Oral activated charcoal prevents experimental cerebral malaria in mice and in a randomized controlled clinical trial in man did not interfere with the pharmacokinetics of parenteral artesunate.

BACKGROUND: Safe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. Oral activated charcoal (oAC) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers. METHODS/PRINCIPAL FINDINGS: We found that oAC provided significant protection against P. berghei ANKA-induced ECM, increasing overall survival time compared to untreated mice (p<0.0001; hazard ratio 16.4; 95% CI 6.73 to 40.1). Protection from ECM by oAC was associated with reduced numbers of splenic TNF(+) CD4(+) T cells and multifunctional IFNgamma(+)TNF(+) CD4(+) and CD8(+) T cells. Furthermore, we identified a whole blood gene expression signature (68 genes) associated with protection from ECM. To evaluate whether oAC might affect current best available anti-malarial treatment, we conducted a randomized controlled open label trial in 52 human volunteers (ISRCTN NR. 64793756), administering artesunate (AS) in the presence or absence of oAC. We demonstrated that co-administration of oAC was safe and well-tolerated. In the 26 subjects further analyzed, we found no interference with the pharmacokinetics of parenteral AS or its pharmacologically active metabolite dihydroartemisinin. CONCLUSIONS/SIGNIFICANCE: oAC protects against ECM in mice, and does not interfere with the pharmacokinetics of parenteral artesunate. If future studies succeed in establishing the efficacy of oAC in human malaria, then the characteristics of being inexpensive, well-tolerated at high doses and requiring no sophisticated storage would make oAC a relevant candidate for adjunct therapy to reduce mortality from severe malaria, or for immediate treatment of suspected severe malaria in a rural setting. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN64793756

T-cell contact-dependent regulation of CC and CXC chemokine production in monocytes through differential involvement of NFκB: implications for rheumatoid arthritis

We and others have reported that rheumatoid arthritis (RA) synovial T cells can activate human monocytes/macrophages in a contact-dependent manner to induce the expression of inflammatory cytokines, including tumour necrosis factor alpha (TNFα). In the present study we demonstrate that RA synovial T cells without further activation can also induce monocyte CC and CXC chemokine production in a contact-dependent manner. The transcription factor NFκB is differentially involved in this process as CXC chemokines but not CC chemokines are inhibited after overexpression of IκBα, the natural inhibitor of NFκB. This effector function of RA synovial T cells is also shared by T cells activated with a cytokine cocktail containing IL-2, IL-6 and TNFα, but not T cells activated by anti-CD3 cross-linking that mimics TCR engagement. This study demonstrates for the first time that RA synovial T cells as well as cytokine-activated T cells are able to induce monocyte chemokine production in a contact-dependent manner and through NFκB-dependent and NFκB-independent mechanisms, in a process influenced by the phosphatidyl-inositol-3-kinase pathway. Moreover, this study provides further evidence that cytokine-activated T cells share aspects of their effector function with RA synovial T cells and that their targeting in the clinic has therapeutic potential

A mindfulness-based intervention to increase resilience to stress in university students (the Mindful Student Study): a pragmatic randomised controlled trial

Background More young people are going to university, but there is concern about an increasing demand for student mental health services. We designed a pragmatic randomised controlled trial to test the hypothesis that providing mindfulness courses to university students would promote their resilience to stress. Methods University of Cambridge students without severe mental illness or crisis (self-assessed) were remotely randomised to join an 8-week mindfulness course adapted for university students (MSS), or to mental health support as usual (SAU). The primary outcome was self-reported psychological distress during the examination period measured using the Clinical Outcomes in Routine Evaluation Outcome Measure. Main outcome intention-to-treat analysis was masked to allocation. Trial registration: ACTRN12615001160527 (complete). Findings In total, 616 students were randomised (circa 3% of all students; 309 to MSS, 307 to SAU); 74% completed the primary outcome measure; 65% of the MSS arm participants completed at least half of the MSS course. MSS reduced distress scores during the exam period compared with SAU (β=-0.44, 95%CI -0.60 to -0.29; p < 0.0001); 57% of SAU participants had distress scores above an accepted clinical threshold level compared with 37% of MSS participants. On average, six students needed to be offered the MSS course to prevent one from experiencing clinical levels of distress (number needed to treat 6, 95%CI 4 to 10). SAU distress worsened over the year whereas MSS scores improved after the course and were maintained during exams. Active monitoring revealed no adverse reactions related to self-harm, suicidality or harm to others. Interpretation The main limitation of this trial is the lack of control for non-specific effects. However, the provision of mindfulness training appears an effective component of a wider student mental health strategy. Funding University of Cambridge and NIHR Collaboration for Leadership in Applied Health Research and Care East of England.University of Cambridge and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East of England

High-efficiency gene transfer into nontransformed cells: utility for studying gene regulation and analysis of potential therapeutic targets

The elucidation of the signalling pathways involved in inflammatory diseases, such as rheumatoid arthritis, could provide long sought after targets for therapeutic intervention. Gene regulation is complex and varies depending on the cell type, as well as the signal eliciting gene activation. However, cells from certain lineages, such as macrophages, are specialised to degrade exogenous material and consequently do not easily transfect. Methods for high-efficiency gene transfer into primary cells of various lineages and disease states are desirable, as they remove the uncertainties associated with using transformed cell lines. Significant research has been undertaken into the development of nonviral and viral vectors for basic research, and as vehicles for gene therapy. We briefly review the current methods of gene delivery and the difficulties associated with each system. Adenoviruses have been used extensively to examine the role of various cytokines and signal transduction molecules in the pathogenesis of rheumatoid arthritis. This review will focus on the involvement of different signalling molecules in the production of tumour necrosis factor alpha by macrophages and in rheumatoid synovium. While the NF-kappaB pathway has proven to be a major mediator of tumour necrosis factor alpha production, it is not exclusive and work evaluating the involvement of other pathways is ongoing

Intracranial internal carotid aneurysm causing diplopia

Internal carotid intracranial aneurysms are a relatively rare form of intracranial aneurysm that presents with diplopia, retro-orbital pain and unilateral headaches. The symptoms are progressive and the diagnosis should be considered in a patient presenting with these complaints. Underlying hypertension and advanced age are specific risk factors

The Dawn of Open Access to Phylogenetic Data

The scientific enterprise depends critically on the preservation of and open access to published data. This basic tenet applies acutely to phylogenies (estimates of evolutionary relationships among species). Increasingly, phylogenies are estimated from increasingly large, genome-scale datasets using increasingly complex statistical methods that require increasing levels of expertise and computational investment. Moreover, the resulting phylogenetic data provide an explicit historical perspective that critically informs research in a vast and growing number of scientific disciplines. One such use is the study of changes in rates of lineage diversification (speciation - extinction) through time. As part of a meta-analysis in this area, we sought to collect phylogenetic data (comprising nucleotide sequence alignment and tree files) from 217 studies published in 46 journals over a 13-year period. We document our attempts to procure those data (from online archives and by direct request to corresponding authors), and report results of analyses (using Bayesian logistic regression) to assess the impact of various factors on the success of our efforts. Overall, complete phylogenetic data for ~60% of these studies are effectively lost to science. Our study indicates that phylogenetic data are more likely to be deposited in online archives and/or shared upon request when: (1) the publishing journal has a strong data-sharing policy; (2) the publishing journal has a higher impact factor, and; (3) the data are requested from faculty rather than students. Although the situation appears dire, our analyses suggest that it is far from hopeless: recent initiatives by the scientific community -- including policy changes by journals and funding agencies -- are improving the state of affairs

Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV) following in vivo escape from neutralising antibody

&lt;b&gt;BACKGROUND:&lt;/b&gt; In the acute phase of infection with feline immunodeficiency virus (FIV), the virus targets activated CD4+ T cells by utilising CD134 (OX40) as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs) 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo.&lt;p&gt;&lt;/p&gt; &lt;b&gt;RESULTS:&lt;/b&gt; Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134.&lt;p&gt;&lt;/p&gt; &lt;b&gt;CONCLUSIONS:&lt;/b&gt; The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.&lt;p&gt;&lt;/p&gt

Extracellular cell stress (heat shock) proteins - immune responses and disease: an overview

Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory ‘danger signals’ for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells. The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals/non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining/regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins, therefore, form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease

Electroweak Symmetry Breaking in the DSSM

We study the theoretical and phenomenological consequences of modifying the Kahler potential of the MSSM two Higgs doublet sector. Such modifications naturally arise when the Higgs sector mixes with a quasi-hidden conformal sector, as in some F-theory GUT models. In the Delta-deformed Supersymmetric Standard Model (DSSM), the Higgs fields are operators with non-trivial scaling dimension 1 < Delta < 2. The Kahler metric is singular at the origin of field space due to the presence of quasi-hidden sector states which get their mass from the Higgs vevs. The presence of these extra states leads to the fact that even as Delta approaches 1, the DSSM does not reduce to the MSSM. In particular, the Higgs can naturally be heavier than the W- and Z-bosons. Perturbative gauge coupling unification, a large top quark Yukawa, and consistency with precision electroweak can all be maintained for Delta close to unity. Moreover, such values of Delta can naturally be obtained in string-motivated constructions. The quasi-hidden sector generically contains states charged under SU(5)_GUT as well as gauge singlets, leading to a rich, albeit model-dependent, collider phenomenology.Comment: v3: 40 pages, 3 figures, references added, typos correcte

Melatonin Chimeras Alter Reproductive Development and Photorefractoriness in Siberian Hamsters

Nightly melatonin (MEL) durations > 8 h provoke gonadal regression and decreases in body mass, whereas signals < 7 h stimulate gonadal and somatic growth in male Siberian hamsters. The authors sought to determine the minimum frequency of short MEL signals sufficient to induce the long-day phenotype in several photoperiodic traits. D,L-propranolol (hereafter propranolol) injections shortened MEL signals on the night of treatment without altering MEL on the subsequent night; this permitted interpolation of short MEL signals at variable frequencies against a background of long MEL signals (chimeras). Hamsters kept in short days (10 h light/day, 10L) were injected with propranolol 6 h after dark onset for 28 consecutive weeks beginning at 30 days of age (Week 0) either every other day or once every 3, 6, or 9 days. Control animals were injected with saline or with propranolol during the light phase or were transferred to long days (16L) at Week 0. Hamsters in 16L underwent rapid gonadal development and increases in body mass and displayed summer pelage color, as did hamsters treated with propranolol every other day. Animals treated with propranolol less frequently than every other day uniformly maintained undeveloped gonads and winter-like body weights, but pelage color becameproportionately darker with increased frequency of propranolol treatments. The onset of spontaneous testicular development in 10L was unaffected by propranolol injections. After termination of injections at Week 28, testicular regression was not observed in most 10L animals that previously had undergone spontaneous testicular development; however, 40% of hamsters that had been injected with propranolol every 3rd night did manifest the winter phenotype after Week 28. In an alternating sequence, short MEL signals completely override long signals and induce the summer phenotype. Threshold frequencies differ for MEL stimulation of long-day pelage and gonadal phenotypes. The timing and development of refractoriness to MEL does not depend in any simple manner on the number of long MEL signals or on the accumulation of a reaction product produced by long, and depleted by short, MEL signals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67291/2/10.1177_074873098129000345.pd