Poxviruses such as the causative agent of smallpox have developed multiple strategies to suppress immune responses, including the suppression of DC activation. Since poxviruses are large DNA viruses, we hypothesized that their detection by DCs may involve the endosomal DNA recognition receptor TLR9. Indeed, we have shown here that DC recognition of ectromelia virus (ECTV), the causative agent of mousepox, completely depended on TLR9. The importance of TLR9 was highlighted by the fact that mice lacking TLR9 showed drastically increased susceptibility to infection with ECTV. In contrast, we found that the strongly attenuated poxvirus modified vaccinia virus Ankara (MVA) activated DCs by both TLR9-dependent and -independent pathways. We therefore tested whether we could use the broader induction of immune responses by MVA to protect mice from a lethal infection with ECTV. Indeed, MVA given at the same time as a lethal dose of ECTV protected mice from death. Importantly, MVA also rescued TLR9-deficient mice if administered 2 full days after an otherwise lethal infection with ECTV. Therefore, these data suggest an essential role for TLR9 in the defense against poxviruses. In addition, postexposure application of MVA may protect against lethal poxvirus infection.

The results demonstrated the feasibility of applying the CS strategy to evaluate LV function and volumes with high accuracy in patients. The single-breath-hold CS strategy has the potential to replace the multi-breath-hold standard cardiac magnetic resonance technique.

To cite this article: Plaimauer B, Kremer Hovinga JA, Juno C, Wolfsegger MJ, Skalicky S, Schmidt M, Grillberger L, Hasslacher M, Knö bl P, Ehrlich H, Scheiflinger F. Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost 2011; 9: 936-44.Summary. Background: Severe deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 as observed in acquired thrombotic thrombocytopenic purpura (TTP) is caused by inhibitory and non-inhibitory autoantibodies directed against the protease. Current treatment with plasma exchange is considered to remove circulating antibodies and to concurrently replenish the deficient enzyme. Objectives: To explore the use of recombinant ADAMTS13 (rADAMTS13) as a potential therapeutic agent in acquired TTP, we investigated its efficacy in normalizing VWF-cleaving activity in the presence of ADAMTS13 inhibitors. Methods: Thirty-six plasma samples from TTP patients were adjusted to predefined inhibitor titers, and recovery of ADAMTS13 activity was analyzed following supplementation with rADAMTS13. Results: We showed a linear relation between the inhibitor titer measured and effective rADAMTS13 concentration necessary for reconstitution of VWF-cleaving activity in the presence of neutralizing autoantibodies. Conclusions: Our results support the further investigation of the potential therapeutic applicability of rADAMTS13 as an adjunctive therapy in acquired TTP.

BackgroundCardiovascular cine magnetic resonance (CMR) accelerated by compressed sensing (CS) is used to assess left ventricular (LV) function. However, it is difficult for prospective CS cine CMR to capture the complete end-diastolic phase, which can lead to underestimation of the end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF), compared to retrospective standard cine CMR. This prospective study aimed to evaluate the diagnostic quality and accuracy of single-breath-hold full cardiac cycle CS cine CMR, acquired over two heart beats, to quantify LV volume in comparison to multi-breath-hold standard cine CMR.MethodsEighty-one participants underwent standard segmented breath-hold cine and CS real-time cine CMR examinations to obtain a stack of eight contiguous short-axis images with same high spatial (1.7 × 1.7 mm2) and temporal resolution (41 ms). Two radiologists independently performed qualitative analysis of image quality (score, 1 [i.e., “nondiagnostic”] to 5 [i.e., “excellent”]) and quantitative analysis of the LV volume measurements.ResultsThe total examination time was 113 ± 7 s for standard cine CMR and 24 ± 4 s for CS cine CMR (p < 0.0001). The CS cine image quality was slightly lower than standard cine (4.8 ± 0.5 for standard vs. 4.4 ± 0.5 for CS; p < 0.0001). However, all image quality scores for CS cine were above 4 (i.e., good). No significant differences existed between standard and CS cine MR for all quantitative LV measurements. The mean differences with 95 % confidence interval (CI), based on Bland–Altman analysis, were 1.3 mL (95 % CI, −14.6 – 17.2) for LV end-diastolic volume, 0.2 mL (95 % CI, −9.8 to10.3) for LV end-systolic volume, 1.1 mL (95 % CI, −10.5 to 12.7) for LV stroke volume, 1.0 g (95 % CI, −11.2 to 13.3) for LV mass, and 0.4 % (95 % CI, −4.8 – 5.6) for LV ejection fraction. The interobserver and intraobserver variability for CS cine MR ranged from −4.8 – 1.6 % and from −7.3 – 9.3 %, respectively, with slopes of the regressions ranging 0.88–1.0 and 0.86–1.03, respectively.ConclusionsSingle-breath-hold full cardiac cycle CS real-time cine CMR could evaluate LV volume with excellent accuracy. It may replace multi-breath-hold standard cine CMR.

Chorioallantois vaccinia virus Ankara (CVA) is the parental virus of modified vaccinia virus Ankara (MVA), which was derived from CVA by more than 570 passages in chicken embryo fibroblasts (CEF). MVA became severely host-cell-restricted to avian cells and has strongly diminished virulence in mammalian hosts, while maintaining good immunogenicity. We determined the complete coding sequence of the parental CVA and mapped the exact positions of the six major deletions that emerged in the MVA genome. All six major deletions occurred in regions of the CVA genome where one or more truncated or fragmented open reading frames (ORFs) pre-existed. The CVA genome contains 229 ORFs of which 51 are fragments of full-length orthopoxvirus (OPV) genes, including fragmented orthologues of C9L and M1L (encoding two well-conserved ankyrin-like proteins), A39R (encoding a semaphorin-like protein) and A55R (encoding a kelch-like protein). Phylogenetic analysis demonstrated that MVA was most closely related to CVA, followed by the vaccinia virus (VACV) strain DUKE, a patient-derived isolate of the Dryvax vaccine virus. Loss or mutation of genes outside the six major deletions are assumed to contribute to the restricted host range phenotype of MVA. In support of this notion, deletions, insertions and non-synonymous mutations were found in 122 of the 195 ORFs remaining in MVA when compared with their CVA counterparts. Thus, detailed knowledge of the CVA genomic sequence is a prerequisite to further dissect the genetic basis of the MVA host range phenotype as well as the particular immunological properties of MVA.

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Background: Conventional 2D inversion recovery (IR) and phase sensitive inversion recovery (PSIR) late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) have been widely incorporated into routine CMR for the assessment of myocardial viability. However, reliable suppression of fat signal, and increased isotropic spatial resolution and volumetric coverage within a clinically feasible scan time remain a challenge. In order to address these challenges, this work proposes a highly efficient respiratory motion-corrected 3D whole-heart water/fat LGE imaging framework. Methods: An accelerated IR-prepared 3D dual-echo acquisition and motion-corrected reconstruction framework for whole-heart water/fat LGE imaging was developed. The acquisition sequence includes 2D image navigators (iNAV), which are used to track the respiratory motion of the heart and enable 100% scan efficiency. Non-rigid motion information estimated from the 2D iNAVs and from the data itself is integrated into a high-dimensional patchbased undersampled reconstruction technique (HD-PROST), to produce high-resolution water/fat 3D LGE images. A cohort of 20 patients with known or suspected cardiovascular disease was scanned with the proposed 3D water/fat LGE approach. 3D water LGE images were compared to conventional breath-held 2D LGE images (2-chamber, 4chamber and stack of short-axis views) in terms of image quality (1: full diagnostic to 4: non-diagnostic) and presence of LGE findings. Results: Image quality was considered diagnostic in 18/20 datasets for both 2D and 3D LGE magnitude images, with comparable image quality scores (2D: 2.05 ± 0.72, 3D: 1.88 ± 0.90, p-value = 0.62) and overall agreement in LGE findings. Acquisition time for isotropic high-resolution (1.3mm 3) water/fat LGE images was 8.0 ± 1.4 min (3-fold acceleration, 60-88 slices covering the whole heart), while 2D LGE images were acquired in 5.6 ± 2.2 min (12-18 slices, including pauses between breath-holds) albeit with a lower spatial resolution (1.40-1.75 mm in-plane × 8 mm

BackgroundSimultaneous-Multi-Slice (SMS) perfusion imaging has the potential to acquire multiple slices, increasing myocardial coverage without sacrificing in-plane spatial resolution. To maximise signal-to-noise ratio (SNR), SMS can be combined with a balanced steady state free precession (bSSFP) readout. Furthermore, application of gradient-controlled local Larmor adjustment (GC-LOLA) can ensure robustness against off-resonance artifacts and SNR loss can be mitigated by applying iterative reconstruction with spatial and temporal regularisation. The objective of this study was to compare cardiovascular magnetic resonance (CMR) myocardial perfusion imaging using SMS bSSFP imaging with GC-LOLA and iterative reconstruction to 3 slice bSSFP.MethodsTwo contrast-enhanced rest perfusion sequences were acquired in random order in 8 patients: 6-slice SMS bSSFP and 3 slice bSSFP. All images were reconstructed with TGRAPPA. SMS images were also reconstructed using a non-linear iterative reconstruction with L1 regularisation in wavelet space (SMS-iter) with 7 different combinations for spatial (λσ) and temporal (λτ) regularisation parameters. Qualitative ratings of overall image quality (0 = poor image quality, 1 = major artifact, 2 = minor artifact, 3 = excellent), perceived SNR (0 = poor SNR, 1 = major noise, 2 = minor noise, 3 = high SNR), frequency of sequence related artifacts and patient related artifacts were undertaken. Quantitative analysis of contrast ratio (CR) and percentage of dark rim artifact (DRA) was performed.ResultsAmong all SMS-iter reconstructions, SMS-iter 6 (λσ 0.001 λτ 0.005) was identified as the optimal reconstruction with the highest overall image quality, least sequence related artifact and higher perceived SNR. SMS-iter 6 had superior overall image quality (2.50 ± 0.53 vs 1.50 ± 0.53, p = 0.005) and perceived SNR (2.25 ± 0.46 vs 0.75 ± 0.46, p = 0.010) compared to 3 slice bSSFP. There were no significant differences in sequence related artifact, CR (3.62 ± 0.39 vs 3.66 ± 0.65, p = 0.88) or percentage of DRA (5.25 ± 6.56 vs 4.25 ± 4.30, p = 0.64) with SMS-iter 6 compared to 3 slice bSSFP.ConclusionsSMS bSSFP with GC-LOLA and iterative reconstruction improved image quality compared to a 3 slice bSSFP with doubled spatial coverage and preserved in-plane spatial resolution. Future evaluation in patients with coronary artery disease is warranted.Electronic supplementary materialThe online version of this article (10.1186/s12968-018-0502-7) contains supplementary material, which is available to authorized users.