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Showing papers by "John Radcliffe Hospital published in 2008"


Journal ArticleDOI
TL;DR: This is the first description of circulating microRNAs and suggests that micro RNAs have potential as non‐invasive diagnostic markers for DLBCL and possibly other cancers.
Abstract: Circulating nucleic acids have been shown to have potential as non-invasive diagnostic markers in cancer. We therefore investigated whether microRNAs also have diagnostic utility by comparing levels of tumour-associated MIRN155 (miR-155), MIRN210 (miR-210) and MIRN21 (miR-21) in serum from diffuse large B-cell lymphoma (DLBCL) patients (n = 60) with healthy controls (n = 43). Levels were higher in patient than control sera (P = 0.009, 0.02 and 0.04 respectively). Moreover, high MIRN21 expression was associated with relapse-free survival (P = 0.05). This is the first description of circulating microRNAs and suggests that microRNAs have potential as non-invasive diagnostic markers for DLBCL and possibly other cancers.

1,691 citations


Journal ArticleDOI
TL;DR: It is believed that this strategy can be successfully applied at present in order to unravel the contribution of rare variants to the multifactorial inheritance of common diseases, which could lead to the implementation of much needed preventative screening schemes.
Abstract: Here, we give a historical overview of the search for genetic variants that influence the susceptibility of an individual to a chronic disease, from RA Fisher's seminal work to the current excitement of whole-genome association studies (WGAS). We then discuss the concepts behind the identification of common variants as disease causal factors and contrast them to the basic ideas that underlie the rare variant hypothesis. The identification of rare variants involves the careful selection of candidate genes to examine, the availability of highly efficient resequencing techniques and the appropriate assessment of the functional consequences of the implicated variant. We believe that this strategy can be successfully applied at present in order to unravel the contribution of rare variants to the multifactorial inheritance of common diseases, which could lead to the implementation of much needed preventative screening schemes.

1,131 citations


Journal ArticleDOI
TL;DR: Observations suggest an enrichment of both IL-17+CD4+ and CD8+ T cells in active MS lesions as well as an important role for IL- 17 in MS pathogenesis, with some remarkable differences from the experimental autoimmune encephalomyelitis model.
Abstract: Recent findings in the animal model for multiple sclerosis (MS), experimental autoimmune encephalomyelitis, implicate a novel CD4+ T-cell subset (TH17), characterized by the secretion of interleukin-17 (IL-17), in disease pathogenesis. To elucidate its role in MS, brain tissues from patients with MS were compared to controls. We detected expression of IL-17 mRNA (by in situ hybridization) and protein (by immunohistochemistry) in perivascular lymphocytes as well as in astrocytes and oligodendrocytes located in the active areas of MS lesions. Further, we found a significant increase in the number of IL-17+ T cells in active rather than inactive areas of MS lesions. Specifically, double immunofluorescence showed that IL-17 immunoreactivity was detected in 79% of T cells in acute lesions, 73% in active areas of chronic active lesions, but in only 17% of those in inactive lesions and 7% in lymph node control tissue. CD8+, as well as CD4+, T cells were equally immunostained for IL-17 in MS tissues. Interestingly, and in contrast to lymph node T cells, no perivascular T cells showed FoxP3 expression, a marker of regulatory T cells, at any stage of MS lesions. These observations suggest an enrichment of both IL-17+CD4+ and CD8+ T cells in active MS lesions as well as an important role for IL-17 in MS pathogenesis, with some remarkable differences from the experimental autoimmune encephalomyelitis model.

1,113 citations


Journal ArticleDOI
TL;DR: This work examined the functional properties of brain networks based on spontaneous fluctuations within brain systems using functional magnetic resonance imaging to hypothesized that functional connectivity of intrinsic brain activity in the "default-mode" network (DMN) is affected by normal aging and that this relates to cognitive function.
Abstract: Normal aging is associated with cognitive decline. Functions such as attention, information processing, and working memory are compromised. It has been hypothesized that not only regional changes, but also alterations in the integration of regional brain activity (functional brain connectivity) underlie the observed agerelated deficits. Here, we examined the functional properties of brain networks based on spontaneous fluctuations within brain systems using functional magnetic resonance imaging. We hypothesized that functional connectivity of intrinsic brain activity in the ‘‘default-mode’’ network (DMN) is affected by normal aging and that this relates to cognitive function. Ten younger and 22 older subjects were scanned at ‘‘rest,’’ that is, lying awake with eyes closed. Our results show decreased activity in older versus younger subjects in 2 resting-state networks (RSNs) resembling the previously described DMN, containing the superior and middle frontal gyrus, posterior cingulate, middle temporal gyrus, and the superior parietal region. These results remain significant after correction for RSN-specific gray matter volume. The relevance of these findings is illustrated by the correlation between reduced activity of one of these RSNs and less effective executive functioning/processing speed in the older group.

1,106 citations


Journal ArticleDOI
TL;DR: Reinforcement learning models that focus on the striatum and dopamine can predict the choices of animals and people but representation of reward expectation and of reward prediction errors that are pertinent to decision making are not confined to these regions but are also found in prefrontal and cingulate cortex.
Abstract: Reinforcement learning models that focus on the striatum and dopamine can predict the choices of animals and people. Representations of reward expectation and of reward prediction errors that are pertinent to decision making, however, are not confined to these regions but are also found in prefrontal and cingulate cortex. Moreover, decisions are not guided solely by the magnitude of the reward that is expected. Uncertainty in the estimate of the reward expectation, the value of information that might be gained by taking a course of action and the cost of an action all influence the manner in which decisions are made through prefrontal and cingulate cortex.

817 citations


Journal ArticleDOI
13 Nov 2008-Nature
TL;DR: It is demonstrated that social information may be acquired using the same associative processes assumed to underlie reward-based learning, and suggested that human social valuation can be realized by means of the same Associative processes previously established for learning other, simpler, features of the environment.
Abstract: Our decisions are guided by information learnt from our environment. This information may come via personal experiences of reward, but also from the behaviour of social partners. Social learning is widely held to be distinct from other forms of learning in its mechanism and neural implementation; it is often assumed to compete with simpler mechanisms, such as reward-based associative learning, to drive behaviour. Recently, neural signals have been observed during social exchange reminiscent of signals seen in studies of associative learning. Here we demonstrate that social information may be acquired using the same associative processes assumed to underlie reward-based learning. We find that key computational variables for learning in the social and reward domains are processed in a similar fashion, but in parallel neural processing streams. Two neighbouring divisions of the anterior cingulate cortex were central to learning about social and reward-based information, and for determining the extent to which each source of information guides behaviour. When making a decision, however, the information learnt using these parallel streams was combined within ventromedial prefrontal cortex. These findings suggest that human social valuation can be realized by means of the same associative processes previously established for learning other, simpler, features of the environment.

798 citations


Journal ArticleDOI
01 Feb 2008
TL;DR: EFSUMB study group M. Claudon, D. Cosgrove, T. Tranquart, L. Thorelius, and H. Whittingham study group L. de.
Abstract: EFSUMB study group M. Claudon1, D. Cosgrove2, T. Albrecht3, L. Bolondi4, M. Bosio5, F. Calliada6, J.-M. Correas7, K. Darge8, C. Dietrich9, M. D'On ofrio10, D. H. Evans11, C. Filice12, L. Greiner13, K. Jäger14, N. de. Jong15, E. Leen16, R. Lencioni17, D. Lindsell18, A. Martegani19, S. Meairs20, C. Nolsøe21, F. Piscaglia22, P. Ricci23, G. Seidel24, B. Skjoldbye25, L. Solbiati26, L. Thorelius27, F. Tranquart28, H. P. Weskott29, T. Whittingham30

755 citations


Journal ArticleDOI
TL;DR: It is demonstrated that mucin misfolding and ER stress initiate colitis in mice, and that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stressed pathology and relevant environmental epidemiology are warranted.
Abstract: Background MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis.

656 citations


Journal ArticleDOI
TL;DR: Understanding the mutually inhibitory effects that pain and reward processing have on each other, and the neural mechanisms that underpin such modulation, is important for alleviating unnecessary suffering and improving well-being.
Abstract: Pain and pleasure are powerful motivators of behaviour and have historically been considered opposites. Emerging evidence from the pain and reward research fields points to extensive similarities in the anatomical substrates of painful and pleasant sensations. Recent molecular-imaging and animal studies have demonstrated the important role of the opioid and dopamine systems in modulating both pain and pleasure. Understanding the mutually inhibitory effects that pain and reward processing have on each other, and the neural mechanisms that underpin such modulation, is important for alleviating unnecessary suffering and improving well-being.

650 citations


Journal ArticleDOI
TL;DR: The contribution of attention, expectation and reappraisal are discussed as three basic mechanisms that are important for the cognitive modulation of pain.

628 citations


Journal ArticleDOI
TL;DR: Studies in Canada have provided strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of multiple sclerosis, but the available data accommodate more than one type of environmental effect.
Abstract: Studies in Canada have provided strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of multiple sclerosis (MS). However, the available data accommodate more than one type of environmental effect. Migration studies show that changes to early environment can greatly affect risk, and there are recent indications that risk can be altered in situ. The rising incidence rates of MS in Canada implied by longitudinal increases in sex ratio place this effect in temporal context and narrow the candidates for mediating the effect of environment. Similarly, geographical patterns in Australia imply that modifiable environmental factors hold the key to preventing some 80% of cases. Genetic epidemiology provides overwhelming evidence that genetic background has an important complementary role. If genetic factors are held constant, the environment sets the disease threshold. Although these could be independent additive risk factors, it seems more likely that susceptibility is mediated by direct interactions between the environment and genes.

Journal ArticleDOI
TL;DR: In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children, particularly in children under 1 y of age.
Abstract: Background Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia. Methods and Findings Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08–1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl) was the major complication associated with Pv, accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126). Conclusions In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing.

Journal ArticleDOI
TL;DR: The mechanisms of opioid-induced respiratory depression, from the cellular to the systems level, are reviewed to highlight gaps in current understanding, and to suggest avenues for further research.
Abstract: Respiratory depression limits the use of opioid analgesia. Although well described clinically, the specific mechanisms of opioid action on respiratory control centres in the brain have, until recently, been less well understood. This article reviews the mechanisms of opioid-induced respiratory depression, from the cellular to the systems level, to highlight gaps in our current understanding, and to suggest avenues for further research. The ultimate aim of combating opioid-induced respiratory depression would benefit patients in pain and potentially reduce deaths from opioid overdose. By integrating recent findings from animal studies with those from human volunteer and clinical studies, further avenues for investigation are proposed, which may eventually lead to safer opioid analgesia.

Journal ArticleDOI
TL;DR: Clinically, data suggest that improvement over conventional therapy can be achieved in stem cell treatment for AMI, and adequately powered trials using optimal dosing, longer term outcome assessments, more reliable, and more patient-centred outcomes are required.
Abstract: The search strategy included MEDLINE, EMBASE, the Cochrane Library, and Current Controlled Trials Register through to August 2007 for randomized controlled trials of BMSC treatment for AMI. Thirteen trials (14 compari- sons) with a total of 811 participants were included. Data were analysed using a random effects model. Overall, stem cell therapy improved left ventricular ejection fraction (LVEF) by 2.99% (95% confidence interval (CI), 1.26-4.72%, P ¼ 0.0007), significantly reduced left ventricular end-systolic volume (LVESV) by 4.74 mL (95% CI, 27.84 to 21.64 mL, P ¼ 0.003), and myocardial lesion area by 3.51% (95% CI, 25.91 to 21.11%, P ¼ 0.004) compared with controls. Subgroup analysis revealed that there was statistical significant difference in LEVF in favour of BMSCs when cells were infused within 7 days following AMI and when the BMSC dose administered was higher than 10 8 BMSCs. In addition, there were trends in favour of benefit for most clinical outcomes examined, although it should be acknowledged that the 95%CI included no significant difference. Conclusion Stem cell treatment for AMI still holds promise. Clinically, these data suggest that improvement over conventional therapy can be achieved. Further, adequately powered trials using optimal dosing, longer term outcome assessments, more reliable, and more patient-centred outcomes are required.

Journal ArticleDOI
TL;DR: mounting evidence from mice with cell restrictive, repressible or chimeric expression of mutant SOD1 transgenes and bone marrow transplants supports non-neuronal origins of neuroprotection in ALS.

Journal ArticleDOI
TL;DR: This work proposes a group inference approach which includes inference of outliers using a robust general linear model (GLM) approach which combines the benefits of outlier inference with thebenefits of using variance information from lower levels in the hierarchy.

Journal ArticleDOI
11 Jul 2008-Cell
TL;DR: It is shown that multiple proteins play a role in generating increased rigidity of infected erythrocytes and may provide targets for antivirulence based therapies to a disease responsible for millions of deaths annually.

Journal ArticleDOI
TL;DR: Since ATF4 is induced by tumour microenvironmental factors, and regulates processes relevant to cancer progression, it might serve as a potential therapeutic target in cancer.

Journal ArticleDOI
TL;DR: This paper aims to define the global geographic distribution of P. falciparum malaria in 2007 and to provide a preliminary description of its transmission intensity within this range, and to release the most contemporary summary of the population at risk of P.'s falcips malaria within these limits.
Abstract: Background The efficient allocation of financial resources for malaria control using appropriate combinations of interventions requires accurate information on the geographic distribution of malaria risk. An evidence-based description of the global range of Plasmodium falciparum malaria and its endemicity has not been assembled in almost 40 y. This paper aims to define the global geographic distribution of P. falciparum malaria in 2007 and to provide a preliminary description of its transmission intensity within this range.

Journal ArticleDOI
TL;DR: Assessment of the epidemiological characteristics of malaria in Kilifi, Kenya during a period of decreasing transmission intensity finds sustained reduction in exposure to infection leads to changes in mean age and presentation of disease similar to those described in multisite studies.

Journal ArticleDOI
TL;DR: Ex vivo analysis of cross-reactive CD4+ and CD8+ memory T cell responses to overlapping peptides spanning the full proteome of influenza A and influenza A in healthy individuals from the United Kingdom and Viet Nam shows that vaccine formulas inducing heterosubtypic T cell-mediated immunity may confer broad protection against avian and human influenza A viruses.
Abstract: The threat of avian influenza A (H5N1) infection in humans remains a global health concern. Current influenza vaccines stimulate antibody responses against the surface glycoproteins but are ineffective against strains that have undergone significant antigenic variation. An alternative approach is to stimulate pre-existing memory T cells established by seasonal human influenza A infection that could cross-react with H5N1 by targeting highly conserved internal proteins. To determine how common cross-reactive T cells are, we performed a comprehensive ex vivo analysis of cross-reactive CD4+ and CD8+ memory T cell responses to overlapping peptides spanning the full proteome of influenza A/Viet Nam/CL26/2005 (H5N1) and influenza A/New York/232/2004 (H3N2) in healthy individuals from the United Kingdom and Viet Nam. Memory CD4+ and CD8+ T cells isolated from the majority of participants exhibited human influenza-specific responses and showed cross-recognition of at least one H5N1 internal protein. Participant CD4+ and CD8+ T cells recognized multiple synthesized influenza peptides, including peptides from the H5N1 strain. Matrix protein 1 (M1) and nucleoprotein (NP) were the immunodominant targets of cross-recognition. In addition, cross-reactive CD4+ and CD8+ T cells recognized target cells infected with recombinant vaccinia viruses expressing either H5N1 M1 or NP. Thus, vaccine formulas inducing heterosubtypic T cell-mediated immunity may confer broad protection against avian and human influenza A viruses.

Journal ArticleDOI
TL;DR: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity, and the high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression.
Abstract: BACKGROUND: In 1999, meningococcal serogroup C conjugate (MCC) vaccines were introduced in the United Kingdom for those under 19 years of age. The impact of this intervention on asymptomatic carriage of meningococci was investigated to establish whether serogroup replacement or protection by herd immunity occurred. METHODS: Multicenter surveys of carriage were conducted during vaccine introduction and on 2 successive years, resulting in a total of 48,309 samples, from which 8599 meningococci were isolated and characterized by genotyping and phenotyping. RESULTS: A reduction in serogroup C carriage (rate ratio, 0.19) was observed that lasted at least 2 years with no evidence of serogroup replacement. Vaccine efficacy against carriage was 75%, and vaccination had a disproportionate impact on the carriage of sequence type (ST)-11 complex serogroup C meningococci that (rate ratio, 0.06); these meningococci also exhibited high rates of capsule expression. CONCLUSIONS: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity. The high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression. High vaccine efficacy against disease in young children, who were not protected long-term by the schedule initially used, is attributed to the high vaccine efficacy against carriage in older age groups.

Journal ArticleDOI
TL;DR: The aims of this review are to identify the risks associated with prone positioning and how these risks may be anticipated and minimized and the published techniques for various practical procedures in this position.
Abstract: Prone positioning of patients during anaesthesia is required to provide operative access for a wide variety of surgical procedures. It is associated with predictable changes in physiology but also with a number of complications, and safe use of the prone position requires an understanding of both issues. We have reviewed the development of the prone position and its variants and the physiological changes which occur on prone positioning. The complications associated with this position and the published techniques for various practical procedures in this position will be discussed. The aim of this review is to identify the risks associated with prone positioning and how these risks may be anticipated and minimized.

Journal ArticleDOI
01 Nov 2008-Brain
TL;DR: A strong relationship between AQP4-Abs and clinical state is demonstrated, and the hypothesis that these antibodies are involved in the pathogenesis of NMO is supported.
Abstract: Neuromyelitis optica (NMO) is a severe inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the spinal cord and optic nerves. Recently, a highly specific serum reactivity to CNS microvessels, subpia and Virchow-Robin spaces was described in patients with NMO [called NMO-IgG (NMO-immunoglobulin G)]. Subsequently, aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Strong support for a pathogenic role of the antibody would come from studies demonstrating a correlation between AQP4-Ab (AQP4-antibody) titres and the clinical course of disease. In this study, we determined AQP4-Ab serum levels in 96 samples from eight NMO-IgG positive patients (median follow-up 62 months) in a newly developed fluorescence-based immunoprecipitation assay employing recombinant human AQP4. We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates. Our results demonstrate a strong relationship between AQP4-Abs and clinical state, and support the hypothesis that these antibodies are involved in the pathogenesis of NMO.

Journal ArticleDOI
TL;DR: In HIV-1 and hepatitis C virus infections, iron overload is associated with poor prognosis and could be partly caused by the viruses themselves.
Abstract: Fundamental cellular operations, including DNA synthesis and the generation of ATP, require iron. Viruses hijack cells in order to replicate, and efficient replication needs an iron-replete host. Some viruses selectively infect iron-acquiring cells by binding to transferrin receptor 1 during cell entry. Other viruses alter the expression of proteins involved in iron homeostasis, such as HFE and hepcidin. In HIV-1 and hepatitis C virus infections, iron overload is associated with poor prognosis and could be partly caused by the viruses themselves. Understanding how iron metabolism and viral infection interact might suggest new methods to control disease.

Journal ArticleDOI
09 Oct 2008-Nature
TL;DR: This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes.
Abstract: Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.

Journal ArticleDOI
TL;DR: The evolving field of bacterial typing and the genomic technologies that enable comparative analysis of multiple genomes and the metagenomes of complex microbial environments are reviewed, and the implications of the genomic era for the future of microbiology are addressed.
Abstract: Genomics has revolutionized every aspect of microbiology. Now, 13 years after the first bacterial genome was sequenced, it is important to pause and consider what has changed in microbiology research as a consequence of genomics. In this article, we review the evolving field of bacterial typing and the genomic technologies that enable comparative analysis of multiple genomes and the metagenomes of complex microbial environments, and address the implications of the genomic era for the future of microbiology.

Journal ArticleDOI
TL;DR: The historical development of malaria endemicity indices and their contemporary relevance are reviewed at a time when many malaria-endemic countries are scaling up their malaria control activities and reconsidering their prospects for elimination.
Abstract: The quantification of malaria transmission for the classification of malaria risk has long been a concern for epidemiologists. During the era of the Global Malaria Eradication Programme, measurements of malaria endemicity were institutionalised by their incorporation into rules outlining defined action points for malaria control programmes. We review the historical development of these indices and their contemporary relevance. This is at a time when many malaria-endemic countries are scaling-up their malaria control activities and reconsidering their prospects for elimination. These considerations are also important to an international community that has recently been challenged to revaluate the prospects for malaria eradication.

Journal ArticleDOI
TL;DR: It is demonstrated that the absence of invariant NKT cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality.
Abstract: Infection with influenza A virus (IAV) presents a substantial threat to public health worldwide, with young, elderly, and immunodeficient individuals being particularly susceptible. Inflammatory responses play an important role in the fatal outcome of IAV infection, but the mechanism remains unclear. We demonstrate here that the absence of invariant NKT (iNKT) cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality. Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The crosstalk between iNKT and MDSCs was CD1d- and CD40-dependent. Furthermore, IAV infection and exposure to TLR agonists relieved the suppressive activity of MDSCs. Finally, we extended these results to humans by demonstrating the presence of myeloid cells with suppressive activity in the PBLs of individuals infected with IAV and showed that their suppressive activity is substantially reduced by iNKT cell activation. These findings identify what we believe to be a novel immunomodulatory role of iNKT cells, which we suggest could be harnessed to abolish the immunosuppressive activity of MDSCs during IAV infection.

Journal ArticleDOI
TL;DR: Despite human isolation from seasonal changes in temperature, food and photoperiod in the industrialised nations, the seasons still appear to have a small, but significant, impact upon when individuals are born and many aspects of health.