Marfan syndrome and pregnancy: maternal and neonatal outcomes

Objective To report outcomes in a recent series of pregnancies in women with Marfan syndrome (MFS). Design Retrospective case note review. Setting Tertiary referral unit (Chelsea and Westminster and Royal Brompton Hospitals). Sample Twenty-nine pregnancies in 21 women with MFS between 1995 and 2010. Methods Multidisciplinary review of case records. Main outcome measures Maternal and neonatal mortality and morbidity of patients with MFS and healthy controls. Results There were no maternal deaths. Significant cardiac complications occurred in five pregnancies (17%): one woman experienced a type–A aortic dissection; two women required cardiac surgery within 6 months of delivery; and a further two women developed impaired left ventricular function during the pregnancy. Women with MFS were also more likely to have obstetric complications (OR 3.29, 95% CI 1.30–8.34), the most frequent of which was postpartum haemorrhage (OR 8.46, 95% CI 2.52–28.38). There were no perinatal deaths, although babies born to mothers with MFS were delivered significantly earlier than those born to the control group (median 39 versus 40 weeks of gestation, Mann–Whitney U–test, P = 0.04). These babies were also significantly more likely to be small for gestational age (24% in the MFS group versus 6% in the controls; OR 4.95, 95% CI 1.58–15.55). Conclusions Pregnancy in women with MFS continues to be associated with significant rates of maternal, fetal, and neonatal complications. Effective pre-pregnancy counselling and meticulous surveillance during pregnancy, delivery, and the puerperium by an experienced multidisciplinary team are warranted for women with MFS

Review of Journal of Cardiovascular Magnetic Resonance 2014

There were 102 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2014, which is a 6 % decrease on the 109 articles published in 2013. The quality of the submissions continues to increase. The 2013 JCMR Impact Factor (which is published in June 2014) fell to 4.72 from 5.11 for 2012 (as published in June 2013). The 2013 impact factor means that the JCMR papers that were published in 2011 and 2012 were cited on average 4.72 times in 2013. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal’s impact over the last 5 years has been impressive. Our acceptance rate is <25 % and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality papers to JCMR for publication

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology

Right atrial area and right ventricular outflow tract akinetic length predict sustained tachyarrhythmia in repaired tetralogy of Fallot

AIMS: Repaired tetralogy of Fallot (rtoF) patients are at risk of atrial or ventricular tachyarrhythmia and sudden cardiac death. Risk stratification for arrhythmia remains difficult. We investigated whether cardiac anatomy and function predict arrhythmia. METHODS: One-hundred-and-fifty-four adults with rtoF, median age 30.8 (21.9–40.2) years, were studied with a standardised protocol including cardiovascular magnetic resonance (CMR) and prospectively followed up over median 5.6 (4.6–7.0) years for the pre-specified endpoints of new-onset atrial or ventricular tachyarrhythmia (sustained ventricular tachycardia/ventricular fibrillation). RESULTS: Atrial tachyarrhythmia (n = 11) was predicted by maximal right atrial area indexed to body surface area (RAAi) on four-chamber cine-CMR (Hazard ratio 1.17, 95% Confidence Interval 1.07–1.28 per cm(2)/m(2); p = 0.0005, survival receiver operating curve; ROC analysis, area under curve; AUC 0.74 [0.66–0.81]; cut-off value 16 cm(2)/m(2)). Atrial arrhythmia-free survival was reduced in patients with RAAi ≥ 16 cm(2)/m(2) (logrank p = 0.0001). Right ventricular (RV) restrictive physiology on echocardiography (n = 38) related to higher RAAi (p = 0.02) and had similar RV dilatation compared with remaining patients. Ventricular arrhythmia (n = 9) was predicted by CMR RV outflow tract (RVOT) akinetic area length (Hazard ratio 1.05, 95% Confidence Interval 1.01–1.09 per mm; p = 0.003, survival ROC analysis, AUC 0.77 [0.83–0.61]; cut-off value 30 mm) and decreased RV ejection fraction (Hazard ratio 0.93, 95% Confidence Interval 0.87–0.99 per %; p = 0.03). Ventricular arrhythmia-free survival was reduced in patients with RVOT akinetic region length > 30 mm (logrank p = 0.02). CONCLUSION: RAAi predicts atrial arrhythmia and RVOT akinetic region length predicts ventricular arrhythmia in late follow-up of rtoF. These are simple, feasible measurements for inclusion in serial surveillance and risk stratification of rtoF patients

Regulatory T Cells in Human Lymphatic Filariasis: Stronger Functional Activity in Microfilaremics

Infection with filarial parasites is associated with T cell hyporesponsiveness, which is thought to be partly mediated by their ability to induce regulatory T cells (Tregs) during human infections. This study investigates the functional capacity of Tregs from different groups of filarial patients to suppress filaria-specific immune responses during human filariasis. Microfilaremic (MF), chronic pathology (CP) and uninfected endemic normal (EN) individuals were selected in an area endemic for Brugia timori in Flores island, Indonesia. PBMC were isolated, CD4CD25hi cells were magnetically depleted and in vitro cytokine production and proliferation in response to B. malayi adult worm antigen (BmA) were determined in total and Treg-depleted PBMC. In MF subjects BmA-specific T and B lymphocyte proliferation as well as IFN-gamma, IL-13 and IL-17 responses were lower compared to EN and CP groups. Depletion of Tregs restored T cell as well as B cell proliferation in MF-positives, while proliferative responses in the other groups were not enhanced. BmA-induced IL-13 production was increased after Treg removal in MF-positives only. Thus, filaria-associated Tregs were demonstrated to be functional in suppressing proliferation and possibly Th2 cytokine responses to BmA. These suppressive effects were only observed in the MF group and not in EN or CP. These findings may be important when considering strategies for filarial treatment and the targeted prevention of filaria-induced lymphedema

Myocardial Architecture, Mechanics, and Fibrosis in Congenital Heart Disease

Congenital heart disease (CHD) is the most common category of birth defect, affecting 1% of the population and requiring cardiovascular surgery in the first months of life in many patients. Due to advances in congenital cardiovascular surgery and patient management, most children with CHD now survive into adulthood. However, residual and postoperative defects are common resulting in abnormal hemodynamics, which may interact further with scar formation related to surgical procedures. Cardiovascular magnetic resonance (CMR) has become an important diagnostic imaging modality in the long-term management of CHD patients. It is the gold standard technique to assess ventricular volumes and systolic function. Besides this, advanced CMR techniques allow the acquisition of more detailed information about myocardial architecture, ventricular mechanics, and fibrosis. The left ventricle (LV) and right ventricle have unique myocardial architecture that underpins their mechanics; however, this becomes disorganized under conditions of volume and pressure overload. CMR diffusion tensor imaging is able to interrogate non-invasively the principal alignments of microstructures in the left ventricular wall. Myocardial tissue tagging (displacement encoding using stimulated echoes) and feature tracking are CMR techniques that can be used to examine the deformation and strain of the myocardium in CHD, whereas 3D feature tracking can assess the twisting motion of the LV chamber. Late gadolinium enhancement imaging and more recently T1 mapping can help in detecting fibrotic myocardial changes and evolve our understanding of the pathophysiology of CHD patients. This review not only gives an overview about available or emerging CMR techniques for assessing myocardial mechanics and fibrosis but it also describes their clinical value and how they can be used to detect abnormalities in myocardial architecture and mechanics in CHD patients

Brugia malayi Microfilariae Induce a Regulatory Monocyte/Macrophage Phenotype That Suppresses Innate and Adaptive Immune Responses

Background Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. Aim To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses. Methodology and principal findings Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner. Conclusions and significance Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning

Asymmetric Origin for Gravitino Relic Density in the Hybrid Gravity-Gauge Mediated Supersymmetry Breaking

We propose the hybrid gravity-gauge mediated supersymmetry breaking where the gravitino mass is about several GeV. The strong constraints on supersymmetry viable parameter space from the CMS and ATLAS experiments at the LHC can be relaxed due to the heavy colored supersymmetric particles, and it is consistent with null results in the dark matter (DM) direct search experiments such as XENON100. In particular, the possible maximal flavor and CP violations from the relatively small gravity mediation may naturally account for the recent LHCb anomaly. In addition, because the gravitino mass is around the asymmetric DM mass, we propose the asymmetric origin of the gravitino relic density and solve the cosmological coincident problem on the DM and baryon densities \Omega_{\rm DM}:\Omega_{B}\approx 5:1. The gravitino relic density arises from asymmetric metastable particle (AMP) late decay. However, we show that there is no AMP candidate in the minimal supersymmetric Standard Model (SM) due to the robust gaugino/Higgsino mediated wash-out effects. Interestingly, AMP can be realized in the well motivated supersymmetric SMs with vector-like particles or continuous U(1)_R symmetry. Especially, the lightest CP-even Higgs boson mass can be lifted in the supersymmetric SMs with vector-like particles.Comment: RevTex4, 21 pages, 1 figure, minor corrections, JHEP versio

Altered T Cell Memory and Effector Cell Development in Chronic Lymphatic Filarial Infection That Is Independent of Persistent Parasite Antigen

Chronic lymphatic filarial (LF) infection is associated with suppression of parasite-specific T cell responses that persist even following elimination of infection. While several mechanisms have been implicated in mediating this T cell specific downregulation, a role for alterations in the homeostasis of T effector and memory cell populations has not been explored. Using multiparameter flow cytometry, we investigated the role of persistent filarial infection on the maintenance of T cell memory in patients from the filarial-endemic Cook Islands. Compared to filarial-uninfected endemic normals (EN), microfilaria (mf) positive infected patients (Inf) had a reduced CD4 central memory (TCM) compartment. In addition, Inf patients tended to have more effector memory cells (TEM) and fewer effector cells (TEFF) than did ENs giving significantly smaller TEFF ∶ TEM ratios. These contracted TCM and TEFF populations were still evident in patients previously mf+ who had cleared their infection (CLInf). Moreover, the density of IL-7Rα, necessary for T memory cell maintenance (but decreased in T effector cells), was significantly higher on memory cells of Inf and CLInf patients, although there was no evidence for decreased IL-7 or increased soluble IL7-Rα, both possible mechanisms for signaling defects in memory cells. However, effector cells that were present in Inf and CLInf patients had lower percentages of HLA-DR suggesting impaired function. These changes in T cell populations appear to reflect chronicity of infection, as filarial-infected children, despite the presence of active infection, did not show alterations in the frequencies of these T cell phenotypes. These data indicate that filarial-infected patients have contracted TCM compartments and a defect in effector cell development, defects that persist even following clearance of infection. The fact that these global changes in memory and effector cell compartments do not yet occur in infected children makes early treatment of LF even more crucial