FDG PET is a robust tool for the diagnosis of spondylodiscitis: a meta-analysis of diagnostic data.

PURPOSE: Spondylodiscitis is a rare infectious entity that requires multimodal diagnostic procedures. We evaluated the diagnostic performance of 18F-FDG PET on suspected spondylodiscitis based on published literature. PATIENTS AND METHODS: We searched the PubMed and EMBASE for pertinent studies up to July 2013. We implemented a patient-based meta-analysis of diagnostic data for FDG PET (the index test) against clinical, laboratory, and/or radiologic evidence of disease (the reference standard). A bivariate analysis was implemented to account for variability beyond the threshold effect. The individual patient data analysis was used to assess confounding factors that moderate diagnostic performance. RESULTS: Twelve studies provided the diagnostic data on FDG PET and spondylodiscitis, comprising 224 patients. The combined sensitivity across studies was 0.97 [95% confidence interval (CI), 0.83-1.00], the specificity was 0.88 (95% CI, 0.74-0.95), and the area under the curve was 0.98 (95% CI, 0.96-0.99). For prior probabilities greater than 0.50, the corresponding positive predictive value was 0.96 (0.93-0.98), and the negative predictive value was 0.85 (0.82-0.88). In the individual patient data analysis, metallic implants, dual PET/CT scanners and the addition of other imaging modalities to confirm disease were significant outcome moderators; only PET/CT remained significant in the adjusted analysis. PET/CT scanners improved the diagnostic performance, as opposed to the clinical data (age, sex, lesion site), which did not alter outcome. CONCLUSIONS: FDG PET is a robust diagnostic test when spondylodiscitis is suspected and is excellent for exclusion of infectious spondylodiscitis given its low likelihood ratio negative (<0.1). Importantly, this diagnostic test is unaffected by other confounders, including the presence of implants, when PET/CT is used.

The role of TLR4 896 A>G and 1196 C>T in susceptibility to infections: a review and meta-analysis of genetic association studies.

BACKGROUND: Toll-like receptor 4 plays a role in pathogen recognition, and common polymorphisms may alter host susceptibility to infectious diseases. PURPOSE: To review the association of two common polymorphisms (TLR4 896A>G and TLR4 1196C>T) with infectious diseases. DATA SOURCES: We searched PubMed and EMBASE up to March 2013 for pertinent literature in English, and complemented search with references lists of eligible studies. STUDY SELECTION: We included all studies that: reported an infectious outcome; had a case-control design and reported the TLR4 896A>G and/or TLR4 1196C>T genotype frequencies; 59 studies fulfilled these criteria and were analyzed. DATA EXTRACTION: Two authors independently extracted study data. DATA SYNTHESIS: The generalized odds ratio metric (ORG) was used to quantify the impact of TLR4 variants on disease susceptibility. A meta-analysis was undertaken for outcomes reported in >1 study. Eleven of 37 distinct outcomes were significant. TLR4 896 A>G increased risk for all parasitic infections (ORG 1.59; 95%CI 1.05-2.42), malaria (1.31; 95%CI 1.04-1.66), brucellosis (2.66; 95%CI 1.66-4.27), cutaneous leishmaniasis (7.22; 95%CI 1.91-27.29), neurocysticercosis (4.39; 95%CI 2.53-7.61), Streptococcus pyogenes tonsillar disease (2.93; 95%CI 1.24-6.93) , typhoid fever (2.51; 95%CI 1.18-5.34) and adult urinary tract infections (1.98; 95%CI 1.04-3.98), but was protective for leprosy (0.36; 95%CI 0.22-0.60). TLR4 1196 C>T effects were similar to TLR4 896 A>G for brucellosis, cutaneous leishmaniasis, leprosy, typhoid fever and S. pyogenes tonsillar disease, and was protective for bacterial vaginosis in pregnancy (0.55; 95%CI 0.31-0.98) and Haemophilus influenzae tonsillar disease (0.42; 95%CI 0.17-1.00). The majority of significant associations were among predominantly Asian populations and significant associations were rare among European populations. CONCLUSIONS: Depending on the type of infection and population, TLR4 polymorphisms are associated with increased, decreased or no difference in infectious disease. This may be due to differential functional expression of TLR4, the co-segregation of TLR4 variants or a favorable inflammatory response.

Interleukin-6 polymorphisms and hematologic malignancy: a re-appraisal of evidence from genetic association studies.

CONTEXT: Interleukin-6 (IL-6) is implicated in the pathophysiology of hematologic neoplasia. OBJECTIVE: To review the role of IL-6 single nucleotide polymorphisms (SNPs) in hematologic neoplasia. METHODS: PubMed and EMBASE search of genetic association studies. Effects were summarized using the model-free generalized odds ratio (ORG), and the mode of inheritance was estimated for significant associations. RESULTS: Seventeen articles provided data on 20 distinct SNPs. The IL-6 receptor rs8192284 was associated with an increased risk of hematologic malignancy (combined ORG 1.42, 95%CI 1.03-1.96), including multiple myeloma (ORG 1.39, 95%CI 0.99-1.95). The IL-6 promoter rs1800795 conferred protection against young adult Hodgkin's disease (ORG 0.68, 95%CI 0.48-0.95). Significant single-study effects for four other SNPs-disease associations were estimated. The IL-6 promoter rs1800795 and rs1800797 were not associated with overall susceptibility to non-Hodgkin's lymphomas. CONCLUSIONS: There is accumulating evidence that the IL-6 promoter, receptor and signal transducer SNPs can modify disease susceptibility.

Arrangement of subunits in functional NMDA receptors.

Ionotropic glutamate receptors (iGluRs), including the NMDA receptor subtype, are ligand-gated ion channels critical to fast signaling in the CNS. NMDA receptors are obligate heterotetramers composed of two GluN1 and typically two GluN2 subunits. However, the arrangement of GluN subunits in functional receptors-whether like subunits are adjacent to (N1/N1/N2/N2) or diagonal to (N1/N2/N1/N2) one another-remains unclear. Recently, a crystal structure of a homomeric AMPA receptor revealed that the four identical subunits adopt two distinct and subunit-specific conformations termed A/C and B/D with subunits of like conformations (e.g., A/C) diagonal to one another. In the structure, the two conformers were notable at the level of the linkers (S1-M1, M3-S2, and S2-M4) that join the ligand-binding domain to the transmembrane ion channel with the M3-S2 linker positioned more proximal to the central axis of the channel pore in the A/C conformation and S2-M4 more proximal in the B/D conformation. Using immunoblots and functional assays, we show that introduced cysteines in the M3/M3-S2 linker of GluN1, but not GluN2, show dimer formation and oxidation-induced changes in current amplitudes predictive of the A/C conformation. Conversely, introduced cysteines in the S2-M4 linker of GluN2, but not GluN1, showed similar functional effects, suggesting that the GluN2 subunit adopts the B/D conformation. Thus, we show that NMDA receptors, like AMPA receptors, possess distinct subunit-specific conformations with GluN1 approximating the A/C and GluN2 the B/D conformation. GluN subunits are therefore positioned in a N1/N2/N1/N2 arrangement in functional NMDA receptors.

Subunit-specific contribution of pore-forming domains to NMDA receptor channel structure and gating.

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that contribute to fundamental physiological processes such as learning and memory and, when dysfunctional, to pathophysiological conditions such as neurodegenerative diseases, stroke, and mental illness. NMDARs are obligate heteromultimers typically composed of NR1 and NR2 subunits with the different subunits underlying the functional versatility of NMDARs. To study the contribution of the different subunits to NMDAR channel structure and gating, we compared the effects of cysteine-reactive agents on cysteines substituted in and around the M1, M3, and M4 segments of the NR1 and NR2C subunits. Based on the voltage dependence of cysteine modification, we find that, both in NR1 and NR2C, M3 appears to be the only transmembrane segment that contributes to the deep (or voltage dependent) portion of the ion channel pore. This contribution, however, is subunit specific with more positions in NR1 than in NR2C facing the central pore. Complimentarily, NR2C makes a greater contribution than NR1 to the shallow (or voltage independent) portion of the pore with more NR2C positions in pre-M1 and M3-S2 linker lining the ion-conducting pathway. Substituted cysteines in the M3 segments in NR1 and NR2C showed strong, albeit different, state-dependent reactivity, suggesting that they play central but structurally distinct roles in gating. A weaker state dependence was observed for the pre-M1 regions in both subunits. Compared to M1 and M3, the M4 segments in both NR1 and NR2C subunits had limited accessibility and the weakest state dependence, suggesting that they are peripheral to the central pore. Finally, we propose that Lurcher mutation-like effects, which were identified in and around all three transmembrane segments, occur for positions located at dynamic protein-protein or protein-lipid interfaces that have state-dependent accessibility to methanethiosulfonate (MTS) reagents and therefore can affect the equilibrium between open and closed states following reactions with MTS reagents.