CMR in Patients With Severe Myocarditis Diagnostic Value of Quantitative Tissue Markers Including Extracellular Volume Imaging

AbstractObjectivesThis study evaluated the accuracy of T2, T1, and extracellular volume (ECV) quantification as novel quantitative tissue markers in comparison with standard “Lake-Louise” cardiac magnetic resonance (CMR) criteria to diagnose myocarditis.BackgroundNovel approaches using T2 and T1 mapping may overcome the limitations of signal intensity-based parameters, which would potentially result in a better diagnostic accuracy compared with standard CMR techniques in suspected myocarditis.MethodsCMR was performed in 104 patients with myocarditis and 21 control subjects at 1.5-T. Patients with myocarditis underwent CMR 2 weeks (interquartile range: 1 to 7 weeks) after presentation with new-onset heart failure (n = 66) or acute chest pain (n = 38). T2 and T1 mapping were implemented into a standard protocol including T2-weighted (T2w), early gadolinium enhancement (EGE) CMR, and late gadolinium enhancement (LGE) CMR. T2 quantification was performed using a free-breathing, navigator-gated multiecho sequence. T1 quantification was performed using the modified Look-Locker inversion recovery sequence before and after administration of 0.075 mmol/kg gadobenate dimeglumine. T2, T1, and ECV maps were generated using a plug-in for the OsiriX software (Pixmeo, Bernex, Switzerland) to calculate mean global myocardial T2, T1, and ECV values.ResultsThe diagnostic accuracies of conventional CMR were 70% (95% confidence interval [CI]: 61% to 77%) for T2w CMR, 59% (95% CI: 56% to 73%) for EGE, and 67% (95% CI: 59% to 75%) for LGE. The diagnostic accuracies of mapping techniques were 63% (95% CI: 53% to 73%) for myocardial T2, 69% (95% CI: 60% to 76%) for native myocardial T1, and 76% (95% CI: 68% to 82%) for global myocardial ECV. The diagnostic accuracy of CMR was significantly improved to 90% (95% CI: 84% to 95%) by a stepwise approach, using the presence of LGE and myocardial ECV ≥27% as diagnostic criteria, compared with 79% (95% CI: 71% to 85%; p = 0.0043) for the Lake-Louise criteria.ConclusionsIn patients with clinical evidence for subacute, severe myocarditis, ECV quantification with LGE imaging significantly improved the diagnostic accuracy of CMR compared with standard Lake-Louise criteria

In vitro selectivity, in vivo biodistribution and tumour uptake of annexin V radiolabelled with a positron emitting radioisotope

The availability of a noninvasive method to detect and quantify apoptosis in tumours will enable tumour response to several cancer therapies to be assessed. We have synthesised two radiotracers, annexin V and the N-succinimidyl-3-iodobenzoic acid (SIB) derivative of annexin V, labelled with radio-iodine (124I and 125I) and provided proof of the concept by assessing specific binding and biodistribution of these probes to apoptotic cells and tumours. We have also assessed the tumour uptake of [124I]annexin V in a mouse model of apoptosis. RIF-1 cells induced to undergo apoptosis in vitro showed a drug concentration-dependent increased binding of [125I]annexin V and [125I]SIB–annexin V. In the same model system, there was an increase in terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL)-positive cells and a decrease in clonogenic survival. Radiotracer binding was completely inhibited by preincubation with unlabelled annexin V. In RIF-1 tumour-bearing mice, rapid distribution of [125I]SIB–annexin V-derived radioactivity to kidneys was observed and the radiotracer accumulated in urine. The binding of [125I]SIB–annexin V to RIF-1 tumours increased by 2.3-fold at 48 h after a single intraperitoneal injection of 5-fluorouracil (165 mg kg−1 body weight), compared to a 4.4-fold increase in TUNEL-positive cells measured by immunostaining. Positron emission tomography images with both radiotracers demonstrated intense localisation in the kidneys and bladder. Unlike [124I]SIB–annexin V, [124I]annexin V also showed localisation in the thyroid region presumably due to deiodination of the radiolabel. [124I]SIB–annexin V is an attractive candidate for in vivo imaging of apoptosis by PET

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile range from 4.2 × 10−9 to 4.1 × 10−8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome

Assessment of causality of natriuretic peptides and atrial fibrillation and heart failure : a Mendelian randomization study in the FINRISK cohort

Aims Natriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and previous studies several single-nucleotide poly-morphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. We investigated the causal relationship between natriuretic peptides and AF as well as HF using a Mendelian randomization approach. Methods and results N-terminal pro B-type natriuretic peptide (NT-proBNP) (N= 6669), B-type natriuretic peptide (BNP) (N= 6674), and mid-regional pro atrial natriuretic peptide (MR-proANP) (N= 6813) were measured in the FINRISK 1997 cohort. N=30 common SNPs related to NT-proBNP, BNP, and MR-proANP were selected from studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF, separately. Polygenic risk scores (PRSs) based on multiple SNPs were used as genetic instrumental variable in Mendelian randomizations. Polygenic risk scores were significantly associated with the three natriuretic peptides. Polygenic risk scores were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation except for small causal betas is unlikely. Conclusion In our Mendelian randomization approach, we confirmed an association between common genetic variation at the NPPA-NPPB locus and natriuretic peptides. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF at the community-level was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms.Peer reviewe

Trivalent live attenuated influenza-simian immunodeficiency virus vaccines: efficacy and evolution of cytotoxic T lymphocyte escape in macaques.

There is an urgent need for a human immunodeficiency virus (HIV) vaccine that induces robust mucosal immunity. CD8+ cytotoxic T lymphocytes (CTLs) apply substantial antiviral pressure, but CTLs to individual epitopes select for immune escape variants in both HIV in humans and SIV in macaques. Inducing multiple simian immunodeficiency virus (SIV)-specific CTLs may assist in controlling viremia. We vaccinated 10 Mane-A1*08401+ female pigtail macaques with recombinant influenza viruses expressing three Mane-A1*08401-restricted SIV-specific CTL epitopes and subsequently challenged the animals, along with five controls, intravaginally with SIVmac251. Seroconversion to the influenza virus vector resulted and small, but detectable, SIV-specific CTL responses were induced. There was a boost in CTL responses after challenge but no protection from high-level viremia or CD4 depletion was observed. All three CTL epitopes underwent a coordinated pattern of immune escape during early SIV infection. CTL escape was more rapid in the vaccinees than in the controls at the more dominant CTL epitopes. Although CTL escape can incur a &quot;fitness&quot; cost to the virus, a putative compensatory mutation 20 amino acids upstream from an immunodominant Gag CTL epitope also evolved soon after the primary CTL escape mutation. We conclude that vaccines based only on CTL epitopes will likely be undermined by rapid evolution of both CTL escape and compensatory mutations. More potent and possibly broader immune responses may be required to protect pigtail macaques from SIV. <br /

Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project

<p>Abstract</p> <p>Background</p> <p>Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the <it>IL18 </it>gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, <it>IL18R1 </it>and <it>IL18RAP</it>, with the risk of developing CVD.</p> <p>Methods</p> <p>Eleven tagging SNPs, 5 in <it>IL18R1 </it>and 6 in <it>IL18RAP</it>, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD.</p> <p>Results</p> <p>We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 <it>IL18 </it>SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful.</p> <p>Conclusion</p> <p>Our analysis suggests that the variability of <it>IL18R1 </it>and <it>IL18RAP </it>genes are unlikely to contribute to modulate the risk of CVD.</p

NGS QC Toolkit: A Toolkit for Quality Control of Next Generation Sequencing Data

Next generation sequencing (NGS) technologies provide a high-throughput means to generate large amount of sequence data. However, quality control (QC) of sequence data generated from these technologies is extremely important for meaningful downstream analysis. Further, highly efficient and fast processing tools are required to handle the large volume of datasets. Here, we have developed an application, NGS QC Toolkit, for quality check and filtering of high-quality data. This toolkit is a standalone and open source application freely available at http://www.nipgr.res.in/ngsqctoolkit.html. All the tools in the application have been implemented in Perl programming language. The toolkit is comprised of user-friendly tools for QC of sequencing data generated using Roche 454 and Illumina platforms, and additional tools to aid QC (sequence format converter and trimming tools) and analysis (statistics tools). A variety of options have been provided to facilitate the QC at user-defined parameters. The toolkit is expected to be very useful for the QC of NGS data to facilitate better downstream analysis

Lean Body Mass, Interleukin 18, and Metabolic Syndrome in Apparently Healthy Chinese

OBJECTIVE: We aimed to investigate how lean body mass is related to circulating Interleukin 18 (IL-18) and its association with metabolic syndrome (MetS) among apparently healthy Chinese. METHODS: A population-based sample of 1059 Chinese men and women aged 35-54 years was used to measure plasma IL-18, glucose, insulin, lipid profile, inflammatory markers and high-molecular-weight (HMW)-adiponectin. Fat mass index (FMI) and lean mass index (LMI) were measured by dual-energy X-ray absorptiometry. MetS was defined by the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. RESULTS: Circulating IL-18 was positively correlated with LMI after adjustment for FMI (correlation coefficient = 0.11, P<0.001). The association with the MetS (odds ratio 3.43, 95% confidence interval 2.01-5.85) was substantially higher in the highest than the lowest quartile of IL-18 after multiple adjustments including body mass index. In the stratified multivariable regression analyses, the positive association between IL-18 and MetS was independent of tertiles of FMI, inflammatory markers and HMW-adiponectin, but significantly interacted with tertile of LMI (P for interaction = 0.010). CONCLUSION: Elevated plasma IL-18 was associated with higher MetS prevalence in apparently healthy Chinese, independent of traditional risk factors, FMI, inflammatory markers and HMW-adiponectin. More studies are needed to clarify the role of lean mass in IL-18 secretion and its associated cardio-metabolic disorders