Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice

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Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

Inherited biotic protection in a Neotropical pioneer plant

Chelonanthus alatus is a bat-pollinated, pioneer Gentianaceae that clusters in patches where still-standing, dried-out stems are interspersed among live individuals. Flowers bear circum-floral nectaries (CFNs) that are attractive to ants, and seed dispersal is both barochorous and anemochorous. Although, in this study, live individuals never sheltered ant colonies, dried-out hollow stems - that can remain standing for 2 years - did. Workers from species nesting in dried-out stems as well as from ground-nesting species exploited the CFNs of live C. alatus individuals in the same patches during the daytime, but were absent at night (when bat pollination occurs) on 60.5% of the plants. By visiting the CFNs, the ants indirectly protect the flowers - but not the plant foliage - from herbivorous insects. We show that this protection is provided mostly by species nesting in dried-out stems, predominantly Pseudomyrmex gracilis. That dried-out stems remain standing for years and are regularly replaced results in an opportunistic, but stable association where colonies are sheltered by one generation of dead C. alatus while the live individuals nearby, belonging to the next generation, provide them with nectar; in turn, the ants protect their flowers from herbivores. We suggest that the investment in wood by C. alatus individuals permitting stillstanding, dried-out stems to shelter ant colonies constitutes an extended phenotype because foraging workers protect the flowers of live individuals in the same patch. Also, through this process these dried-out stems indirectly favor the reproduction (and so the fitness) of the next generation including both their own offspring and that of their siblings, alladding up to a potential case of inclusive fitness in plants

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Isothiocyanates are detected in human synovial fluid following broccoli consumption and can affect the tissues of the knee joint

Osteoarthritis is a major cause of disability and there is no current pharmaceutical treatment which can prevent the disease or slow its progression. Dietary advice or supplementation is clearly an attractive option since it has low toxicity and ease of implementation on a population level. We have previously demonstrated that sulforaphane, a dietary isothiocyanate derived from its glucosinolate precursor which is found in broccoli, can prevent cartilage destruction in cells, in in vitro and in vivo models of osteoarthritis. As the next phase of this research, we enrolled 40 patients with knee osteoarthritis undergoing total knee replacement into a proof-of-principle trial. Patients were randomised to either a low or high glucosinolate diet for 14 days prior to surgery. We detected ITCs in the synovial fluid of the high glucosinolate group, but not the low glucosinolate group. This was mirrored by an increase in ITCs and specifically sulforaphane in the plasma. Proteomic analysis of synovial fluid showed significantly distinct profiles between groups with 125 differentially expressed proteins. The functional consequence of this diet will now be tested in a clinical trial

Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival

Extent: 14 p.The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.Daniel Thomas, Jason A. Powell, Benjamin D. Green, Emma F. Barry, Yuefang Ma, Joanna Woodcock, Stephen Fitter, Andrew C.W. Zannettino, Stuart M. Pitson, Timothy P. Hughes, Angel F. Lopez, Peter R. Shepherd, Andrew H. Wei, Paul G. Ekert and Mark A. Guthridg

Treatment of psychotic symptoms in bipolar disorder with aripiprazole monotherapy: A meta-analysis

Background: We present a systematic review and meta-analysis of the available clinical trials concerning the usefulness of aripiprazole in the treatment of the psychotic symptoms in bipolar disorder.Methods: A systematic MEDLINE and repository search concerning clinical trials for aripiprazole in bipolar disorder was conducted.Results: The meta-analysis of four randomised controlled trials (RCTs) on acute mania suggests that the effect size of aripiprazole versus placebo was equal to 0.14 but a more reliable and accurate estimation is 0.18 for the total Positive and Negative Syndrome Scale (PANSS) score. The effect was higher for the PANSS-positive subscale (0.28), PANSS-hostility subscale (0.24) and PANSS-cognitive subscale (0.20), and lower for the PANSS-negative subscale (0.12). No data on the depressive phase of bipolar illness exist, while there are some data in favour of aripiprazole concerning the maintenance phase, where at week 26 all except the total PANSS score showed a significant superiority of aripiprazole over placebo (d = 0.28 for positive, d = 0.38 for the cognitive and d = 0.71 for the hostility subscales) and at week 100 the results were similar (d = 0.42, 0.63 and 0.48, respectively).Conclusion: The data analysed for the current study support the usefulness of aripiprazole against psychotic symptoms during the acute manic and maintenance phases of bipolar illness. © 2009 Fountoulakis et al; licensee BioMed Central Ltd

A New Direction to Athletic Performance: Understanding the Acute and Longitudinal Responses to Backward Running

Backward running (BR) is a form of locomotion that occurs in short bursts during many overground field and court sports. It has also traditionally been used in clinical settings as a method to rehabilitate lower body injuries. Comparisons between BR and forward running (FR) have led to the discovery that both may be generated by the same neural circuitry. Comparisons of the acute responses to FR reveal that BR is characterised by a smaller ratio of braking to propulsive forces, increased step frequency, decreased step length, increased muscle activity and reliance on isometric and concentric muscle actions. These biomechanical differences have been critical in informing recent scientific explorations which have discovered that BR can be used as a method for reducing injury and improving a variety of physical attributes deemed advantageous to sports performance. This includes improved lower body strength and power, decreased injury prevalence and improvements in change of direction performance following BR training. The current findings from research help improve our understanding of BR biomechanics and provide evidence which supports BR as a useful method to improve athlete performance. However, further acute and longitudinal research is needed to better understand the utility of BR in athletic performance programs