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Background
Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP''s clinical efficacy.Methods and Findings
A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox''s regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan–Meier survival estimates were 97.7% (95% CI 97.3%–98.1%) at day 42 and 97.2% (95% CI 96.7%–97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3–2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%–96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%–21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.Conclusions
DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation. Please see later in the article for the Editors'' Summary 相似文献14.
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In this study we describe the sociodemographic characteristics of people participating in a clinical trial on the safety and immunogenicity of a H5N1 influenza vaccine and we identify the main motivations for joining it. 相似文献
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Background
The Prisoner's Dilemma (PD) is a widely used paradigm to study cooperation in evolutionary biology, as well as in fields as diverse as moral philosophy, sociology, economics and politics. Players are typically assumed to have fixed payoffs for adopting certain strategies, which depend only on the strategy played by the opponent. However, fixed payoffs are not realistic in nature. Utility functions and the associated payoffs from pursuing certain strategies vary among members of a population with numerous factors. In biology such factors include size, age, social status and expected life span; in economics they include socio-economic status, personal preference and past experience; and in politics they include ideology, political interests and public support. Thus, no outcome is identical for any two different players. 相似文献17.
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V?Srinivasan GJM?Maestroni DP?Cardinali AI?Esquifino SR?Pandi?Perumal SC?MillerEmail author 《Immunity & ageing : I & A》2005,2(1):17
Aging is associated with a decline in immune function (immunosenescence), a situation known to correlate with increased incidence
of cancer, infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration
with age. A decrease in functional competence of individual natural killer (NK) cells is found with advancing age. Macrophages
and granulocytes show functional decline in aging as evidenced by their diminished phagocytic activity and impairment of superoxide
generation. There is also marked shift in cytokine profile as age advances, e.g., CD3+ and CD4+ cells decline in number whereas
CD8+ cells increase in elderly individuals. A decline in organ specific antibodies occurs causing reduced humoral responsiveness.
Circulating melatonin decreases with age and in recent years much interest has been focused on its immunomodulatory effect.
Melatonin stimulates the production of progenitor cells for granulocytes-macrophages. It also stimulates the production of
NK cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from NK cells and T-helper
lymphocytes also are enhanced by melatonin. Melatonin presumably regulates immune function by acting on the immune-opioid
network, by affecting G protein-cAMP signal pathway and by regulating intracellular glutathione levels. Melatonin has the
potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state. 相似文献
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Evolution of the WANCY region in amniote mitochondrial DNA 总被引:7,自引:1,他引:6
In most vertebrate mitochondrial genomes, the site for initiation of
light-strand replication, OL, is found within a cluster of five transfer
RNA (tRNA) genes (tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), and
tRNA(Tyr)). This region and part of the adjacent cytochrome c oxydase
subunit I (COI) gene were sequenced for two crocodilian, two turtle, and
one snake species and for Sphenodon punctatus; part of the adjacent
nicotinamide adenine dinucleotide dehydrogenase subunit 2 (ND2) gene was
also sequenced for the crocodilian and turtle species. All had the typical
vertebrate gene order. The turtles and the snake have a lengthy noncoding
sequence between the tRNA(Asn) and tRNA(Cys) genes that we assumed to be
homologous to the mammalian OL. The crocodilians and Sphenodon lack such a
sequence, a condition they share with birds. Most proposed phylogenies for
the amniotes require that OL at this position was lost at least twice
during their diversification or was evolved independently more than once.
Within the five tRNA genes, frequencies of substitutions are much higher in
loops than in stems. Many loops vary dramatically in size among the
species; in the most extreme case, the D-arm of the Sphenodon tRNA(Cys) is
a "D-arm replacement" loop of seven nucleotides. Frequency of transitions
in stems is relatively uniform across tRNAs, but frequency of transversions
varies greatly. Mismatches in stems are infrequent, and their relative
frequency in a specific tRNA is unrelated to the frequency of substitution
in the corresponding gene. Several features of mammalian mitochondrial
tRNAs are conserved in WANCY tRNAs throughout amniotes. The inferred
initiation codon for COI is GTG in crocodilians, turtles, and the snake, a
condition they share with fishes, certain amphibians, and birds. TTG
appears to be the initiation codon for COI in Sphenodon; if correct, this
would be a novel initiation codon for vertebrate mitochondrial DNA.
Phylogenetic analyses of the inferred amino acid sequences of ND2 and COI
support the sister-group relationship of birds and crocodilians and suggest
that mammals are an early derived lineage within the amniotes.
相似文献
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Melanie A. McDowell Julien Marcoux Gareth McVicker Steven Johnson Yu Hang Fong Rebecca Stevens Lesley A. H. Bowman Matteo T. Degiacomi Jun Yan Adam Wise Miriam E. Friede Justin L. P. Benesch Janet E. Deane Christoph M. Tang Carol V. Robinson Susan M. Lea 《Molecular microbiology》2016,99(4):749-766
Flagellar type III secretion systems (T3SS) contain an essential cytoplasmic‐ring (C‐ring) largely composed of two proteins FliM and FliN, whereas an analogous substructure for the closely related non‐flagellar (NF) T3SS has not been observed in situ. We show that the spa33 gene encoding the putative NF‐T3SS C‐ring component in Shigella flexneri is alternatively translated to produce both full‐length (Spa33‐FL) and a short variant (Spa33‐C), with both required for secretion. They associate in a 1:2 complex (Spa33‐FL/C2) that further oligomerises into elongated arrays in vitro. The structure of Spa33‐C2 and identification of an unexpected intramolecular pseudodimer in Spa33‐FL reveal a molecular model for their higher order assembly within NF‐T3SS. Spa33‐FL and Spa33‐C are identified as functional counterparts of a FliM–FliN fusion and free FliN respectively. Furthermore, we show that Thermotoga maritima FliM and FliN form a 1:3 complex structurally equivalent to Spa33‐FL/C2, allowing us to propose a unified model for C‐ring assembly by NF‐T3SS and flagellar‐T3SS. 相似文献