The Spleen CD4(+) T Cell Response to Blood-Stage Plasmodium chabaudi Malaria Develops in Two Phases Characterized by Different Properties

The pivotal role of spleen CD4(+) T cells in the development of both malaria pathogenesis and protective immunity makes necessary a profound comprehension of the mechanisms involved in their activation and regulation during Plasmodium infection. Herein, we examined in detail the behaviour of non-conventional and conventional splenic CD4(+) T cells during P. chabaudi malaria. We took advantage of the fact that a great proportion of CD4(+) T cells generated in CD1d(-/-) mice are I-A(b)-restricted (conventional cells), while their counterparts in I-Ab(-/-) mice are restricted by CD1d and other class IB major histocompatibility complex (MHC) molecules (non-conventional cells). We found that conventional CD4(+) T cells are the main protagonists of the immune response to infection, which develops in two consecutive phases concomitant with acute and chronic parasitaemias. The early phase of the conventional CD4(+) T cell response is intense and short lasting, rapidly providing large amounts of proinflammatory cytokines and helping follicular and marginal zone B cells to secrete polyclonal immunoglobulin. Both TNF-alpha and IFN-gamma production depend mostly on conventional CD4(+) T cells. IFN-gamma is produced simultaneously by non-conventional and conventional CD4(+) T cells. The early phase of the response finishes after a week of infection, with the elimination of a large proportion of CD4(+) T cells, which then gives opportunity to the development of acquired immunity. Unexpectedly, the major contribution of CD1d-restricted CD4(+) T cells occurs at the beginning of the second phase of the response, but not earlier, helping both IFN-gamma and parasite-specific antibody production. We concluded that conventional CD4(+) T cells have a central role from the onset of P. chabaudi malaria, acting in parallel with non-conventional CD4(+) T cells as a link between innate and acquired immunity. This study contributes to the understanding of malaria immunology and opens a perspective for future studies designed to decipher the molecular mechanisms behind immune responses to Plasmodium infection.

Plasma Superoxide Dismutase-1 as a Surrogate Marker of Vivax Malaria Severity

Background: Severe outcomes have been described for both Plasmodium falciparum and P. vivax infections. The identification of sensitive and reliable markers of disease severity is fundamental to improving patient care. An intense pro-inflammatory response with oxidative stress and production of reactive oxygen species is present in malaria. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and antioxidant agents such as superoxide dismutase-1 (SOD-1) are likely candidate biomarkers for disease severity. Here we tested whether plasma levels of SOD-1 could serve as a biomarker of severe vivax malaria. Methodology/Principal Findings: Plasma samples were obtained from residents of the Brazilian Amazon with a high risk for P. vivax transmission. Malaria diagnosis was made by both microscopy and nested PCR. A total of 219 individuals were enrolled: non-infected volunteers (n = 90) and individuals with vivax malaria: asymptomatic (n = 60), mild (n = 50) and severe infection (n = 19). SOD-1 was directly associated with parasitaemia, plasma creatinine and alanine amino-transaminase levels, while TNF-alpha correlated only with the later enzyme. The predictive power of SOD-1 and TNF-alpha levels was compared. SOD-1 protein levels were more effective at predicting vivax malaria severity than TNF-alpha. For discrimination of mild infection, elevated SOD-1 levels showed greater sensitivity than TNF-alpha (76% vs. 30% respectively; p < 0.0001), with higher specificity (100% vs. 97%; p < 0.0001). In predicting severe vivax malaria, SOD-1 levels exhibited higher sensitivity than TNF-alpha (80% vs. 56%, respectively; p < 0.0001; likelihood ratio: 7.45 vs. 3.14; p, 0.0001). Neither SOD-1 nor TNF-alpha could discriminate P. vivax infections from those caused by P. falciparum. Conclusion: SOD-1 is a powerful predictor of disease severity in individuals with different clinical presentations of vivax malaria.

Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance

Background: Despite clinical descriptions of severe vivax malaria cases having been reported, data regarding immunological and inflammatory patterns are scarce. In this report, the inflammatory and immunological status of both mild and severe vivax malaria cases are compared in order to explore immunopathological events in this disease. Methods and Results: Active and passive malaria case detections were performed during 2007 in Buritis, Rondonia, in the Brazilian Amazon. A total of 219 participants enrolled the study. Study individuals were classified according to the presence of Plasmodium vivax infection within four groups: non-infected (n = 90), asymptomatic (n = 60), mild (n = 50) and severe vivax infection (n = 19). A diagnosis of malaria was made by microscopy and molecular assays. Since at present no clear criteria define severe vivax malaria, this study adapted the consensual criteria from falciparum malaria. Patients with severe P. vivax infection were younger, had lived for shorter time in the endemic area, and recalled having experienced less previous malaria episodes than individuals with no malaria infection and with mild or asymptomatic infection. Strong linear trends were identified regarding increasing plasma levels of C reactive protein (CRP), serum creatinine, bilirubins and the graduation of disease severity. Plasma levels of tumour necrosis factor (TNF), interferon-gamma(IFN-gamma) and also IFN-gamma/interleukin-10 ratios were increased and exhibited a linear trend with gradual augmentation of disease severity. Both laboratory parameters of organ dysfunction and inflammatory cytokines were reduced during anti-parasite therapy in those patients with severe disease. Conclusion: Different clinical presentations of vivax malaria infection present strong association with activation of pro-inflammatory responses and cytokine imbalance. These findings are of utmost importance to improve current knowledge about physiopathological concepts of this serious widespread disease.

Hepatitis B Infection Is Associated with Asymptomatic Malaria in the Brazilian Amazon

Background: Areas that are endemic for malaria are also highly endemic for hepatitis B virus (HBV) infection. Nevertheless, it is unknown whether HBV infection modifies the clinical presentation of malaria. This study aimed to address this question. Methodology and Findings: An observational study of 636 individuals was performed in Rondonia, western Amazon, Brazil between 2006 and 2007. Active and passive case detections identified Plasmodium infection by field microscopy and nested Polymerase Chain Reaction (PCR). HBV infections were identified by serology and confirmed by real-time PCR. Epidemiological information and plasma cytokine profiles were studied. The data were analyzed using adjusted multinomial logistic regression. Plasmodium-infected individuals with active HBV infection were more likely to be asymptomatic (OR: 120.13, P < 0.0001), present with lower levels of parasitemia and demonstrate a decreased inflammatory cytokine profile. Nevertheless, co-infected individuals presented higher HBV viremia. Plasmodium parasitemia inversely correlated with plasma HBV DNA levels (r=-0.6; P=0.0003). Conclusion: HBV infection diminishes the intensity of malaria infection in individuals from this endemic area. This effect seems related to cytokine balance and control of inflammatory responses. These findings add important insights to the understanding of the factors affecting the clinical outcomes of malaria in endemic regions.

Determination of the minimum value of the safety factor from geodesic Alfven eigenmodes in Joint European Torus

An analysis of the experimental conditions under which low-frequency (70-150 kHz) Alfven eigertmodes (AE) are excited during the monster sawtooth in Joint European Torus [F Romanelli et al, Proceedings of the 22nd IAEA Fusion Energy Conference, Geneva, Switzerland, 2008] is presented for the specific case of a discharge with ion cyclotron heating (5 MW) Using a simplified AE model for modes excited at the Alfven wave continuum maximum with geodesic corrections taken into account, the temporal evolution of the value of the safety factor q(0) at the magnetic axis is determined We describe a new scheme to determine the time variation of q(0) that works under conditions in which other standard diagnostics, such as the motional Stark effect do not give reliable results such as during a monster sawtooth [doi 10 1063/1 3494212]

Dispersion of electron g-factor with optical transition energy in (In,Ga)As/GaAs self-assembled quantum dots

The electron spin precession about an external magnetic field was studied by Faraday rotation on an inhomogeneous ensemble of singly charged, self-assembled (In,Ga)As/GaAs quantum dots. From the data the dependence of electron g-factor on optical transition energy was derived. A comparison with literature reports shows that the electron g-factors are quite similar for quantum dots with very different geometrical parameters, and their change with transition energy is almost identical. (C) 2011 American Institute of Physics. [doi:10.1063/1.3588413]

Identification of the Schistosoma mansoni TNF-Alpha Receptor Gene and the Effect of Human TNF-Alpha on the Parasite Gene Expression Profile

Background: Schistosoma mansoni is the major causative agent of schistosomiasis. The parasite takes advantage of host signals to complete its development in the human body. Tumor necrosis factor-alpha (TNF-alpha) is a human cytokine involved in skin inflammatory responses, and although its effect on the adult parasite's metabolism and egg-laying process has been previously described, a comprehensive assessment of the TNF-alpha pathway and its downstream molecular effects is lacking. Methodology/Principal Findings: In the present work we describe a possible TNF-alpha receptor (TNFR) homolog gene in S. mansoni (SmTNFR). SmTNFR encodes a complete receptor sequence composed of 599 amino acids, and contains four cysteine-rich domains as described for TNFR members. Real-time RT-PCR experiments revealed that SmTNFR highest expression level is in cercariae, 3.5 (+/- 0.7) times higher than in adult worms. Downstream members of the known human TNF-alpha pathway were identified by an in silico analysis, revealing a possible TNF-alpha signaling pathway in the parasite. In order to simulate parasite's exposure to human cytokine during penetration of the skin, schistosomula were exposed to human TNF-alpha just 3 h after cercariae-to-schistosomula in vitro transformation, and large-scale gene expression measurements were performed with microarrays. A total of 548 genes with significantly altered expression were detected, when compared to control parasites. In addition, treatment of adult worms with TNF-alpha caused a significantly altered expression of 1857 genes. Interestingly, the set of genes altered in adults is different from that of schistosomula, with 58 genes in common, representing 3% of altered genes in adults and 11% in 3 h-old early schistosomula. Conclusions/Significance: We describe the possible molecular elements and targets involved in human TNF-alpha effect on S. mansoni, highlighting the mechanism by which recently transformed schistosomula may sense and respond to this host mediator at the site of cercarial penetration into the skin.

Characterization of global transcription profile of normal and HPV-immortalized keratinocytes and their response to TNF treatment

Background: Persistent infection by high risk HPV types (e.g. HPV-16, -18, -31, and -45) is the main risk factor for development of cervical intraepithelial neoplasia and cervical cancer. Tumor necrosis factor (TNF) is a key mediator of epithelial cell inflammatory response and exerts a potent cytostatic effect on normal or HPV16, but not on HPV18 immortalized keratinocytes. Moreover, several cervical carcinoma-derived cell lines are resistant to TNF anti-proliferative effect suggesting that the acquisition of TNF-resistance may constitute an important step in HPV-mediated carcinogenesis. In the present study, we compared the gene expression profiles of normal and HPV16 or 18 immortalized human keratinocytes before and after treatment with TNF for 3 or 60 hours. Methods: In this study, we determined the transcriptional changes 3 and 60 hours after TNF treatment of normal, HPV16 and HPV18 immortalized keratinocytes by microarray analysis. The expression pattern of two genes observed by microarray was confirmed by Northern Blot. NF-kappa B activation was also determined by electrophoretic mobility shift assay (EMSA) using specific oligonucleotides and nuclear protein extracts. Results: We observed the differential expression of a common set of genes in two TNF-sensitive cell lines that differs from those modulated in TNF-resistant ones. This information was used to define genes whose differential expression could be associated with the differential response to TNF, such as: KLK7 (kallikrein 7), SOD2 (superoxide dismutase 2), 100P (S100 calcium binding protein P), PI3 (protease inhibitor 3, skin-derived), CSTA (cystatin A), RARRES1 (retinoic acid receptor responder 1), and LXN (latexin). The differential expression of the KLK7 and SOD2 transcripts was confirmed by Northern blot. Moreover, we observed that SOD2 expression correlates with the differential NF-kappa B activation exhibited by TNF-sensitive and TNF-resistant cells. Conclusion: This is the first in depth analysis of the differential effect of TNF on normal and HPV16 or HPV18 immortalized keratinocytes. Our findings may be useful for the identification of genes involved in TNF resistance acquisition and candidate genes which deregulated expression may be associated with cervical disease establishment and/or progression.

Toxicity of High-Dose Intravitreal Adalimumab (Humira) in the Rabbit

Purpose: To evaluate the ocular toxicity of escalating doses of intravitreous adalimumab (Humira (R)) in the rabbit eye. Methods: Thirty New Zealand albino rabbits received intravitreous injections of 0.5mg (6 eyes), 1.0mg (6 eyes), 2.5mg (6 eyes), 5mg (6 eyes), and 10mg (6 eyes) adalimumab. Slit lamp biomicroscopy and fundoscopy were carried out at baseline, day 7, and day 14 after intravitreous injection, whereas electroretinography (ERG) was carried out at baseline and day 14. Animals were euthanized on day 14, and histopathological examination of the eyes was performed. Results: Slit lamp biomicroscopy and fundoscopy were normal in all eyes receiving doses up to 5mg. In the 10mg group, 3 of 6 eyes showed mild anterior chamber inflammatory reaction on day 7. Similarly, scotopic and photopic a- and b-wave ERG amplitudes at baseline and day 14 were similar in all groups up to 5mg, but there was a significant decrease in the photopic-wave ERG response in the 10mg group (P = 0.046). Finally, histopathology demonstrated no differences among eyes receiving balanced salt solution, 0.5, 1.0, 2.5, 5.0, or 10mg of adalimumab. Conclusions: Intravitreous adalimumab exhibited no associated ocular short-term toxicity in rabbit eyes up to the 5mg dose. In the 10mg group mild clinical findings and ERG amplitude reduction could reflect early toxicity.

Ric-8A, a G alpha protein guanine nucleotide exchange factor potentiates taste receptor signaling

Taste receptors for sweet, bitter and umami tastants are G-protein-coupled receptors (GPCRs). While much effort has been devoted to understanding G-protein-receptor interactions and identifying the components of the signalling cascade downstream of these receptors, at the level of the G-protein the modulation of receptor signal transduction remains relatively unexplored. In this regard a taste-specific regulator of G-protein signaling (RGS), RGS21, has recently been identified. To study whether guanine nucleotide exchange factors (GEFs) are involved in the transduction of the signal downstream of the taste GPCRs we investigated the expression of Ric-8A and Ric-8B in mouse taste cells and their interaction with G-protein subunits found in taste buds. Mammalian Ric-8 proteins were initially identified as potent GEFs for a range of G alpha subunits and Ric-8B has recently been shown to amplify olfactory signal transduction. We find that both Ric-8A and Ric-8B are expressed in a large portion of taste bud cells and that most of these cells contain IP3R-3 a marker for sweet, umami and bitter taste receptor cells. Ric-8A interacts with G alpha-gustducin and G alpha i2 through which it amplifies the signal transduction of hTas2R16, a receptor for bitter compounds. Overall, these findings are consistent with a role for Ric-8 in mammalian taste signal transduction.

Effect of bench press exercise intensity on muscle soreness and inflammatory mediators

This study compared four different intensities of a bench press exercise for muscle soreness, creatine kinase activity, interleukin (IL)-1, IL-6, tumor necrosis factor- (TNF-), and prostaglandin E2 (PGE2) concentrations in the blood. Thirty-five male Brazilian Army soldiers were randomly assigned to one of five groups: 50% one-repetition maximum (1-RM), 75% 1-RM, 90% 1-RM, 110% 1-RM, and a control group that did not perform the exercise. The total volume (setsrepetitionsload) of the exercise was matched among the exercise groups. Muscle soreness and plasma creatine kinase activity increased markedly (P0.05) after exercise, with no significant differences among the groups. Serum PGE2 concentration also increased markedly (P0.05) after exercise, with a significantly (P0.05) greater increase in the 110% 1-RM group compared with the other groups. A weak but significant (P0.05) correlation was found between peak muscle soreness and peak PGE2 concentration, but no significant correlation was evident between peak muscle soreness and peak creatine kinase activity, or peak creatine kinase activity and peak PGE2 concentration. All groups showed no changes in IL-1, IL-6 or TNF-. Our results suggest that the intensity of bench press exercise does not affect the magnitude of muscle soreness and blood markers of muscle damage and inflammation.

Experimental chronic low-frequency resistance training produces skeletal muscle hypertrophy in the absence of muscle damage and metabolic stress markers

Volitional animal resistance training constitutes an important approach to modeling human resistance training. However, the lack of standardization protocol poses a frequent impediment to the production of skeletal muscle hypertrophy and the study of related physiological variables (i.e., cellular damage/inflammation or metabolic stress). Therefore, the purposes of the present study were: (1) to test whether a long-term and low frequency experimental resistance training program is capable of producing absolute increases in muscle mass; (2) to examine whether cellular damage/inflammation or metabolic stress is involved in the process of hypertrophy. In order to test this hypothesis, animals were assigned to a sedentary control (C, n = 8) or a resistance trained group (RT, n = 7). Trained rats performed 2 exercise sessions per week (16 repetitions per day) during 12 weeks. Our results demonstrated that the resistance training strategy employed was capable of producing absolute mass gain in both soleus and plantaris muscles (12%, p<0.05). Furthermore, muscle tumor necrosis factor (TNF-alpha) protein expression (soleus muscle) was reduced by 24% (p<0.01) in trained group when compared to sedentary one. Finally, serum creatine kinase (CK) activity and serum lactate concentrations were not affected in either group. Such information may have practical applications if reproduced in situations where skeletal muscle hypertrophy is desired but high mechanical stimuli of skeletal muscle and inflammation are not. Copyright (C) 2010 John Wiley & Sons, Ltd.

Exercise training changes IL-10/TNF-alpha ratio in the skeletal muscle of post-MI rats

Heart failure (HF) is associated with changes in the skeletal muscle (SM) which might be a consequence of the unbalanced local expression of pro- (TNF-alpha) and anti- (IL-10) inflammatory cytokines, leading to inflammation-induced myopathy, and SM wasting. This local effect of HF on SM may, on the other hand, contribute to systemic inflammation, as this tissue actively secretes cytokines. Since increasing evidence points out to an anti-inflammatory effect of exercise training, the goal of the present study was to investigate its effect in rats with HF after post-myocardial infarction (MI), with special regard to the expression of TNF-alpha and IL-10 in the soleus and extensor digitorum longus (EDL), muscles with different fiber composition. Wistar rats underwent left thoracotomy with ligation of the left coronary artery, and were randomly assigned to either a sedentary (Sham-operated and MI sedentary) or trained (Sham-operated and MI trained) group. Animals in the trained groups ran on a treadmill (0% grade at 13-20 m/min) for 60 min/day, 5 days/week, for 8-10 weeks. The training protocol was able to reverse the changes induced by MI, decreasing TNF-alpha protein (26%, P < 0.05) and mRNA (58%, P < 0.05) levels in the soleus, when compared with the sedentary MI group. Training also increased soleus IL-10 expression (2.6-fold, P < 0.001) in post-MI HF rats. As a consequence, the IL-10/TNF-alpha ratio was increased. This ""anti-inflammatory effect"" was more pronounced in the soleus than in the EDL, suggesting a fiber composition dependent response. (C) 2009 Elsevier Ltd. All rights reserved.

Environments for nursing scholarship and journal impact factor in five countries

Background: Universities worldwide are seeking objective measures for the assessment of their faculties` research products to evaluate them and to attain prestige. Despite concerns, the impact factors (IF) of journals where faculties publish have been adopted. Research objective: The study aims to explore conditions created within five countries as a result of policies requiring or not requiring faculty to publish in high IF journals, and the extent to which these facilitated or hindered the development of nursing science. Design: The design was a multiple case study of Brazil, Taiwan, Thailand (with IF policies, Group A), United Kingdom and the United States (no IF policies, Group B). Key informants from each country were identified to assist in subject recruitment. Methods: A questionnaire was developed for data collection. The study was approved by a human subject review committee. Five faculty members of senior rank from each country participated. All communication occurred electronically. Findings: Groups A and B countries differed on who used the policy and the purposes for which it was used. There were both similarities and differences across the five countries with respect to hurdles, scholar behaviour, publishing locally vs. internationally, views of their science, steps taken to internationalize their journals. Conclusions: In group A countries, Taiwan seemed most successful in developing its scholarship. Group B countries have continued their scientific progress without such policies. IF policies were not necessary motivators of scholarship; factors such as qualified nurse scientists, the resource base in the country, may be critical factors in supporting science development.