Summary of TLR4 polymorphisms associated with infectious diseases.

<p>Summary of TLR4 polymorphisms associated with infectious diseases.</p

Genotypic and allelic comparisons between Typhoid cases and controls.

1<p>ND = not done.</p

Mutation detection in the T4_promoter fragment.

<p>Three polymorphisms were detected by dHPLC in the T4_promoter fragment and were verified by DNA sequencing. The four dHPLC graphs correspond to the wild-type sequence (A), SNPs T-441C (B), SNP A-271G (C) and SNP G-259C (D). The wild-type pattern is visible in all dHPLC graphs as a 1 peak trace. SNP T-441C is identified by an unequal height 2 peak trace (B), SNP A-271G is identified by an equal height 2 peak trace (C) and SNP G-259C is identified by a 3 peak trace (D). The positions of the sequence variants in the T4_promoter fragment identified by dHPLC were determined by DNA sequencing. All SNPs were present in the heterozygous state.</p

The distribution of <i>S.</i> Typhi MIC to ofloxacin in seven RCTs.

<p>Histogram showing the distribution of <i>S.</i> Typhi MICs (<0.06, 0.06, 0.125, 0.25, 0.5 and 1 µg/mL) to ofloxacin over seven individual randomised. The proportion of <i>S.</i> Typhi strains with the corresponding MIC are shaded accordingly, white; study TY1 (1992–1993) n = 19 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001163#pntd.0001163-Smith2" target="_blank">[25]</a>, very light grey; study CT1 (1993–1994) n = 102 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001163#pntd.0001163-Vinh1" target="_blank">[26]</a>, light grey; study TY2 (1993–1996) n = 103 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001163#pntd.0001163-Nguyen1" target="_blank">[24]</a>, mid grey; study DTC (1994–1995) n = 154 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001163#pntd.0001163-Vinh2" target="_blank">[28]</a>, dark grey; study DN (1995–1996) n = 55 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001163#pntd.0001163-Cao1" target="_blank">[29]</a>, very dark grey; study TY3 (1997–1998) n = 45 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001163#pntd.0001163-Chinh1" target="_blank">[23]</a> and black; study DTY2 (1998–2001) n = 62 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001163#pntd.0001163-Parry3" target="_blank">[27]</a>.</p

Primers used to generate amplicons for mutation detection in <i>TLR4</i> by dHPLC.

1<p>nucleotides in bold represent GC clamps added to the primer to improve the melting profile of the generated amplicon for mutation detection.</p>2<p>the temperatures used in dHPLC for each fragment to accurately identify sequence changes in TLR4.</p

<i>TLR4</i> gene structure and fragment design for dHPLC.

<p>E1, E2, E3 denotes exons 1, 2, and 3. E2a denotes an alternative exon 2. I1, I2, I3 denotes intronic sequences. 5′UTR and 3′UTR represent the untranslated regions. The lines underneath the gene structure show the approximate positions of the 11 fragments designed for mutation detection by dHPLC. The names of each fragment are above the lines.</p

The relationship between increasing <i>S.</i> Typhi MIC to ofloxacin and clinical failure.

<p>Histogram showing the proportion of enteric fever patients who failed treatment (white columns) or had persistent fever (black columns) (>38°C) for more than seven days after the commencement of treatment. Data was combined from seven randomised clinical trials and is comprised from 540 children and adults recruited with uncomplicated enteric fever. The patients are divided according to the MIC to ofloxacin of the infecting isolate.</p

The positions of the <i>TLR4</i> polymorphisms in the genomic sequence and the polypeptide sequence.

<p>Three polymorphisms were identified in the upstream region (T-441C, A-271G, G-259C), one in intron 2 (T4025A), one in exon 2 (C4215G), and five in exon 3 (C7944T, A7947G, A8177G, C8850T, G9605T). E1, E2, E3, E2a, represent exons 1, 2, 3 and the alternative exon 2. Transcriptional site indicated as +1. 6 exonic polymorphisms cause a change in amino acid residue, with 5 in the ectoplasmic domain and 1 in the plasma membrane domain. LRR denotes; leucine rich repeat. TIR denotes; Toll/IL-1R domain.</p

The duration of febrile episodes in enteric fever patients infected with <i>S.</i> Typhi organisms with a range of MICs to ofloxacin.

<p>Kaplan Meir curve showing the proportion of patients remaining febrile (>38°C) after the start of treatment with ofloxacin. Data is composed from fever clearance times of 540 children and adults with uncomplicated enteric fever recruited to seven randomised clinical trial and treated with oral ofloxacin. The curves are divided according to the ofloxacin MIC of the infecting isolates and are highlighted on the diagram.</p

Admission features of 540 ofloxacin treated enteric fever patients recruited to clinical trials.

a<p>) continuous variables given as median (interquartile range), and proportions as number (%).</p>b<p>) Analysis of variance for proportions, Kruskall Wallis test for continuous variables.</p>c<p>) MDR – resistant to ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole.</p>d<p>) NaR – resistant to nalidixic acid.</p