HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.

The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS.

Echocardiography and Lung Ultrasound in Long COVID and Post-COVID Syndrome, a Review Document of the Austrian Society of Pneumology and the Austrian Society of Ultrasound in Medicine.

Lung ultrasound has the potential to enable standardized follow-up without radiation exposure and with lower associated costs in comparison to CT scans. It is a valuable tool to follow up on patients after a COVID-19 infection and evaluate if there is pulmonary fibrosis developing. Echocardiography, including strain imaging, is a proven tool to assess various causes of dyspnea and adds valuable information in the context of long COVID care. Including two-dimensional (2D) strain imaging, a better comprehension of myocardial damage in post-COVID syndrome can be made. Especially 2D strain imaging (left and the right ventricular strain) can provide information about prognosis.

Neutrophil extracellular traps and fibrocytes in ST-segment elevation myocardial infarction.

Leukocyte-mediated inflammation is central in atherothrombosis and ST-segment elevation myocardial infarction (STEMI). Neutrophil extracellular traps (NETs) have been shown to enhance atherothrombosis and stimulate fibroblast function. We analyzed the effects of NETs on cardiac remodeling after STEMI. We measured double-stranded (ds)DNA and citrullinated histone H3 (citH3) as NET surrogate markers in human culprit site and femoral blood collected during primary percutaneous coronary intervention (n = 50). Fibrocytes were characterized in whole blood by flow cytometry, and in culprit site thrombi and myocardium by immunofluorescence. To investigate mechanisms of fibrocyte activation, isolated NETs were used to induce fibrocyte responses in vitro. Enzymatic infarct size was assessed using creatine-phosphokinase isoform MB area under the curve. Left ventricular function was measured by transthoracic echocardiography. NET surrogate markers were increased at the culprit site compared to the femoral site and were positively correlated with infarct size and left ventricular dysfunction at follow-up. In vitro, NETs promoted fibrocyte differentiation from monocytes and induced fibrocyte activation. Highly activated fibrocytes accumulated at the culprit site and in the infarct transition zone. Our data suggest that NETs might be important mediators of fibrotic remodeling after STEMI, possibly by stimulating fibrocytes.

Regression of left atrial diameter after kidney transplantation is associated with prolonged survival: an observational study.

Renal transplantation reduces the dramatically elevated risk of cardiovascular death in dialysis patients. We previously showed that left atrial diameter before transplantation predicts cardiovascular and overall mortality. Now, we investigated the association of changes in cardiac morphology after transplantation and mortality. We retrospectively analyzed data from the Austrian transplant repository using multivariable Cox and competing risk models and multivariable logistic regression for the prediction of changes in cardiac morphology. We identified 414 patients with a median follow-up of 8 years and observed a significant progression of mean diameter of left atrium (LA), right atrium and right ventricle and a significant regression of left ventricle. Complete case analysis of 243 patients with a regression of initially enlarged LA diameter had a significantly lower risk of adjusted overall and cardiovascular mortality; hazard ratio (HR 0.45, 95% CI 0.30-0.69, P < 0.001, 124 deaths), and HR of 0.43 [95% CI 0.21-0.92, P = 0.029, 48 cardiovascular (CV) deaths], respectively. Only age at transplantation was significantly associated with regression of LA (OR 0.75, 95% CI 0.60-0.93, P = 0.007). Patients with regression of LA after kidney transplantation exhibited a lower overall and CV mortality risk. Besides age, peritoneal dialysis and antihypertensive therapy were mediators of LA regression.

Osteopontin is elevated in patients with mitral annulus calcification independent from classic cardiovascular risk factors.

BACKGROUND: Osteopontin (OPN) regulates the Ca(++)-deposition in bone and coronary arteries. Elevated OPN were also associated with (aortic) valve calcification in healthy individuals. This study aimed to investigate the association between OPN levels and mitral annulus calcification (MAC) in patients with coronary artery disease (CAD). METHODS: In this cross-sectional study OPN-levels were measured in 223 non-or ex-smoking patients (160 male, mean age: 61,09 ± 11,02 years; 63 female: mean age: 67,49 ± 7,87 years) with CAD. Plasma OPN levels were measured by ELISA and MAC was evaluated by echocardiography. RESULTS: Forward stepwise logistic regression analysis (likelihood quotient) showed significantly higher OPN-levels in patients with MAC compared to patient without calcified mitral annulus independent from the classic risk factors age and severity of coronary artery disease (CAD). In addition to age and the severity of CAD, the circulating OPN amount was a significant predictor for MAC. CONCLUSIONS: This is the first clinical trial which observed increased circulating OPN levels in MAC, suggesting a distinct role of OPN in the process of MAC. Considering the current knowledge about OPN it is more likely that OPN does not promote but counteracts valve calcification and therefore is elevated in course of a calcification processes.

Pulmonary Hypertension in Heart Failure. Epidemiology, Right Ventricular Function, and Survival.

RATIONALE: Patients with pulmonary hypertension due to left heart disease (PH-LHD) and a diastolic pulmonary vascular pressure gradient ≥ 7 mm Hg, representing PH out of proportion to pulmonary arterial wedge pressure, have pulmonary vascular disease and increased mortality. Little information exists on this condition, recently labeled as "combined pre- and post-capillary PH" (Cpc-PH). OBJECTIVES: To investigate epidemiology, risk factors, right ventricular function, and outcomes in patients with chronic heart failure and Cpc-PH. METHODS: The study population was identified from a retrospective chart review of a clinical database of 3,107 stable patients who underwent first diagnostic right heart catheterization and from a prospective cohort of 800 consecutive patients at a national university-affiliated tertiary center. MEASUREMENTS AND MAIN RESULTS: The retrospective cohort had 664 patients with systolic heart failure (SHF) and 399 patients with diastolic heart failure (DHF), 12% of whom were classified as Cpc-PH. The prospective cohort had 172 patients with SHF (14% Cpc-PH) and 219 patients with DHF (12% Cpc-PH). Chronic obstructive pulmonary disease (P = 0.034) and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio (P = 0.015) predicted Cpc-PH in SHF. Younger age (P = 0.004), valvular heart disease (P = 0.046), and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio predicted Cpc-PH in DHF (P = 0.016). Right ventricular-pulmonary vascular coupling was worse in Cpc-PH patients (end-systolic elastance to effective arterial elastance [Ees/Ea]: SHF: 1.05 ± 0.25; P = 0.002; DHF: 1.17 ± 0.27; P = 0.027) than in those with isolated post-capillary PH (Ees/Ea: SHF: 1.52 ± 0.51; DHF: 1.45 ± 0.29). CONCLUSIONS: Cpc-PH is rare in chronic heart failure. Right ventricular-pulmonary vascular coupling is poor in Cpc-PH and could be one explanation for dismal outcomes.

Just Scan It!-Weapon Reconstruction in Computed Tomography on Historical and Current Swiss Military Guns.

Cross-sectional imaging, such as computed tomography, has been increasingly implemented in both historic and recent postmortem forensic investigations. It aids in determining cause and manner of death as well as in correlating injuries to possible weapons. This study illuminates the feasibility of reconstructing guns in computed tomography and gives a distinct overview of historic and recent Swiss Army guns.

Is winter worse for stressed fish? The consequences of exogenous cortisol manipulation on over-winter survival and condition of juvenile largemouth bass.

Over-winter mortality is an important selective force for warm-water fish (e.g., centrarchids) that live in temperate habitats. Inherent challenges faced by fish during winter may be compounded by additional stressors that activate the hypothalamic-pituitary-interrenal axis, either before or during winter, leading to negative sub-lethal impacts on fish health and condition, and possibly reducing chance of survival. We used experimental cortisol manipulation to test the hypothesis that juvenile largemouth bass (Micropterus salmoides) exposed to semi-chronic elevation in cortisol prior to winter would experience higher levels of over-winter mortality, physiological alterations and impaired immune status relative to control and sham-treated bass. Over-winter survival in experimental ponds was high, averaging 83%, and did not differ among treatment groups. Over the study period, bass exhibited an average increase in mass of 19.4%, as well as a slight increase in Fulton's condition factor, but neither measure differed among groups. Hepatosomatic index in cortisol-treated bass was 23% lower than in control fish, suggesting lower energy status, but white muscle lipid content was similar across all groups. Lastly, there was no difference in spleen somatic index or parasite load among treatment groups, indicating no long-term immune impairment related to our cortisol manipulation. The current study adds to a growing body of literature on glucocorticoid manipulations where field-based findings are not consistent with laboratory-based conceptual understanding of multiple stressors. This suggests that field conditions may provide fish with opportunities to mitigate negative effects of some stressors.

T cell epitope mapping of JC polyoma virus-encoded proteome reveals reduced T cell responses in HLA-DRB1*04:01+ donors.

JC polyomavirus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. It is only during immunocompromise and especially impaired CD4(+) T cell function in the brain, as seen in AIDS patients or natalizumab-treated multiple sclerosis patients, that JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4(+) T cells likely play an important role in controlling JCV infection, we here describe the T cell response to JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. We identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. We observed positive JCV-specific T cell responses in 28.6% to 77.6%, humoral immune response in 42.6% to 89.4%, and urinary viral shedding in 36.4% to 45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01(+), DRB1*07(+), DRB1*11(+), DRB1*13(+), DRB1*15(+), and DRB1*03(+) individuals. We show for the first time that JCV-specific T cell responses may be directed not only against JCV VP1 and large T antigen but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01(+) individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV.

TCR bias and HLA cross-restriction are strategies of human brain-infiltrating JC virus-specific CD4+ T cells during viral infection.

Virus-specific CD4(+) T cells play a central role in control of viral pathogens including JC polyoma virus (JCV) infection. JCV is a ubiquitous small DNA virus that leads to persistent infection of humans with no clinical consequences. However, under circumstances of immunocompromise, it is able to cause an opportunistic and often fatal infection of the brain called progressive multifocal leukoencephalopathy (PML). PML has emerged as a serious adverse event in multiple sclerosis patients treated with the anti-VLA-4 mAb natalizumab, which selectively inhibits cell migration across the blood-brain barrier and the gut's vascular endothelium thus compromising immune surveillance in the CNS and gut. In a multiple sclerosis patient who developed PML under natalizumab treatment and a vigorous immune response against JCV after Ab washout, we had the unique opportunity to characterize in detail JCV-specific CD4(+) T cell clones from the infected tissue during acute viral infection. The in-depth analysis of 14 brain-infiltrating, JCV-specific CD4(+) T cell clones demonstrated that these cells use an unexpectedly broad spectrum of different strategies to mount an efficient JCV-specific immune response including TCR bias, HLA cross-restriction that increases avidity and influences in vivo expansion, and a combination of Th1 and Th1-2 functional phenotypes. The level of combinatorial diversity in TCR- and HLA-peptide interactions used by brain-infiltrating, JCV-specific CD4(+) T cells has not, to our knowledge, been reported before in humans for other viral infections and confirms the exceptional plasticity that characterizes virus-specific immune responses.

HLA-DR15-derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis.

The HLA-DR15 haplotype confers the largest part of the genetic risk to develop multiple sclerosis, a prototypic CD4+ T cell-mediated autoimmune disease. The mechanisms how certain HLA-class II molecules functionally contribute to autoimmune diseases are still poorly understood, but probably involve shaping an autoimmune-prone T cell repertoire during central tolerance in the thymus and subsequently maintaining or even expanding it in the peripheral immune system. Self-peptides that are presented by disease-associated HLA-class II molecules most likely play important roles during both processes. Here, we examined the functional involvement of the HLA-DR15 haplotype in autologous proliferation in multiple sclerosis and the contribution of HLA-DR15 haplotype-derived self-peptides in an in vitro system. We observe increased autologous T cell proliferation in patients with multiple sclerosis in relation to the multiple sclerosis risk-associated HLA-DR15 haplotype. Assuming that the spectrum of self-peptides that is presented by the two HLA-DR15 allelic products is important for sustaining autologous proliferation we performed peptide elution and identification experiments from the multiple sclerosis-associated DR15 molecules and a systematic analysis of a DR15 haplotype-derived self-peptide library. We identify HLA-derived self-peptides as potential mediators of altered autologous proliferation. Our data provide novel insights about perturbed T cell repertoire dynamics and the functional involvement of the major genetic risk factor, the HLA-DR15 haplotype, in multiple sclerosis.

5-azacytidine promotes an inhibitory T-cell phenotype and impairs immune mediated antileukemic activity.

Demethylating agent, 5-Azacytidine (5-Aza), has been shown to be active in treatment of myeloid malignancies. 5-Aza enhances anticancer immunity, by increasing expression of tumor-associated antigens. However, the impact of 5-Aza immune responses remains poorly understood. Here, T-cell mediated tumor immunity effects of 5-Aza, are investigated in vitro and in vivo. T-cells from healthy donors were treated with 5-Aza and analyzed by qRT-PCR and flow cytometry for changes in gene expression and phenotype. Functionality was assessed by a tumor lysis assay. Peripheral blood from patients treated with 5-Aza after alloSCT was monitored for changes in T-cell subpopulations. 5-Aza treatment resulted in a decrease in CD8+ T-cells, whereas CD4+ T-cells increased. Furthermore, numbers of IFN-γ + T-helper 1 cells (Th1) were reduced, while Treg-cells showed substantial increase. Additionally, CD8+ T-cells exhibited limited killing capacity against leukemic target cells. In vivo data confirm the increase of Treg compartment, while CD8+ T-effector cell numbers were reduced. 5-Aza treatment results in a shift from cytotoxic to regulatory T-cells with a functional phenotype and a major reduction in proinflammatory Th1-cells, indicating a strong inhibition of tumor-specific T-cell immunity by 5-Aza.

Impact of tricuspid regurgitation on survival in patients with chronic heart failure: unexpected findings of a long-term observational study.

AIMS: Tricuspid regurgitation (TR) is common in patients with chronic heart failure (CHF) but its prognostic impact is unclear. METHODS AND RESULTS: A total of 576 consecutive patients with CHF were prospectively included. The impact of moderate and severe (significant) TR on the combined endpoint death/heart transplantation/left ventricular-assist device implantation was assessed. Patients were followed for 5.8 ± 4.2 (maximum 14.4) years. Kaplan-Meier analysis showed a worse outcome of patients with significant TR (P < 0.0001). By multivariable analysis, amino terminal pro B-type natriuretic peptide (NT-proBNP) (P = 0.0028), systolic left ventricular function (LVF) (P = 0.0014), serum sodium, NYHA functional class, systolic blood pressure, right atrial size (all P = 0.0001), but not TR were significantly related with the outcome. However, as soon as the strong interaction between TR and LVF was included in the model, significant TR determined outcome as well (P = 0.0059). Therefore, in a second analysis patients were stratified for LVF. In patients with mildly or moderately impaired LVF, TR was significantly related with the outcome (HR: 1.368, CI: 1.070-1.748, P = 0.0125), whereas in patients with severely depressed LVF it was not (P = 0.1401). As a proof of concept, we additionally stratified patients according to serum NT-proBNP concentrations. In patients with NT-proBNP concentrations below the median (≤ 280 fmol/mL), TR was related with the outcome (HR: 2.512, CI: 1.127-5.597, P = 0.0242) but it was not in patients with NT-proBNP concentrations above the median (P = 0.3935). CONCLUSION: The prognostic impact of TR depends on the severity of CHF. While TR was significantly related with excess mortality in mild to moderate CHF, it provided no additive value in advanced disease when compared with established risk factors.

Long-term outcome of bicuspid aortic valve disease.

AIMS: Bicuspid aortic valve (BAV) is a common congenital condition that is frequently associated with aortic stenosis (AS) and aortic regurgitation (AR), as well as aortic aneurysms, but specific outcome data are scarce. The present study sought to assess outcomes in a large cohort of consecutive patients with BAV. METHODS AND RESULTS: A total of 581 consecutive patients (median age 29 years, 157 female) with BAV were included in the study and followed prospectively in a heart valve clinic follow-up programme. The overall survival rate after 10 years was 94.5%. During follow-up, 158 patients developed an indication for surgery. Event-free survival rates were 97%, 94%, 87%, and 73% at 1, 2, 5, and 10 years, respectively. In the multivariable analysis, event rates were independently predicted by AS [subdistribution hazard ratio (SHR) 2.3 per degree of severity], AR (SHR 1.5 per degree of severity), baseline aortic dilatation ≥ 40 mm (SHR 1.9), and age (SHR 1.3) (P < 0.001). CONCLUSION: BAV disease is associated with a high rate of cardiac events, but state-of-the-art care results in good survival with low rates of infective endocarditis, aortic dissection, and sudden death. Incremental degrees of AS and regurgitation, the presence of aortic dilatation, and age are predictive of cardiac events.

Annular remodelling predicts outcome in isolated severe tricuspid regurgitation: a registry-based echocardiographic analysis.

AIMS: Depending on volume status, secondary tricuspid regurgitation (sTR) has a strong dynamic component. In contrast, associated structural dilatation of the tricuspid annulus and the right heart chambers may be less volume dependent. This study aimed to assess the prognostic value of right heart remodelling in isolated severe sTR (isoTR). METHODS AND RESULTS: A total of 36 000 patients from the longitudinal echocardiographic database of our tertiary centre were screened for severe isoTR [vena contracta (VC) ≥ 7 mm] in the absence of atrial fibrillation (AF), other valve disease, and/or reduced systolic left ventricular function. Echocardiographic examinations were re-read, focusing on right ventricular (RV) parameters and on quantitative and qualitative parameters of isoTR. All-cause mortality was defined as the primary endpoint. Two hundred and sixteen patients fulfilled the inclusion criteria. Severe TR was predominant; only few were classified in the new grades massive [n = 23 (10%)] and torrential TR [n = 4 (2%)]. During a median follow-up of 35 months (20-53), all-cause mortality was 31% (n = 67). Multivariate Cox regression analysis revealed no association of VC, effective regurgitant orifice area, or regurgitant volume with all-cause mortality. However, indexed RV end-diastolic diameter (P < 0.001), indexed right atrial dimensions (P = 0.019), and particularly tricuspid valve (TV) annulus diameter diastole index (P = 0.002) and TV annulus diameter systole index (P = 0.001) were significantly associated with outcome. CONCLUSION: Severe isolated TR in the absence of AF is a rare finding with a grim prognosis. Tricuspid annular diameter dimensions rather than quantitative measures of TR proved to be of significant prognostic value indicating a continuous remodelling leading to a 'point of no return' with a dismal outcome.

Echocardiographic assessment of left atrial appendage morphology and function-an expert proposal by the German Working Group of Cardiovascular Ultrasound.

The left atrial appendage is a blind ending cardiac structure prone to blood stasis due to its morphology. This structure is a preferred region of thrombogenesis in relation to reduced myocardial contractility of the atrial wall. Blood stasis occurs primarily in low flow conditions. One of the tasks of echocardiography is the analysis of morphology and function of the left atrial appendage. The detection of thrombi by echocardiography is difficult and must be carried out thoroughly and carefully to avoid potential complications-especially in the context of rhythm control. The assessment of thromboembolic risk, especially in patients with unknown and presumed atrial fibrillation is a second challenge by characterizing atrial function and flow conditions in the left atrial appendage. Thus, this proposal focuses on the obvious problems of echocardiography when assessing left atrial appendage and the role of this method in planning a potential interventional closure of left atrial appendage.

Echocardiographic assessment of atrial, ventricular, and valvular function in patients with atrial fibrillation-an expert proposal by the german working group of cardiovascular ultrasound.

Echocardiography in patients with atrial fibrillation is challenging due to the varying heart rate. Thus, the topic of this expert proposal focuses on an obvious gap in the current recommendations about diagnosis and treatment of atrial fibrillation (AF)-the peculiarities and difficulties of echocardiographic imaging. The assessment of systolic and diastolic function-especially in combination with valvular heart diseases-by echocardiography can basically be done by averaging the results of echocardiographic measurements of the respective parameters or by the index beat approach, which uses a representative cardiac cycle for measurement. Therefore, a distinction must be made between the functionally relevant status, which is characterized by the averaging method, and the best possible hemodynamic status, which is achieved with the most optimal left ventricular (LV) filling according to the index beat method with longer previous RR intervals. This proposal focuses on left atrial and left ventricular function and deliberately excludes problems of echocardiography when assessing left atrial appendage in terms of its complexity. Echocardiography of the left atrial appendage is therefore reserved for its own expert proposal.

Correlation between Lignin-Carbohydrate Complex Content in Grass Lignins and Phenolic Aldehyde Production by Rapid Spray Ozonolysis.

We provide strong evidence that the amounts of phenolic aldehydes (vanillin and p-hydroxybenzaldehyde, pHB) selectively released during rapid ozonolysis of grass lignins are correlated with the unsubstituted aryl carbons of lignin-carbohydrate complexes present in these lignins. In the case of acetosolv lignin from corn stover, we observed a steady yield of vanillin and pHB (cumulatively ∼5 wt % of the initial lignin). We demonstrate the continuous ozonolysis of the lignin in a spray reactor at ambient temperature and pressure. In sharp contrast, similar ozonolysis of acetosolv lignin from corn cobs resulted in a twofold increase in the combined yield (∼10 wt %) of vanillin and pHB. Structural analysis with 1H-13C heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance revealed that signals assigned to unsubstituted aryl carbons of lignin-carbohydrate complexes are quantitatively correlated to phenolic aldehyde production from spray ozonolysis. The ratios of the integrated peak volumes corresponding to coumarates and ferulates in the HSQC spectra of cob and corn stover lignins (SLs) are 2.4 and 2.0, respectively. These ratios are nearly identical to the observed 2.3-fold increase in pHB and 1.8-fold increase in vanillin production rates from corn cob lignin compared to corn SL. Considering that the annual U.S. lignin capacity from these grass lignin sources is ∼60 million MT, the value creation potential from these flavoring agents is conservatively ∼$50 million annually from just 10% of the lignin. These new insights into structure/product correlation and spray reactor characteristics provide rational guidance for developing viable technologies to valorize grass lignins.

Left atrial size predicts outcome in severe but asymptomatic mitral regurgitation.

Patients with severe asymptomatic primary mitral regurgitation (MR) can be safely managed with an active surveillance strategy. Left atrial (LA) size is affected by MR severity, left ventricular function and is also associated with the risk of atrial fibrillation and may be an integrative parameter for risk stratification. The present study sought to determine the predictive value of LA size in a large series of asymptomatic patients with severe MR. 280 consecutive patients (88 female, median age 58 years) with severe primary MR and no guideline-based indications for surgery were included in a follow-up program until criteria for mitral surgery were reached. Event-free survival was determined and potential predictors of outcome were assessed. Survival free of any indication for surgery was 78% at 2 years, 52% at 6 years, 35% at 10 years and 19% at 15 years, respectively. Left atrial (LA) diameter was the strongest independent echocardiographic predictor of event-free survival with incremental predictive value for the thresholds of 50, 60 and 70 mm, respectively. In a multivariable analysis that encompassed age at baseline, previous history of atrial fibrillation, left ventricular end systolic diameter), LA diameter, sPAP > 50 mmHg and year of inclusion, LA diameter was the strongest independent echocardiographic predictor of event-free survival (adjusted HR = 1.039, p < 0.001). LA size is a simple and reproducible predictor of outcome in asymptomatic severe primary MR. In particular, it may help to identify patients who may benefit from early elective valve surgery in heart valve centers of excellence.

Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma.

The role of different receptors in natural-killer- (NK-) cell-mediated cytotoxicity against multiple myeloma (MM) cells is unknown. We investigated if an enhancement of NK-cell-mediated cytotoxicity against MM could be reached by blocking of the inhibitory leukocyte immunoglobulin-like receptor 1 (LIR-1). Our investigations revealed high levels of LIR-1 expression not only on the NK cell line NK-92, but also on myeloma cells (MOLP-8, RPMI8226) as well as on a lymphoblastoid cell line (LBCL; IM-9). Subsequent cytotoxicity assays were designed to show the isolated effects of LIR-1 blocking on either the effector or the tumor side to rule out receptor-receptor interactions. Although NK-92 was shown to be capable of myeloma cell lysis, inhibition of LIR-1 on NK-92 did not enhance cytotoxicity. Targeting the receptor on MM and LBCL did not also alter NK-92-mediated lysis. We come to the conclusion that LIR-1 alone does not directly influence NK-cell-mediated cytotoxicity against myeloma. To our knowledge, this work provides the first investigation of the inhibitory capability of LIR-1 in NK-92-mediated cytotoxicity against MM and the first functional evaluation of LIR-1 on MM and LBCL.