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Background and Aims: The use of virtual reality (VR) therapy has grown considerably, as it is effective for reducing pain and anxiety in different clinical areas. However, it has not been well evaluated for coronary angiography and angioplasty. This study aimed to compare VR therapy with pharmacological sedation (Sedation) for reducing pain in patients undergoing a planned coronary angiography or coronary/peripheral angioplasty., Methods: In this prospective randomized controlled trial, patients were randomly allocated to one of two groups before catheterization: a Sedation group (injection of midazolam and fentanyl) or a VR group (Deepsen VR headset). The primary outcome measure was the maximum pain during the procedure (visual analogue scale: 0-10). The secondary outcome measures were anxiety following the procedure (Spielberger State Anxiety Inventory: 20-80), the occurrence of arterial spasm, the haemodynamic profile and patient satisfaction., Results: The VR group ( n  = 63) had a mean pain rating of 2.5; for the Sedation group ( n  = 59) this was 1.0. This did not meet the criterion for non-inferiority. Anxiety was comparable between the two groups (VR: 25.4; Sedation: 24.7), as was the occurrence of arterial spasm (VR: 7.9%; Sedation: 8.5%; p  = 0.91), but blood pressure was higher in the VR group (140.2/71.7 mmHg vs. 121.8/64.7 mmHg). There were no VR-related adverse effects, and patient satisfaction was high for both groups., Conclusions: Virtual reality therapy was not non-inferior to pharmacological sedation for reducing pain during coronary angiography or angioplasty. However, it reduced anxiety to a comparable level. Virtual reality therapy represents an alternative to pharmacological sedation, which is well accepted by patients., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings. Between December 2020 and July 2022, we performed 158277 PCRs for our staff, students, and their household contacts, free of charge. Our average turnaround time was 16 h and 37 min from user registration to result delivery. KCL TEST combined open-source automation and in-house non-commercial reagents, which allows for rapid implementation and repurposing. Importantly, our data parallel those of the UK Office for National Statistics, though we detected a lower positive rate and virtually no delta wave. Our observations strongly support regular asymptomatic community testing as an important measure for decreasing outbreaks and providing safe working spaces. Universities can therefore provide agile, resilient, and accurate testing that reflects the infection rate and trend of the general population. Our findings call for the early integration of academic institutions in pandemic preparedness, with capabilities to rapidly deploy highly skilled staff, as well as develop, test, and accommodate efficient low-cost pipelines., (© The Author(s) 2024. Published by Oxford University Press.)

Aim: To develop a model to discriminate non-specific abdominal pain (NSAP) from organic pain in the paediatric emergency department (PED) and evaluate the added value of laboratory markers., Methods: Prospective cohort study in an urban French PED including all patients aged ≥4 years with abdominal pain between November 2020 and May 2021. The outcome was the discrimination between NSAP (patients coded to have only "pain" or "constipation") and organic pain (all other diagnoses) using stepwise backward multivariate logistic regression method with bootstrap resampling., Results: The study enrolled 246 patients. Overall, 163 patients (66.2%) had NSAP. Four variables associated with organic pain: pain in the epigastric region (OR 0.48 [0.23-0.99]), worsening pain (0.57 [0.32-0.99]), pain migration (0.42 [0.17-0.99]) and vomiting (0.47 [0.26-0.84]) were integrated in a clinical model. To discriminate NSAP with a probability of 65%, model sensitivity was 71.8% (64.9-78.7), specificity was 53.0% (42.3-63.7), and the Net Benefit (NB) was 15.4%. White Blood Count and C-reactive protein results improved discriminative capacity of the model (AUC 0.708 [0.643-0.773] vs. 0.654 [0.585-0.723], p = 0.01) with a supplementary NB of 12%. Patient follow-up showed 95% diagnostic accuracy., Conclusion: This study reveals a four-clinical predictor model with a NB of 15% in predicting NSAP. Validation studies are necessary., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: This study sought to determine the best left ventricular ejection fraction (LVEF) cutoff value to predict long-term mortality in patients with asymptomatic or minimally symptomatic severe aortic stenosis (AS) and LVEF ≥50% under conservative management and after surgical correction of AS., Background: Aortic valve replacement (AVR) is a Class I indication in asymptomatic patients with severe AS and LVEF <50%. However, this is an uncommon situation in asymptomatic severe AS (<1% of patients), usually occurring late in the course of the disease. No data are available concerning the prognostic value of LVEF in asymptomatic or minimally symptomatic AS patients with preserved LVEF (≥50%) in order to identify a LVEF threshold value associated with increased mortality., Methods: This analysis included 1,678 patients with preserved LVEF and no or minimal symptoms, with a diagnosis of severe AS. The population was divided into 3 groups: LVEF <55%, LVEF 55% to 59%, and LVEF ≥60%., Results: Five-year survival rate was 72 ± 2% for patients with LVEF ≥60%, 74 ± 2% for patients with LVEF between 55% and 59%, and 59 ± 4% for patients with LVEF <55% (p < 0.001). Under initially conservative or initially surgical management (surgery within 3 months after baseline echocardiography), patients with LVEF <55% displayed significant excess mortality compared to patients with LVEF≥ 60% (adjusted hazard ratio [HR]: 2.44 [95% confidence interval: 1.51 to 3.94]; p < 0.001 and 2.51 [95% confidence interval: 1.58 to 4.00]; p < 0.001, respectively), whereas patients with LVEF between 55% and 59% had comparable prognosis to those with LVEF ≥60% (p = 0.53 and p = 0.36, respectively). In patients with LVEF <55%, initial conservative management was associated with increased mortality compared to initial surgical management, even after covariate adjustment (adjusted hazard ratio [HR]: 2.70 [95% confidence interval: 1.98 to 3.67]; p < 0.001)., Conclusions: In patients with severe AS, preserved LVEF and no or minimal symptoms at the time of diagnosis, LVEF <55% is a marker of poor outcome, with medical or surgical management suggesting that these patients should be considered for surgery before this stage., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II + myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c + conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory T H 1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a -/- mice lack cDC2s, have CD4 + T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory T H 1* cells.

Aims: This work aimed to investigate a cohort of patients presenting with stent thrombosis (ST) explored by optical coherence tomography (OCT) to identify the underlying mechanical abnormalities in case of bifurcation lesions., Methods and Results: The PESTO study was a prospective national registry involving 29 French catheterisation facilities. Patients with acute coronary syndromes were prospectively screened for presence of definite ST and analysed by OCT after culprit lesion reopening. The cohort involved 120 subjects, including 21 patients (17.5% of the global PESTO group; median age: 62.6 yrs; 76% male) with bifurcation lesions. The clinical presentation was acute or subacute ST in 34%, late ST in 5% and very late ST in 62% of the patients. The main underlying mechanisms were strut malapposition in 33%, stent underexpansion in 19% and isolated strut uncoverage in 19% of the cases. The proximal main branch was involved in 71%, distal main branch in 52% and jailed side branch in 5% of the patients., Conclusions: In this cohort, bifurcation lesions represented a limited number of all ST cases. Different sections of the bifurcation could be involved. Although the underlying mechanisms were various, strut malapposition was the most frequently observed cause.

Background: Stent thrombosis (ST) may be triggered by different phenomena, including underlying device abnormalities and modification of the antiplatelet therapy (APT) regimen. This work investigated the characteristics of APT regimens and their relationships with ST mechanisms among a large cohort of patients evaluated by optical coherence tomography (OCT)., Methods and results: A prospective multicenter registry was screened for patients with confirmed ST. OCT was performed after the initial intervention to the culprit lesion. ST was classified as acute (AST), subacute (SAST), late (LST) and very late (VLST). OCT records were analyzed in a central core laboratory. A total of 120 patients (median age 62 years, 89% male) were included in the study. VLST was the clinical presentation in 75%, LST in 6% and SAST+AST in 19% of the patients. Single APT (SAPT) was given in 61%, double APT (DAPT) in 27% and no APT in 12% of the cases at the time of the ST. A recent (≤15 days) APT modification was reported in 22% of the patients. An underlying mechanical abnormality was identified by OCT in 96.7% of the cases. Ruptured neoatherosclerotic lesions were significantly more frequent in patients without APT compared with the others., Conclusions: ST mostly occurs in patients receiving DAPT or SAPT. Any underlying mechanical abnormality of ST can be involved, irrespective of the APT regimen.

Background: Clinical and echocardiography follow-up is recommended in patients with aortic stenosis to detect symptom onset, thus a watchful waiting approach has to be safe and effective. For both AS patients and their general practitioners, evaluation of valvular heart disease (VHD) knowledge, after the indexed specialized assessment has never been measured., Aims: To evaluate the knowledge of clinical symptoms of aortic stenosis by both patients and their general practitioner., Methods: Sixty-four patients, with moderate to severe and initially asymptomatic AS (median AVA (interquartile range) 1.01(0.80-1.15) cm2) previously referred to a tertiary center and medically managed for at least 6 months after the index echocardiogram, and their primary care doctors were interviewed on the phone and asked to answer specific questions related to knowledge of aortic stenosis symptoms., Results: Fifty-six percent of patients quoted shortness of breath as one of the aortic stenosis symptoms, and only 16% knew the 3 aortic stenosis symptoms. Fifty percent of patients reported having received sufficient information regarding aortic stenosis; only 48% remembered receiving information regarding specific symptoms. Only 14% general practitioners quoted the 3 specific symptoms. According to the initial recommendation, only 41 patients (64%) benefitted from a 6-to-12 month clinical and echocardiography follow up., Conclusion: GPs are not sufficiently trained to safely manage AS patients in the community and to ensure adequate follow-up and monitoring. AS patients were not properly informed about their diagnosis and symptomatology. Hence, therapeutic education should be improved for patients with asymptomatic AS and continuous medical education on VHD should be reinforced, for GPs.

The objective of this study was to estimate the French national updated reference levels (RLs) for coronary angiography (CA) and percutaneous coronary intervention (PCI) by a dose audit from a large data set of unselected procedures and in standard-sized patients. Kerma-area product (PKA), air kerma at interventional point (Ka,r), fluoroscopy time (FT), and the number of registered frames (NFs) and runs (NRs) were collected from 51 229 CAs and 42 222 PCIs performed over a 12-month period at 61 French hospitals. RLs estimated by the 75th percentile in CAs and PCIs performed in unselected patients were 36 and 78 Gy.cm² for PKA, 498 and 1285 mGy for Ka,r, 6 and 15 min for FT, and 566 and 960 for NF, respectively. These values were consistent with the RLs calculated in standard-sized patients. The large difference in dose between sexes leads us to propose specific RLs in males and females. The results suggest a trend for a time-course reduction in RLs for interventional coronary procedures., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Objectives: DES thrombosis may be triggered by different mechanisms that are difficult to identify by angiography alone. This work aimed to investigate and compare the characteristics of stent thrombosis (ST) between 1st- and 2nd-generation drug-eluting stents (DES) among a large cohort of patients explored by optical coherence tomography (OCT)., Methods and Results: The PESTO study was a prospective national registry involving 29 French catheterization facilities. Patients with acute coronary syndromes were prospectively screened for presence of definite ST and analyzed by OCT after culprit lesion deocclusion. The analysis involved 71 subjects including 34 patients with 1st-generation DES (DES1G) and 35 patients with 2nd-generation DES (DES2G). Most patients (80%) presented with very late stent thrombosis. The median time between initial PCI and ST was longer in DES1G than DES2G patients (3.8 [2.6-6.5] years vs. 1.1 [0.04-2.3] years, p<0.0001). OCT identified an underlying morphological abnormality in 96% of the cases. Significant malapposition was the main abnormality observed either in DES1G (26%) or DES2G patients (35%). Ruptured neoatherosclerotic lesions were more frequently observed with DES1G than with DES2G (26% vs. 3%, p=0.008). There was no significant difference in percentage of malapposed struts and uncovered struts between groups., Conclusions: In this registry, DES thrombosis mainly occurred ≥1year after initial PCI. OCT identified a mechanical abnormality in the vast majority of the cases. Similar causes were observed between DES1G and DES2G, but neoatherosclerotic lesions were more common in DES1G., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: Angiography has limited value for identifying the causes of stent thrombosis (ST). We studied a large cohort of patients by optical coherence tomography (OCT) to explore ST characteristics and mechanisms., Methods and Results: A prospective multicentre registry was screened for patients with confirmed ST. Optical coherence tomography was performed after initial intervention to the culprit lesion (in 69% of cases in a deferred procedure). Stent thrombosis was classified as acute (AST), sub-acute (SAST), late (LST), and very late (VLST). Optical coherence tomography records were analysed in a central core lab. The analysis included 120 subjects aged 61.7 [51.4-70.7]; 89% male. Very late ST was the clinical presentation in 75%, LST in 6%, SAST in 15%, and AST in 4% of patients. Bare metal stents (BMS) were used in 39%, drug-eluting stents (DES) in 59% and bioresorbable vascular scaffolds in 2% of the cases. Optical coherence tomography identified an underlying morphological abnormality in 97% of cases, including struts malapposition (34%), neoatherosclerotic lesions (22%), major stent underexpansion (11%), coronary evagination (8%), isolated uncovered struts (8%), edge-related disease progression (8%), and neointimal hyperplasia (4%). Ruptured neoatherosclerotic lesions were more frequent with BMS than with DES (36 vs. 14%, P = 0.005), whereas coronary evaginations were more frequent with DES than with BMS (12 vs. 2%, P = 0.04). LST + VLST were mainly related to malapposition (31%) and neoatherosclerosis (28%), while prominent mechanisms for AST + SAST were malapposition (48%) and underexpansion (26%)., Conclusion: In patients with confirmed ST, OCT imaging identified an underlying morphological abnormality in 97% of cases., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity., (Copyright © 2015, American Association for the Advancement of Science.)

Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.

Objective: Mortality in heart failure (AHF) remains high, especially during the first days of hospitalization. New prognostic biomarkers may help to optimize treatment. The aim of the study was to determine metabolites that have a high prognostic value., Methods: We conducted a prospective study on a training cohort of AHF patients (n = 126) admitted in the cardiac intensive care unit and assessed survival at 30 days. Venous plasmas collected at admission were used for (1)H NMR--based metabonomics analysis. Differences between plasma metabolite profiles allow determination of discriminating metabolites. A cohort of AHF patients was subsequently constituted (n = 74) to validate the findings., Results: Lactate and cholesterol were the major discriminating metabolites predicting 30-day mortality. Mortality was increased in patients with high lactate and low total cholesterol concentrations at admission. Accuracies of lactate, cholesterol concentration and lactate to cholesterol (Lact/Chol) ratio to predict 30-day mortality were evaluated using ROC analysis. The Lact/Chol ratio provided the best accuracy with an AUC of 0.82 (P < 0.0001). The acute physiology and chronic health evaluation (APACHE) II scoring system provided an AUC of 0.76 for predicting 30-day mortality. APACHE II score, Cardiogenic shock (CS) state and Lact/Chol ratio ≥ 0.4 (cutoff value with 82% sensitivity and 64% specificity) were significant independent predictors of 30-day mortality with hazard ratios (HR) of 1.11, 4.77 and 3.59, respectively. In CS patients, the HR of 30-day mortality risk for plasma Lact/Chol ratio ≥ 0.4 was 3.26 compared to a Lact/Chol ratio of < 0.4 (P = 0.018). The predictive power of the Lact/Chol ratio for 30-day mortality outcome was confirmed with the independent validation cohort., Conclusion: This study identifies the plasma Lact/Chol ratio as a useful objective and simple parameter to evaluate short term prognostic and could be integrated into quantitative guidance for decision making in heart failure care.

Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56(dim) NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients' fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients' growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56(dim) subset in patients was associated with a lower rate of NK CD56(bright) cell proliferation, and the maturation of NK CD56(bright) cells toward an NK CD56(dim) phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency.

Background: Langerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or 'LCH cells'. Badalian-Very et al. recently reported the presence of a canonical (V600E)B-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients., Methods and Results: Mutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using 'next generation' pyrosequencing. In 9 cases the mutation identified was (V600E)B-RAF. In 2 cases novel polymorphisms were identified. A somatic (600DLAT)B-RAF insertion mimicked the structural and functional consequences of the (V600E)B-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The (600DLAT)B-RAF and (V600E)B-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%-2% relative mutation abundance. A novel germ line (T599A)B-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, (T599A)B-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation., Conclusions: Our data confirmed presence of the (V600E)B-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that (V600E)B-RAF and (600DLAT)B-RAF mutations are somatic mutants enriched in LCH CD1a(+) cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line (T599A)B-RAF allele.

TGF-β superfamily signals play complex roles in regulation of tissue repair and inflammation in mammals [1]. Drosophila melanogaster is a well-established model for the study of innate immune function [2, 3] and wound healing [4-7]. Here, we explore the role and regulation of two TGF-β superfamily members, dawdle and decapentaplegic (dpp), in response to wounding and infection in adult Drosophila. We find that both TGF-β signals exhibit complex regulation in response to wounding and infection, each is expressed in a subset of phagocytes, and each inhibits a specific arm of the immune response. dpp is rapidly activated by wounds and represses the production of antimicrobial peptides; flies lacking dpp function display persistent, strong antimicrobial peptide expression after even a small wound. dawdle, in contrast, is activated by Gram-positive bacterial infection but repressed by Gram-negative infection or wounding; its role is to limit infection-induced melanization. Flies lacking dawdle function exhibit melanization even when uninfected. Together, these data imply a model in which the bone morphogenetic protein (BMP) dpp is an important inhibitor of inflammation following sterile injury whereas the activin-like dawdle determines the nature of the induced immune response., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Langerhans cells (LCs) are a distinct population of dendritic cells that form a contiguous network in the epidermis of the skin. Although LCs possess many of the properties of highly proficient dendritic cells, recent studies have indicated that they are not necessary to initiate cutaneous immunity. In this study, we used a tractable model of cutaneous GVHD, induced by topical application of a Toll-like receptor agonist, to explore the role of LCs in the development of tissue injury. By adapting this model to permit inducible and selective depletion of host LCs, we found that GVHD was significantly reduced when LCs were absent. However, LCs were not required either for CD8 T-cell activation within the draining lymph node or subsequent homing of effector cells to the epidermis. Instead, we found that LCs were necessary for inducing transcription of IFN-γ and other key effector molecules by donor CD8 cells in the epidermis, indicating that they license CD8 cells to induce epithelial injury. These data demonstrate a novel regulatory role for epidermal LCs during the effector phase of an inflammatory immune response in the skin.

Background: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers., Methodology/principal Findings: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification., Conclusions/significance: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF.

We report the first case of percutaneous radio-frequency (RF) ablation procedure in a patient implanted with a HeartMate II left ventricular assist device for refractory heart failure. This procedure was performed for poorly tolerated recurrent atrial arrhythmias. No harmful consequence happened during or after the procedure despite the potential electromagnetic interferences existing between the RF delivery and the functioning of the device.

Monocytes are effectors of the inflammatory response to microbes. Human CD14(+) monocytes specialize in phagocytosis and production of reactive oxygen species and secrete inflammatory cytokines in response to a broad range of microbial cues. Here, we have characterized the functions of human monocytes that lack CD14 (CD14(dim)) and express CD16. CD14(dim) monocytes were genetically distinct from natural killer cells. Gene expression analyses indicated similarities with murine patrolling Gr1(dim) monocytes, and they patrolled the endothelium of blood vessels after adoptive transfer, in a lymphocyte function-associated antigen-1-dependent manner. CD14(dim) monocytes were weak phagocytes and did not produce ROS or cytokines in response to cell-surface Toll-like receptors. Instead, they selectively produced TNF-α, IL-1β, and CCL3 in response to viruses and immune complexes containing nucleic acids, via a proinflammatory TLR7-TLR 8-MyD88-MEK pathway. Thus, CD14(dim) cells are bona fide monocytes involved in the innate local surveillance of tissues and the pathogenesis of autoimmune diseases., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Levosimendan is a new inodilatory agent with calcium sensitizing activity. A major concern regarding the use of inotropic agent in heart failure is their effect on the sympathetic tone. This effect could explain increase in short term mortality with other inotropes. We aimed to assess the effect of levosimendan on sympathetic tone measured directly by microneurogra-phy. In a group of acute decompensated heart failure patients, we assessed cardiac performance by digital plethysmography measurement. Sympathetic tone was assessed through recording of muscle sympathetic nerve activity (MSNA) by micro-neurography. Recording were done blindly, for each patient after dobutamine perfusion was stopped (baseline) and 48 h after levosimendan infusion. Clinical, biological and morphological data were collected. We compared cardiac parameters and MSNA before and after administration of levosimendan. 13 patients were recruited (48 +/- 3.6 years). Systolic blood pressure and rate pressure product (mmHg x Beat/min) decreased significantly after levosimendan infusion (P< 0.05). Cardiac output and stroke volume were significantly increased after levosimendan infusion (P< 0.05). A significant decrease of MSNA activity is observed after levosimendan infusion (P< 0.01). Levosimendan induced improvement of cardiac performance, associated with a decreased in MSNA. This study show for the first time that levosimendan has no direct detrimental effect on the sympathetic nervous system.

CX(3)CR1 expression is associated with the commitment of CSF-1R(+) myeloid precursors to the macrophage/dendritic cell (DC) lineage. However, the relationship of the CSF-1R(+) CX(3)CR1(+) macrophage/DC precursor (MDP) with other DC precursors and the role of CX(3)CR1 in macrophage and DC development remain unclear. We show that MDPs give rise to conventional DCs (cDCs), plasmacytoid DCs (PDCs), and monocytes, including Gr1(+) inflammatory monocytes that differentiate into TipDCs during infection. CX(3)CR1 deficiency selectively impairs the recruitment of blood Gr1(+) monocytes in the spleen after transfer and during acute Listeria monocytogenes infection but does not affect the development of monocytes, cDCs, and PDCs.

An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host.

HIV efficiently spreads in lymphocytes, likely through virological synapses (VSs). These cell-cell junctions share some characteristics with immunological synapses, but cellular proteins required for their constitution remain poorly characterized. We have examined here the role of ZAP-70, a key kinase regulating T-cell activation and immunological synapse formation, in HIV replication. In lymphocytes deficient for ZAP-70, or expressing a kinase-dead mutant of the protein, HIV replication was strikingly delayed. We have characterized further this replication defect. ZAP-70 was dispensable for the early steps of viral cycle, from entry to expression of viral proteins. However, in the absence of ZAP-70, intracellular Gag localization was impaired. ZAP-70 was required in infected donor cells for efficient cell-to-cell HIV transmission to recipients and for formation of VSs. These results bring novel insights into the links that exist between T-cell activation and HIV spread, and suggest that HIV usurps components of the immunological synapse machinery to ensure its own spread through cell-to-cell contacts.

Associations between depression and somatic disorders are common and little studied. We present the results of a retrospective study including 210 psychiatric inpatients, suffering from a major depressive episodes (MDE-DSM III-R criteria). The purpose of this study was: first, to access the prevalence of comorbid MDEs with somatic illness, second to describe the clinical, therapeutic and evolutionary characteristics of MDEs secondary to a physical trouble, comparatively with primary depressions and depressions secondary to another psychiatric disorder. A somatic comorbidity was found in 55% of patients (n = 116), the physical illness being, in 6% of cases, causal regarding MDEs. MDEs with a somatic comorbidity (n = 55) are significantly different from primary MDEs (n = 36) and MDEs secondary to another psychiatric disorder (n = 58), regarding an older age at hospitalization and at first affective episode. Moreover, they are different from MDEs secondary to another psychiatric disorder through fewer past suicide attempts, more episodes with melancholic or psychotic characteristics and a lower frequency of tricyclic antidepressant use. Despite methodologically limited, these results confirm the frequency of physical comorbidity in depressed patients hospitalized in general hospitals, especially in elderly subjects. They also reflect the heterogeneity of the group of secondary depressions, MDEs associated with a somatic illness being closer to MDEs secondary to another psychiatric disorder than to primary MDEs.