage. Thus, our results show that a primary P. yoelii infection induces a heterogeneous and organ-specific response of NKT cells and that CD1d-dependent NKT cells play a minor role in the control of the development of Plasmodium in vivo in our model.     

Effects of acute dopamine depletion on the electrophysiological properties of striatal neurons

The striatum, the main input nucleus of basal ganglia, receives a massive innervation from the entire cerebral cortex and is in charge of the detection of behaviorally relevant signals. In turn, via its projections to the output nuclei of basal ganglia, the striatum contributes to the organization of appropriate compartmental responses. Substantia nigra pars compacta dopaminergic neurons project predominantly to the striatum and regulate striatal functions. Implications of dopaminergic receptors on the physiology of striatal neurons are now well documented. By contrast, the effects of acute dopamine depletion on striatal neurons remain poorly explored. Here, the alpha-methyl-para-tyrosine was used to deplete dopamine from rat brain slices. We analyzed the consequences of a alpha-methyl-para-tyrosine treatment on membrane properties of striatal neurons: the medium-sized spiny neurons and the interneurons (GABAergic, cholinergic and NO-synthase). After acute dopamine depletion, medium-sized spiny neurons became more excitable. GABAergic interneurons became less excitable whereas cholinergic cells displayed an increased excitability. NO-synthase-containing interneurons did not show noticeable changes in their excitability. Such membrane properties changes indicate that striatal circuits should undergo major alteration in cortico-basal ganglia information processing.