Inter-observer agreement for spectral- and time-domain optical coherence tomography image grading: a prospective study

The purpose of this study was to compare inter-observer agreement of Stratus™ OCT versus Spectralis™ OCT image grading in patients with neovascular age-related macular degeneration (AMD). Thirty eyes with neovascular AMD were examined with Stratus™ OCT and Spectralis™ OCT. Four different scan protocols were used for imaging. Three observers graded the images for the presence of various pathologies. Inter-observer agreement between OCT models was assessed by calculating intra-class correlation coefficients (ICC). In Stratus™ OCT highest interobserver agreement was found for subretinal fluid (ICC: 0.79), and in Spectralis™ OCT for intraretinal cysts (IRC) (ICC: 0.93). Spectralis™ OCT showed superior interobserver agreement for IRC and epiretinal membranes (ERM) (ICC(Stratus™): for IRC 0.61; for ERM 0.56; ICC(Spectralis™): for IRC 0.93; for ERM 0.84). Increased image resolution of Spectralis™ OCT did improve the inter-observer agreement for grading intraretinal cysts and epiretinal membranes but not for other retinal changes.

Uncovering the dynamics of cardiac systems using stochastic pacing and frequency domain analyses

Alternans of cardiac action potential duration (APD) is a well-known arrhythmogenic mechanism which results from dynamical instabilities. The propensity to alternans is classically investigated by examining APD restitution and by deriving APD restitution slopes as predictive markers. However, experiments have shown that such markers are not always accurate for the prediction of alternans. Using a mathematical ventricular cell model known to exhibit unstable dynamics of both membrane potential and Ca2+ cycling, we demonstrate that an accurate marker can be obtained by pacing at cycle lengths (CLs) varying randomly around a basic CL (BCL) and by evaluating the transfer function between the time series of CLs and APDs using an autoregressive-moving-average (ARMA) model. The first pole of this transfer function corresponds to the eigenvalue (λalt) of the dominant eigenmode of the cardiac system, which predicts that alternans occurs when λalt≤−1. For different BCLs, control values of λalt were obtained using eigenmode analysis and compared to the first pole of the transfer function estimated using ARMA model fitting in simulations of random pacing protocols. In all versions of the cell model, this pole provided an accurate estimation of λalt. Furthermore, during slow ramp decreases of BCL or simulated drug application, this approach predicted the onset of alternans by extrapolating the time course of the estimated λalt. In conclusion, stochastic pacing and ARMA model identification represents a novel approach to predict alternans without making any assumptions about its ionic mechanisms. It should therefore be applicable experimentally for any type of myocardial cell.

Eukaryotic translation elongation factor 1A (eEF1A) domain I from S. cerevisiae is required but not sufficient for inter-species complementation

Ethanolamine phosphoglycerol (EPG) is a protein modification attached exclusively to eukaryotic elongation factor 1A (eEF1A). In mammals and plants, EPG is linked to conserved glutamate residues located in eEF1A domains II and III, whereas in the unicellular eukaryote Trypanosoma brucei, only domain III is modified by a single EPG. A biosynthetic precursor of EPG and structural requirements for EPG attachment to T. brucei eEF1A have been reported, but nothing is known about the EPG modifying enzyme(s). By expressing human eEF1A in T. brucei, we now show that EPG attachment to eEF1A is evolutionarily conserved between T. brucei and Homo sapiens. In contrast, S. cerevisiae eEF1A, which has been shown to lack EPG is not modified in T. brucei. Furthermore, we show that eEF1A cannot functionally complement across species when using T. brucei and S. cerevisiae as model organisms. However, functional complementation in yeast can be obtained using eEF1A chimera containing domains II or III from other species. In contrast, yeast domain I is strictly required for functional complementation in S. cerevisiae.

Offline fusion of co-registered intravascular ultrasound and frequency domain optical coherence tomography images for the analysis of human atherosclerotic plaques

To demonstrate the feasibility and potential usefulness of an offline fusion of matched optical coherence tomography (OCT) and intravascular ultrasound (IVUS)/virtual histology (IVUS-VH) images.

Echocardiogram versus cardiac magnetic resonance imaging for assessing systolic function of subaortic right ventricle in adults with complete transposition of great arteries and previous atrial switch operation

In adults with congenital heart disease and a systemic right ventricle, subaortic ventricular systolic dysfunction is common. Echocardiographic assessment of systolic right ventricular (RV) function in these patients is important but challenging. The aim of the present study was to assess the reliability of conventional echocardiographic RV functional parameters to quantify the systolic performance of a subaortic right ventricle. We compared 56 contemporary echocardiograms and cardiac magnetic resonance studies in 37 adults, aged 26.9 ± 7.4 years, with complete transposition and a subaortic right ventricle. The fractional area change (FAC), lateral tricuspid annular plane systolic excursion, lateral RV systolic motion velocities by tissue Doppler, RV myocardial performance index, and the rate of systolic RV pressure increase (dp/dt) measured across the tricuspid regurgitant jet were assessed by echocardiography and correlated with the cardiac magnetic resonance-derived RV ejection fraction (EF). The mean RVEF was 48.0 ± 7.8%. FAC (r(2) = 0.206, p = 0.001) and dp/dt (r(2) = 0.173, p = 0.009) significantly correlated with RVEF, and the other nongeometric echocardiographic parameters failed to show a significant correlation with RVEF by linear regression analysis. FAC <33% and dp/dt <1,000 mm Hg/s identified a RVEF of <50% with a sensitivity of 77% and 69% and a specificity of 58% and 87%, respectively. In conclusion, in patients with a systemic right ventricle, routine nongeometric echocardiographic parameters of RV function correlated weakly with cardiac magnetic resonance-derived EF. RV FAC and the measurement of the rate of systolic RV pressure increase (dp/dt) should be preferentially used to assess systemic systolic function in adult patients with a subaortic right ventricle.

Outcome in adult patients after arterial switch operation for transposition of the great arteries

BACKGROUND: The arterial switch operation (ASO) is currently the treatment of choice in neonates with transposition of the great arteries (TGA). The outcome in childhood is encouraging but only limited data for long-term outcome into adulthood exist. METHODS AND RESULTS: We studied 145 adult patients (age>16, median 25years) with ASO followed at our institution. Three patients died in adulthood (mortality 2.4/1000-patient-years). Most patients were asymptomatic and had normal left ventricular function. Coronary lesions requiring interventions were rare (3 patients) and in most patients related to previous surgery. There were no acute coronary syndromes. Aortic root dilatation was frequent (56% patients) but rarely significant (>45mm in 3 patients, maximal-diameter 49mm) and appeared not to be progressive. There were no acute aortic events and no patient required elective aortic root surgery. Progressive neo-aortic-valve dysfunction was not observed in our cohort and only 1 patient required neo-aortic-valve replacement. Many patients (42.1%), however, had significant residual lesions or required reintervention in adulthood. Right ventricular outflow tract lesions or dysfunction of the neo-pulmonary-valve were frequent and 8 patients (6%) required neo-pulmonary-valve replacement. Cardiac interventions during childhood (OR 3.0, 95% CI 1.7-5.4, P<0.0001) were strong predictors of outcome (cardiac intervention/significant residual lesion/death) in adulthood. CONCLUSIONS: Adult patients with previous ASO remain free of acute coronary or aortic complications and have low mortality. However, a large proportion of patients require re-interventions or present with significant right sided lesions. Life-long cardiac follow-up is, therefore, warranted. Periodic noninvasive surveillance for coronary complications appears to be safe in adult ASO patients.

Cannabinoid receptor trafficking in peripheral cells is dynamically regulated by a binary biochemical switch

The cannabinoid G protein-coupled receptors (GPCRs) CB₁ and CB₂ are expressed in different peripheral cells. Localization of GPCRs in the cell membrane determines signaling via G protein pathways. Here we show that unlike in transfected cells, CB receptors in cell lines and primary human cells are not internalized upon agonist interaction, but move between cytoplasm and cell membranes by ligand-independent trafficking mechanisms. Even though CB receptors are expressed in many cells of peripheral origin they are not always localized in the cell membrane and in most cancer cell lines the ratios between CB₁ and CB₂ receptor gene and surface expression vary significantly. In contrast, CB receptor cell surface expression in HL60 cells is subject to significant oscillations and CB₂ receptors form oligomers and heterodimers with CB₁ receptors, showing synchronized surface expression, localization and trafficking. We show that hydrogen peroxide and other nonspecific protein tyrosine phosphatase inhibitors (TPIs) such as phenylarsine oxide trigger both CB₂ receptor internalization and externalization, depending on receptor localization. Phorbol ester-mediated internalization of CB receptors can be inhibited via this switch. In primary human immune cells hydrogen peroxide and other TPIs lead to a robust internalization of CB receptors in monocytes and an externalization in T cells. This study describes, for the first time, the dynamic nature of CB receptor trafficking in the context of a biochemical switch, which may have implications for studies on the cell-type specific effects of cannabinoids and our understanding of the regulation of CB receptor cell surface expression.

Comparison of objectively measured motor behavior with ratings of the motor behavior domain of the Bern Psychopathology Scale (BPS) in schizophrenia

Motor symptoms in schizophrenia occur frequently and are relevant to diagnosis and antipsychotic therapy. To date motor symptoms are difficult to assess and their pathobiology is a widely unresolved issue. The Bern Psychopathology Scale for the assessment of system-specific psychotic symptoms (BPS) was designed to identify homogenous patient groups by focusing on three domains: language, affectivity and motor behavior. The present study aimed to validate the motor behavior domain of the BPS using wrist actigraphy. In total, 106 patients were rated with the BPS and underwent 24 h continuous actigraphy recording. The ratings of the global severity of the motor behavior domain (GSM) as well as the quantitative and the subjective items of the motor behavior domain of the BPS were significantly associated with actigraphic variables. In contrast, the qualitative items of the motor domain failed to show an association with actigraphy. Likewise, scores of the language and the affectivity domains were not related to actigraphic measures. In conclusion, we provided substantial external validity for global, quantitative and subjective ratings of the BPS motor behavior domain. Thus, the BPS is suitable to assess the dimension of quantitative motor behavior in the schizophrenia spectrum.