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Quantifizierung der links- und rechtsventrikulären Funktion Strain Imaging erweitert die klassische Volumetrie der MRT um einen sehr subtilen globalen und regionalen Funktionsparameter. Strain detektiert sehr frühe Funktionseinbußen beider Ventrikel, die visuell noch nicht erkennbar sind. Insbesondere der longitudinale Strain ist bei ischämischen und nichtischämischen Erkrankungen frühzeitig reduziert. Strain hat über die EF hinaus zusätzliche prognostische Bedeutung. Gewebecharakterisierung T1- und T2-Mapping erweitern die klassische Gewebecharakterisierung mit Late Gadolinium Enhancement (LGE) um sehr subtile quantitative Parameter, die diffuse Fibrose (T1) und Ödem (T1 und T2) widerspiegeln. Ischämiediagnostik Die Perfusions-MRT unter Vasodilatatorstress ist das genaueste Verfahren zur Ischämiediagnostik. Die MR-INFORM-Studie zeigt, dass mithilfe der Stress-MRT fast die Hälfte der Katheteruntersuchungen in einem Kollektiv mit hoher Prätestwahrscheinlichkeit vermieden werden kann. Dabei ist die Stress-MRT der FFR-basierten Strategie nicht unterlegen und genauso sicher.

Background Cardiac amyloidosis (CA) is an infiltrative disease characterised by accumulation of amyloid deposits in the extracellular space of the myocardium—comprising transthyretin (ATTR) and light chain (AL) amyloidosis as the most frequent subtypes. Histopathological proof of amyloid deposits by endomyocardial biopsy (EMB) is the gold standard for diagnosis of CA. Cardiovascular magnetic resonance (CMR) allows non-invasive workup of suspected CA. We conducted a multi-centre study to assess the diagnostic value of CMR in comparison to EMB for the diagnosis of CA. Methods We studied N = 160 patients characterised by symptoms of heart failure and presence of left ventricular (LV) hypertrophy of unknown origin who presented to specialised cardiomyopathy centres in Germany and underwent further diagnostic workup by both CMR and EMB. If CA was diagnosed, additional subtyping based on EMB specimens and monoclonal protein studies in serum was performed. The CMR protocol comprised cine- and late-gadolinium-enhancement (LGE)-imaging as well as native and post-contrast T1-mapping (in a subgroup)—allowing to measure extracellular volume fraction (ECV) of the myocardium. Results An EMB-based diagnosis of CA was made in N = 120 patients (CA group) whereas N = 40 patients demonstrated other diagnoses (CONTROL group). In the CA group, N = 114 (95%) patients showed a characteristic pattern of LGE indicative of CA. In the CONTROL group, only 1/40 (2%) patient showed a “false-positive” LGE pattern suggestive of CA. In the CA group, there was no patient with elevated T1-/ECV-values without a characteristic pattern of LGE indicative of CA. LGE-CMR showed a sensitivity of 95% and a specificity of 98% for the diagnosis of CA. The combination of a characteristic LGE pattern indicating CA with unremarkable monoclonal protein studies resulted in the diagnosis of ATTR-CA (confirmed by EMB) with a specificity of 98% [95%-confidence interval (CI) 92–100%] and a positive predictive value (PPV) of 99% (95%-CI 92–100%), respectively. The EMB-associated risk of complications was 3.13% in this study—without any detrimental or persistent complications. Conclusion Non-invasive CMR shows an excellent diagnostic accuracy and yield regarding CA. When combined with monoclonal protein studies, CMR can differentiate ATTR from AL with high accuracy and predictive value. However, invasive EMB remains a safe invasive gold-standard and allows to differentiate CA from other cardiomyopathies that can also cause LV hypertrophy.

The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (

Left ventricular (LV) longitudinal, circumferential, and radial motion can be measured using feature tracking of cardiac magnetic resonance (CMR) images. The aim of our study was to detect differences in LV mechanics between patients with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) who were matched using a propensity score-based model. Between April 2017 and October 2019, 1224 patients were included in our CMR registry, among them 141 with ICM and 77 with DCM. Propensity score matching was used to pair patients based on their indexed end-diastolic volume (EDVi), ejection fraction (EF), and septal T1 relaxation time (psmatch2 module L Feature tracking provided six parameters for global longitudinal, circumferential, and radial strain with corresponding strain rates in each group. Strain parameters were compared between matched pairs of ICM and DCM patients using paired t tests. Propensity score matching yielded 72 patients in each group (DCM mean age 58.6 ± 11.6 years, 15 females; ICM mean age 62.6 ± 13.2 years, 11 females, p = 0.084 and 0.44 respectively; LV-EF 32.2 ± 13.5% vs. 33.8 ± 12.1%, p = 0.356; EDVi 127.2 ± 30.7 ml/m2 vs. 121.1 ± 41.8 ml/m2, p = 0.251; native T1 values 1165 ± 58 ms vs. 1167 ± 70 ms, p = 0.862). There was no difference in global longitudinal strain between DCM and ICM patients (− 10.9 ± 5.5% vs. − 11.2 ± 4.7%, p = 0.72), whereas in DCM patients there was a significant reduction in global circumferential strain (− 10.0 ± 4.5% vs. − 12.2 ± 4.7%, p = 0.002) and radial strain (17.1 ± 8.51 vs. 21.2 ± 9.7%, p = 0.039). Our data suggest that ICM and DCM patients have inherently different myocardial mechanics, even if phenotypes are similar. Our data show that GCS is significantly more impaired in DCM patients. This feature may help in more thoroughly characterizing cardiomyopathy patients.

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC)

Background Sleep and physical activity changes are common in pregnancy, but longitudinal data starting before conception are scarce. Our aim was to determine the changes of the daily total sleep time (TST) and physical activity duration (PAD) from before conception to end of pregnancies in respect of pregestational maternal factors. Methods This longitudinal observational study formed part of the CONIMPREG research project and recruited healthy women planning to become pregnant. Sleep and physical activity were recorded around-the-clock for ≥4 days via actigraphy before conception and during each trimester of pregnancy. Data were adjusted according to pregestational maternal body composition, parity and age. Results Among 123 women with eligible data, the unadjusted mean (95% confidence interval) TST increased from 415.3 min (405.5–425.2 min) before conception to 458.0 min (445.4–470.6 min) in the 1st trimester, remaining high through the 2nd and 3rd trimesters. Variation was substantial before conception (±2SD range: 307–523 min). The unadjusted mean PAD before conception was 363.7 min (±2SD range: 120–608 min), decreasing sharply to 262.1 min in the first trimester and more gradually thereafter. Vigorous and moderate activity decreased more than light activity. TST and PAD were significantly associated with age, parity, and pregestational body fat percentage; lean body mass was negatively correlated with TST. Results were generally unaffected by seasonal variations. Conclusion Marked variations were found in pregestational TST and PAD. Healthy women slept ≥30 min longer during pregnancy, while PAD decreased by ≥ 90 min in early pregnancy and continued to decrease thereafter.

Background Extracellular volume (ECV) quantification by CMR imaging allows the measurement of changes in the extracellular space indicating diffuse edema and fibrosis, especially in early stages of myocardial disease. Usually venous hematocrit (Hct) is needed in order to calculate standard ECV. Recent findings suggest the alternative use of the blood pool T1-relaxation time (T1blood) instead of the venous Hct to generate “synthetic Hct ” and furthermore “synthetic ECV”, allowing a more routine and user-friendly application without the need of a current blood sample. Purpose Purpose of this study is to re-evaluate whether the connection between venous Hct and T1blood can be used to generate a synthetic ECV in a large number of volunteers and patients with various myocardial diseases from a tertiary care centre. Methods 945 volunteers and patients were divided into a derivation (n=490) and a validation group (n=455). Standard ECV was calculated using T1-relaxtion times acquisitioned in the septal myocardium and blood pool, each on pre- and post-contrast Images using a modified look-locker sequence at a 3 Tesla MR-scanner. In addition venous Hct was measured in a blood sample drawn prior to the scan. Synthetic Hct was derived through linear regression analysis between venous Hct and 1/T1blood and was then compared to venous Hct. Also we derived standard ECV and synthetic ECV and examined these using Lin's rho and Bland-Altman comparison. Results In the derivation group venous Hct and 1/T1blood showed a linear relationship (R2=0,22; p=ehz746.02521). This was used to calculate synthetic Hct and synthetic ECV. Synthetic ECV correlated well with standard ECV (Lin's rho= 0,903; p Table 1. Patient characteristics Sex female (%) 312 (33%) Age, yrs 60±15 EDVi, ml/m2 86±31 ESVi, ml/m2 43±30 LVEF, % 54±16 Hematocrit, % 43±5 Figure 1 Conclusion Despite only weak correlation of synthetic and venous Hct we found excellent correlation in synthetic and standard ECV. Therefore we could confirm the value of synthetic ECV in a large cohort of volunteers and patients, providing a feasible and non-invasive marker for extracellular myocardial alterations in everyday clinical practice.

Background There are several tools for primary prevention (e.g. Framingham, ESC) that can be used to predict mortality risk in healthy individuals. However, only a few scores have been validated to predict outcome in patients with cardiovascular disease. One of these instruments is the REACH (REduction of Atherothrombosis for Continued Health) score. The ESC guideline for stable coronary artery disease (CAD) places a clear emphasis on carrying out risk stratification before using invasive treatment. Recent studies have revealed a prognostic value of serum hs-cTnI in patients with stable CAD. Purpose The aim of this study was to evaluate the prognostic information provided by hs-cTnI in stable high-risk CAD patients. Methods Between 2011 and 2014, consecutive stable patients with suspected CAD undergoing coronary angiography were included in the study. Data from a 4-year follow-up was obtained; the study endpoint was defined as all-cause mortality. Serum hs-cTnI was measured before angiography using a high-sensitivity assay. Results A total of 3,742 patients were included, of whom 2,274 (60.1%) had confirmed CAD. Patients with an estimated annual mortality rate above 3% using the REACH score were defined as having high risk (n=996 in the low-risk group, n=1,278 in the high-risk cohort). Patients with higher risk were more often male (81.5% vs. 69.2%, p Conclusion Hs-cTnI was found to be an independent risk factor in low- as well as high-risk patients. Hs-cTnI levels correlate with the REACH risk score. Moreover, it was possible to separate patients at very high and very low risk by combining REACH score and hs-cTnI.

Background Adult heart failure in industrialized nations is primarily due to dilated (DCM) and ischemic cardiomyopathy (ICM). Both diseases are characterized by different pathological pathways. While ICM is predominantly caused by local, subendocardial myocyte necrosis, DCM is characterized by a general myocyte apoptosis involving all myocardial layers. Using feature tracking, longitudinal, circumferential, and radial motion of the left ventricle (LV) can be measured, which allows the function of subendocardial, mostly longitudinal orientated, and subepicardial, mostly circumferential orientated fibers to be assessed independently. Purpose It was the aim of our study to detect differences of LV motion between DCM and ICM patients in a propensity score-matched cohort. Methods Between April 2017 and December 2018 we included 845 patients with a clinical indication for CMR in our tertiary care center registry. Out of this cohort we identified 273 patients with ICM and 126 with DCM. Propensity score matching was used to pair patients in each group based on their indexed enddiastolic volume (EDVi), ejection fraction (EF), septal T1. Feature tracking technique was used for strain analyses quantified on steady state free precession cine CMR images yielding six strain parameters. Results Propensity score matching yielded 59 patients in each group (ICM mean age 59.4±13.0 years, 11 females; DCM mean age 66.5±10.6 years, 15 females; LV-EF 32.6±11.4% vs. 33.0±14.2%, p=0.8178; EDVi 124.2±36 ml/m2 vs. 132.9±42 ml/m2, p=0.0909; native T1 values 1161±66 ms vs. 1164±59 ms, p=0.7049). There was no difference in global longitudinal strain between ICM and DCM patients (−10.9±4.4% vs. −10.6±5.8%, p=0.686), whereas global circumferential strain and radial strain were reduced in DCM patients (−12.0±4.3% vs. −10.31±4.8%, p=0.0190 and 21.1±8.9% vs. 18.0±15.5%, p=0.0386). Conclusion Our data confirm the inherently different mechanics of ICM and DCM patients. While myocardial fibres are globally affected in DCM, myocardial damage is predominantly confined to subendocardial layers in ICM despite equally reduced EF.

Background and aim Obese individuals have a high risk of developing heart failure independent of concomitant diseases like diabetes mellitus or arterial hypertension. Hormones secreted by adipose tissue, so-called adipokines such as retinol binding protein 4 (RBP4) or fatty-acid binding protein 4 (FABP4), might constitute a link between obesity and cardiomyopathy. RBP4 is known to be associated with left ventricular hypertrophy, whereas FABP 4 has been reported to display anti- as well as pro-hypertrophic properties. Purpose The aim of the present study was to investigate the association of FABP4 and RBP4 with cardiac magnet resonance imaging (MRI) parameters. Methods We investigated plasma FABP4 and plasma RBP4 levels in 210 patients (70% men, mean age 63 years) who underwent an MRI examination and tested whether FAPB4 and RBP4 levels were associated with the following MRI parameters using linear cox regression: left ventricular end-diastolic diameter (LVEDD), interventricular septal (IVS) wall thickness, posterior wall thickness (PWT), relative wall thickness (RWT), left ventricular mass index (LVMI), and left ventricular ejection fraction (LVEF). An unadjusted model and a model adjusted for age, sex, body mass index, diabetes mellitus, arterial hypertension, smoking, presence of coronary artery disease, and heart rate were used. Results FABP4 levels were associated with higher PWT (p=0.0044, est. = 0.4) and RWT (p=0.0011, est. = 0.02). The associations were significant in the fully adjusted model (for PWT p=0.013, for RWT p=0.0043). We observed a non-linear, U-shaped relationship between FABP4 and LVEDD, RVEDD, and LVMI. FABP4 levels below the median were associated with lower LVEDD (p=0.0239, est. = −2.7), RVEDD (p=0.0127, est. = −3.3) and LVMI (p In the unadjusted model, RBP4 was associated with higher IVS (p=0.005, est. = 0.59), PWT (p=0.0135, est. = 0.37), and RWT (p=0.036, est. = 0.02); these associations were not significant in the fully adjusted model. Interestingly, an interaction was observed between age and RBP4 in the association with IVS (p interaction = 0.01). Higher RBP4 and older age might have a stronger effect on IVS than age and RBP4 alone (see Figure). Conclusion Anti- and pro-hypertrophic associations between FABP4 and left ventricular size have been reported. Our results suggest that the pro- and anti-hypertrophic effects of FABP4 are dependent on FABP4 concentrations: lower FABP4 levels have an anti-hypertrophic effect, whereas higher levels have a pro-hypertrophic effect. RBP4 was associated with parameters of cardiac hypertrophy determined by MRI, suggesting a possible link between obesity and cardiomyopathy in an age dependent manner.

Background Graft failure caused by allograft rejection and vasculopathy is the most common cause of mortality after heart transplantation. To detect an early allograft rejection, endomyocardial biopsy is still needed. Tissue characterization by T1-mapping and Late gadolinium enhancement is well established in acute and chronic myocardial tissue alterations. Therefore several studies investigated T1-mapping as a potential noninvasive parameter to monitor cardiac allograft vasculopathy and allograft rejection. However it is unclear if T1 is also influenced by pretransplant ischemic time and elapsed time since transplantation. Purpose It was the aim of our study to examine the influence of ischemic and elapsed time since transplantation to the cardiac allograft tissue characteristics measured by CMR T1 relaxation times. Methods Allograft transplant patients underwent stress CMR on a yearly routine. T1-maps were acquired using a modified look locker sequence (MOLLI 3(2)3(2)5) in the midventricular septum. Uni- and multi linear regression analysis was used to predict T1 by ischemic time, time since transplantation, troponin and NT-Pro-BNP. Results 49 cardiac allograft transplanted patients underwent stress CMR (mean age 58.6±11.7 years, left ventricular ejection fraction 62.1±6.8%; indexed enddiastolic volume 68.4±14.7 ml/m2; native T1 1120±51 ms, extracellular volume 0.27±0.04). A significant correlation was found between T1 and NT-Pro-BNP (1519±3639 pg/ml, p=0.003) and a trend for troponin (17.0±12.8 ng/dl, p=0.051). We saw no correlation between T1 and the ischemic time (198.4±44.9 minutes, p=0.1172) and elapse time since transplantation (47±7 month, p=0.9868). In the multivariate regression analysis none of the four parameters were independently associated with the T1 time (p=0.1017). Table 1 Characteristics Mean ± SD p Ischemic time (minutes) 198.4±44.9 0.1172 Time since transplant (month) 47±7 0.9868 NT-Pro-BNP (pg/ml) 1519±3639 0.003 Troponine (ng/dl) 17.0±12.8 0.051 Conclusion There was no significant effect of pretransplant ischemic time and elapse time since transplantation on native T1 times, whereas native T1 was significantly correlated with troponine and NT-Pro-BNP-Levels. T1 is excellently suited to detect acute changes in allograft transplant patients without being influenced by aging of the transplanted heart and the heart's pretransplant condition.

A vaccine that prevents hepatitis C virus (HCV) infection is urgently needed to support an emerging global elimination program. However, vaccine development has been confounded because of HCV's high degree of antigenic variability and the preferential induction of type-specific immune responses with limited potency against heterologous viral strains and genotypes. We showed previously that deletion of the three variable regions from the E2 receptor-binding domain (Δ123) increases the ability of human broadly neutralizing antibodies (bNAbs) to inhibit E2-CD81 receptor interactions, suggesting improved bNAb epitope exposure. In this study, the immunogenicity of Δ123 was examined. We show that high-molecular-weight forms of Δ123 elicit distinct antibody specificities with potent and broad neutralizing activity against all seven HCV genotypes. Antibody competition studies revealed that immune sera raised to high-molecular-weight Δ123 was poly specific, given that it inhibited the binding of human bNAbs directed to three major neutralization epitopes on E2. By contrast, the immune sera raised to monomeric Δ123 predominantly blocked the binding of a non-neutralizing antibody to Δ123, while having reduced ability to block bNAb binding to E2, and neutralization was largely toward the homologous genotype. This increased ability of oligomeric Δ123 to generate bNAbs correlates with occlusion of the non-neutralizing face of E2 in this glycoprotein form. Conclusion: The results from this study reveal new information on the antigenic and immunogenic potential of E2-based immunogens and provide a pathway for the development of a simple, recombinant protein-based prophylactic vaccine for HCV with potential for universal protection. (Hepatology 2017;65:1117-1131).

The hepatitis C virus (HCV) E2 glycoprotein is a major target of the neutralizing antibody (nAb) response, with multiple type-specific and broadly neutralizing antibody (bnAb) epitopes identified. The 412-to-423 region can generate bnAbs that block interaction with the cell surface receptor CD81, with activity toward multiple HCV genotypes. In this study, we reveal the structure of rodent monoclonal antibody 24 (MAb24) with an extensive contact area toward a peptide spanning the 412-to-423 region. The crystal structure of the MAb24–peptide 412-to-423 complex reveals the paratope bound to a peptide hairpin highly similar to that observed with human MAb HCV1 and rodent MAb AP33, but with a different angle of approach. In viral outgrowth experiments, we demonstrated three distinct genotype 2a viral populations that acquired resistance to MAb24 via N415D, N417S, and N415D/H386R mutations. Importantly, the MAb24-resistant viruses exhibited significant increases in sensitivity to the majority of bnAbs directed to epitopes within the 412-to-423 region and in additional antigenic determinants located within E2 and the E1E2 complex. This study suggests that modification of N415 causes a global change in glycoprotein structure that increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable. IMPORTANCE Understanding how antibodies neutralize hepatitis C virus (HCV) is essential for vaccine development. This study reveals for the first time that when HCV develops resistance to a major class of bnAbs targeting the 412-to-423 region of E2, this results in a concomitant increase in sensitivity to neutralization by a majority of other bnAb specificities. Vaccines for the prevention of HCV infection should therefore generate bnAbs directed toward the 412-to-423 region of E2 and additional bnAb epitopes within the viral glycoproteins.

The aim of the present study was to assess indications for induction and describe the characteristics and delivery outcome in medical compared to non-medical/elective inductions. During a three-month period, 1663 term inductions were registered in 24 delivery units in Norway. Inclusion criteria were singleton pregnancies with cephalic presentation at gestational age 37+0 and beyond. Indications, pre-induction Bishop scores, mode of delivery and adverse maternal and fetal outcomes were registered, and compared between the medically indicated and elective induction groups. Ten percent of the inductions were elective, and the four most common indications were maternal request (35%), a previous negative delivery experience or difficult obstetric history (19%), maternal fatigue/tiredness (17%) and anxiety (15%). Nearly half of these inductions were performed at 39+0–40+6 weeks. There were fewer nulliparous women in the elective compared to the medically indicated induction group, 16% vs. 52% (p

NIR predictions of cellulose content and stiffness (modulus of elasticity, MOE) from spectra collected from the radial longitudinal surface of Eucalyptus globulus wood were found to be reliable indicators of zones of non-recoverable collapse associated with the presence of tension wood. Radial sections from 25 quarter-sawn boards cut from plantation-grown E. globulus trees in Spain were scanned to generate radial profiles of NIR-predicted wood properties at 2 mm increments. These boards manifested a range of non-recoverable collapse features, from no collapse to one or more severe collapse bands. Collapse bands occurred where NIR-predicted cellulose content and MOE exceeded threshold levels of 50 % and 25 GPa, respectively for more than four consecutive millimetres. A non-recoverable collapse indicator provided a clear predictor of non-recoverable collapse. A NRCI value ≥100 for a consecutive interval of at least 4 mm successfully predicted all ten NRC bands with shrinkage ≥10 % of board thickness. The potential applications of this tension wood detection method are discussed.

Recent studies identified serum concentrations of the astroglial protein glial fibrillary acidic protein (GFAP) to be indicative of glioblastoma (GBM) in patients with newly diagnosed space occupying cerebral mass lesions. Until now, no data is available whether GFAP serum concentrations decrease after first therapy and whether GFAP may be used as a predictor of survival and an indicator of tumor recurrence. In this prospective study, we included 44 patients with a single space occupying cerebral mass lesion suspicious for GBM. GBM was histopathologically proven in 33 cases. After initial therapy, patients were followed up until tumor recurrence (defined according to the RANO criteria) or death (maximum observation period 78 weeks). Blood was sampled on a regular basis, and GFAP serum levels were determined using an immunofluorescence assay. Prior to any intervention, 14 of the 33 GBM patients had elevated GFAP serum concentrations (median 0.25 µg/L, interquartile range 0.13–0.53), whereas only one out of 11 patients having other tumor entities revealed a slightly increased GFAP serum level (0.06 µg/L). Following surgery (i.e., biopsy, full or partial resection), all initially GFAP positive GBM patients showed decreased serum concentrations. During the follow-up period, we found a minimal GFAP increase in one patient only (0.04 µg/L; week 52), although 23 out of 31 available GBM patients developed tumor progression or died. No difference was found regarding the survival rate and the time to tumor recurrence between initially GFAP positive and GFAP negative GBM patients. In GBM patients, initially elevated GFAP serum concentrations decrease after the first diagnostic or therapeutic intervention. GFAP was not predictive for tumor recurrence.

Adipose tissue plays an important role in energy homeostasis; however, there is only little knowledge about its metabolic activity during critical illness or sepsis. We assessed adipose tissue metabolic activity and local blood flow during experimental endotoxemia in otherwise healthy humans. In a prospective, placebo controlled and randomized experiment we measured changes in lactate, glycerol, and pyruvate concentrations in microdialysate samples of femoral adipose tissue after an intravenous bolus of lipopolysaccharide (LPS, 4 ng/kg). Intravenous endotoxin caused an early and constant increase in interstitial pyruvate, while formation of lactate in adipose tissue was not affected. In contrast, lactate levels in serum were elevated significantly after 90 min (p

BackgroundVirus-like particles (VLPs) are highly immunogenic and proven to induce protective immunity. The small surface antigen (HBsAg-S) of hepatitis B virus (HBV) self-assembles into VLPs and its use as a vaccine results in protective antiviral immunity against HBV infections. Chimeric HBsAg-S proteins carrying foreign epitopes allow particle formation and have the ability to induce anti-foreign humoral and cellular immune responses.Methods/resultsThe insertion of the hypervariable region 1 (HVR1) sequence derived from the envelope protein 2 (E2) of hepatitis C virus (HCV) into the major antigenic site of HBsAg-S (‘a’-determinant) resulted in the formation of highly immunogenic VLPs that retained the antigenicity of the inserted HVR1 sequence. BALB/c mice were immunized with chimeric VLPs, which resulted in antisera with anti-HCV activity. The antisera were able to immunoprecipitate native HCV envelope complexes (E1E2) containing homologous or heterologous HVR1 sequences. HCV E1E2 pseudotyped HIV-1 particles (HCVpp) were used to measure entry into HuH-7 target cells in the presence or absence of antisera that were raised against chimeric VLPs. Anti-HVR1 VLP sera interfered with entry of entry-competent HCVpps containing either homologous or heterologous HVR1 sequences. Also, immunizations with chimeric VLPs induced anti-surface antigen (HBsAg) antibodies, indicating that HBV-specific antigenicity and immunogenicity of the ‘a’-determinant region is retained.ConclusionsA multivalent vaccine against different pathogens based on the HBsAg delivery platform should be possible. We hypothesize that custom design of VLPs with an appropriate set of HCV-neutralizing epitopes will induce antibodies that would serve to decrease the viral load at the initial infecting inoculum.

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 form a heterodimer and mediate receptor interactions and viral fusion. Both E1 and E2 are targets of the neutralizing antibody (NAb) response and are candidates for the production of vaccines that generate humoral immunity. Previous studies demonstrated that N-terminal hypervariable region 1 (HVR1) can modulate the neutralization potential of monoclonal antibodies (MAbs), but no information is available on the influence of HVR2 or the intergenotypic variable region (igVR) on antigenicity. In this study, we examined how the variable regions influence the antigenicity of the receptor binding domain of E2 spanning HCV polyprotein residues 384 to 661 (E2 661 ) using a panel of MAbs raised against E2 661 and E2 661 lacking HVR1, HVR2, and the igVR (Δ123) and well-characterized MAbs isolated from infected humans. We show for a subset of both neutralizing and nonneutralizing MAbs that all three variable regions decrease the ability of MAbs to bind E2 661 and reduce the ability of MAbs to inhibit E2-CD81 interactions. In addition, we describe a new MAb directed toward the region spanning residues 411 to 428 of E2 (MAb24) that demonstrates broad neutralization against all 7 genotypes of HCV. The ability of MAb24 to inhibit E2-CD81 interactions is strongly influenced by the three variable regions. Our data suggest that HVR1, HVR2, and the igVR modulate exposure of epitopes on the core domain of E2 and their ability to prevent E2-CD81 interactions. These studies suggest that the function of HVR2 and the igVR is to modulate antibody recognition of glycoprotein E2 and may contribute to immune evasion. IMPORTANCE This study reveals conformational and antigenic differences between the Δ123 and intact E2 661 glycoproteins and provides new structural and functional data about the three variable regions and their role in occluding neutralizing and nonneutralizing epitopes on the E2 core domain. The variable regions may therefore function to reduce the ability of HCV to elicit NAbs directed toward the conserved core domain. Future studies aimed at generating a three-dimensional structure for intact E2 containing HVR1, and the adjoining NAb epitope at residues 412 to 428, together with HVR2, will reveal how the variable regions modulate antigenic structure.

Hepatitis delta virus (HDV) is encapsidated by the envelope proteins of hepatitis B virus (HBV). The major HBV lamivudine (LMV)-resistant mutations in the polymerase gene within the reverse transcriptase (rt) region at rtM204V or rtM204I are associated with changes in the overlapping envelope gene products, in particular, the gene encoding small envelope protein (s) at sI195M or sW196L/S/Stop. We have demonstrated that the LMV resistance mutations corresponding to sW196L/S inhibited secretion of HDV particles, while changes corresponding to sI195M did not affect secretion. Differential efficiencies of HBsAg proteins expressed by LMV-resistant HBV to support HDV secretion may have consequences for clinical prognosis as coinfected patients are treated with antiviral agents.

Experimental endotoxemia as a model of the initial septic response affects the autonomic nervous system with profound cardiovascular sequelae. Whether the postsynaptic sympathoneural activity to the muscle vascular bed is altered in the early septic phase remains to be determined. The present study aimed to elucidate the early effects of LPS on muscle sympathetic nerve activity (MSNA) and cardiovascular regulation in healthy humans. Young, healthy volunteers randomly received either an LPS bolus (4 ng/kg body wt, n = 11) or placebo (saline; n = 7). Experimental baroreflex assessment (baseline measurements followed by infusion of vasoactive drugs nitroprusside/phenylephrine) was done prior to and 90 min following LPS or placebo challenge. MSNA, heart rate, blood pressure, and blood levels of catecholamines, TNF-α and IL-6 were measured sequentially. Endotoxin but not placebo-induced flu-like symptoms and elevated cytokine levels. In contrast to placebo, LPS significantly suppressed MSNA burst frequency 90 min after injection [mean ± SE: 12.1 ± 2.9 vs. 27.5 ± 3.3 burst/min (post- vs. pre-LPS); P < 0.005] but increased heart rate [78.4 ± 3.1 vs. 60.6 ± 2.0 beats/min (post- vs. pre-LPS); P < 0.001]. Baseline blood pressure was not altered, but baroreflex testing demonstrated a blunted MSNA response and uncoupling of heart rate modulation to blood pressure changes in the endotoxin group. We conclude that endotoxin challenge in healthy humans has rapid suppressive effects on postsynaptic sympathetic nerve activity to the muscle vascular bed and alters baroreflex function which may contribute to the untoward cardiovascular effects of sepsis.