Influence of scoring parameter settings on Agatston and volume scores for coronary calcification

Current multi-detector CT and electron beam tomography (EBT) technology enables the evaluation of coronary calcification. Multiple software packages are available to quantify calcification using several scoring algorithms implementing user-definable scoring parameters. We investigated the effect of scoring parameters on the calcium score outcome. Three parameters (four-connected or eight-connected, lesion size threshold and interpolation) are evaluated. Their theoretical influence on the scoring outcome is shown using simplified examples. To evaluate the effect in real data, we performed calcium scoring on randomly chosen EBT scans from 50 participants in an epidemiological study. Both the Agatston and volume scores were calculated. Changing from eight-connected to four-connected connectivity decreased both Agatston and volume scores (mean variability Agatston 3.15% and volume score –3.52%). Decreasing the threshold from 4 to 2 pixels increased the calcium scores because smaller lesions were also selected as calcified plaques (mean variability Agatston 16.23% and volume score 18.66%). Finally, the use of interpolation had a large negative effect on the volume score (mean variability –29.67%) and almost no effect on the Agatston score. Parameter settings in software for quantification for coronary calcification affect the calcium score outcome. Therefore, parameter settings for calcium scoring should be standardized.     

Coronary artery calcification score by multislice computed tomography predicts the outcome of dobutamine cardiovascular magnetic resonance imaging

The aim of this study was to determine whether a coronary artery calcium (CAC) score of less than 11 can reliably rule out myocardial ischemia detected by dobutamine cardiovascular magnetic resonance imaging (CMR) in patients suspected of having myocardial ischemia. In 114 of 136 consecutive patients clinically suspected of myocardial ischemia with an inconclusive diagnosis of myocardial ischemia, dobutamine CMR was performed and the CAC score was determined. The CAC score was obtained by 16-row multidetector compued tomography (MDCT) and was calculated according to the method of Agatston. The CAC score and the results of the dobutamine CMR were correlated and the positive predictive value (PPV) and the negative predictive value (NPV) of the CAC score for dobutamine CMR were calculated. A total of 114 (87%) of the patients were eligible for this study. There was a significant correlation between the CAC score and dobutamine CMR (p<0.001). Patients with a CAC score of less than 11 showed no signs of inducible ischemia during dobutamine CMR. For a CAC score of less than 101, the NPV and the PPV of the CAC score for the outcome of dobutamine CMR were, respectively, 0.96 and 0.29. In patients with an inconclusive diagnosis of myocardial ischemia a MDCT CAC score of less than 11 reliably rules out myocardial ischemia detected by dobutamine CMR.     

Non-invasive assessment of coronary calcification

Electron-beam tomography (EBT) and multi-detector computed tomography (MDCT) enable the noninvasive assessment of coronary calcification. The amount of coronary calcification, as detected by EBT, has a close relation with the amount of coronary atherosclerosis, which is the substrate for the occurrence of myocardial infarction and sudden cardiac death. Calcification of the coronary arteries can be seen as a cumulative measure of life-time exposure to cardiovascular risk factors. Several studies have shown that the amount of coronary calcification is associated with the risk of coronary heart disease. Therefore, coronary calcification is a promising method for non-invasive detection of asymptomatic subjects at high risk of developing coronary heart disease. Whether measurement of coronary calcification also increases the predictive power of coronary events based on cardiovascular risk factors is topic of current research. Medical Radiology, Diagnostic Imaging Series: Coronary Radiology, ‘Epidemiology of Coronary Calcification’, R. Vliegenthart and H.H.S. Oei, 2004, pp. 215–224.     

Human regulatory T cells control xenogeneic graft-versus-host disease induced by autologous T cells in RAG2-/-gammac-/- immunodeficient mice.

PURPOSE: Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4+CD25+ regulatory T cells (Treg) can prevent GvHD. Toward understanding the role of human Treg in stem cell transplantation, we studied their capacity to modulate T-cell-dependent xenogeneic (x)-GvHD in a new model where x-GvHD is induced in RAG2-/-gammac-/- mice by i.v. administration of human peripheral blood mononuclear cells (PBMC). EXPERIMENTAL DESIGN: Human PBMC, depleted of or supplemented with autologous CD25+ Tregs, were administered in mice at different doses. The development of x-GvHD, in vivo expansion of human T cells, and secretion of human cytokines were monitored at weekly intervals. RESULTS: Depletion of CD25+ cells from human PBMC significantly exacerbated x-GvHD and accelerated its lethality. In contrast, coadministration of Treg-enriched CD25+ cell fractions with autologous PBMC significantly reduced the lethality of x-GvHD. Treg administration significantly inhibited the explosive expansion of effector CD4+ and CD8+ T cells. Interestingly, protection from x-GvHD after Treg administration was associated with a significant increase in plasma levels of interleukin-10 and IFN-gamma, suggesting the de novo development of TR1 cells. CONCLUSIONS: These results show, for the first time, the potent in vivo capacity of naturally occurring human Tregs to control GvHD-inducing autologous T cells, and indicate that this xenogeneic in vivo model may provide a suitable platform to further explore the in vivo mechanisms of T-cell down-regulation by naturally occurring human Tregs.     

Heredo-ataxia in a large Dutch pedigree M.R.I. findings

One segment of a large Dutch pedigree with heredoataxia is presented. The clinical and genetic features of the disease, together with the M.R.I. findings, indicate the diagnosis of autosomal dominant late onset olivo-ponto-cerebellar atrophy. The clinical picture remained invariant through successive generations.

Emphasis is put on the diagnostic usefulness of M.R.I. technique in the absence of neuropathological data.     

Immunodiagnostically applicable monoclonal antibodies to the circulating anodic antigen of Schistosoma mansoni bind to small,defined oligosaccharide epitopes

Gut-associated glycoproteins constitute a major group of the circulating excretory antigens produced by human Schistosoma species. The O-glycans of the relatively abundant circulating anodic antigen (CAA) from S. mansoni carry long stretches of unique -->6(GlcA beta 1-->3)GalNAc beta 1--> repeats. Specific anti-carbohydrate monoclonal antibodies (mAbs) are essential tools for the immunodiagnostic detection of CAA in the serum or urine of Schistosoma-infected subjects. In order to define the epitopes recognised by these anti-CAA mAbs, we screened a series of protein-coupled synthetic di- to pentasaccharide building blocks of the CAA polysaccharide for immunoreactivity, using ELISA and surface plasmon resonance spectroscopy. It was shown that anti-CAA IgM mAbs preferentially recognise -->6(GlcA beta 1-->3)GalNAc beta 1--> disaccharide units. Interestingly, no mouse anti-CAA mAbs of the IgG class were found that bind to the synthetic epitopes, although many of the IgG mAbs tested do recognise native CAA in a carbohydrate-dependent manner. In addition, both IgM and IgG class antibodies could be detected in human infection sera using the synthetic CAA fragments. These synthetic schistosome glycan epitopes and their matching set of specific mAbs are useful tools that further the development of diagnostic methods and are helpful in defining the immunological responses of the mammalian hosts to schistosome glycoconjugates.     

Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases

Endocannabinoids are thought to function as retrograde messengers, which modulate neurotransmitter release by activating presynaptic cannabinoid receptors. Anandamide and 2-arachidonoylglycerol (2-AG) are the two best studied endogenous lipids which can act as endocannabinoids. Together with the proteins responsible for their biosynthesis, inactivation and the cannabinoid receptors, these lipids constitute the endocannabinoid system. This system is proposed to be involved in various neurodegenerative diseases such as Parkinson's and Huntington's diseases as well as Multiple Sclerosis. It has been demonstrated that the endocannabinoid system can protect neurons against glutamate excitotoxicity and acute neuronal damage in both in vitro and in vivo models. In this paper we review the data concerning the involvement of the endocannabinoid system in neurodegenerative diseases in which neuronal cell death may be elicited by excitotoxicity. We focus on the biosynthesis of endocannabinoids and on their modes of action in animal models of these neurodegenerative diseases.     

Complement-induced cell death by rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity.

PURPOSE: The use of the CD20-specific antibody rituximab has greatly improved the response to treatment of CD20+ follicular lymphoma. Despite the success of rituximab, resistance has been reported and prognostic markers to predict individual response are lacking. The level of CD20 expression on tumors has been related to response, but results of several studies are contradictory and no clear relationship could be established. Complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) are thought to be important effector mechanisms, but the exact mechanism of rituximab-mediated cell kill is still unknown. Importantly, no data have been reported on the combined contribution of CDC and ADCC. EXPERIMENTAL DESIGN: We have developed a system of clonally related CEM-CD20 cells by retroviral transfer of the human CD20 cDNA (n = 90). This set of cells, with the CD20 molecule as the only variable, was used to study the importance of CD20 expression level on rituximab-mediated CDC, ADCC, and the combination. RESULTS: We show a sigmoidal correlation of CD20 expression level and rituximab-mediated killing via CDC but not ADCC. On both high and low CD20-expressing cells, all CD20 molecules were translocated into lipid rafts after rituximab binding. Furthermore, CDC and ADCC act simultaneously and CDC-resistant cells are sensitive to ADCC and vice versa. CONCLUSIONS: These findings suggest that CDC depends on CD20 expression level and that both CDC and ADCC act complementary. These data give new insights into novel strategies to improve the efficacy of CD20-specific antibodies for the treatment of CD20+ tumors.     

Early imaging biomarkers of lung cancer,COPD and coronary artery disease in the general population: rationale and design of the ImaLife (Imaging in Lifelines) Study

Lung cancer, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD) are expected to cause most deaths by 2050. State-of-the-art computed tomography (CT) allows early detection of lung cancer and simultaneous evaluation of imaging biomarkers for the early stages of COPD, based on pulmonary density and bronchial wall thickness, and of CAD, based on the coronary artery calcium score (CACS), at low radiation dose. To determine cut-off values for positive tests for elevated risk and presence of disease is one of the major tasks before considering implementation of CT screening in a general population. The ImaLife (Imaging in Lifelines) study, embedded in the Lifelines study, is designed to establish the reference values of the imaging biomarkers for the big three diseases in a well-defined general population aged 45 years and older. In total, 12,000 participants will undergo CACS and chest acquisitions with latest CT technology. The estimated percentage of individuals with lung nodules needing further workup is around 1–2%. Given the around 10% prevalence of COPD and CAD in the general population, the expected number of COPD and CAD is around 1000 each. So far, nearly 4000 participants have been included. The ImaLife study will allow differentiation between normal aging of the pulmonary and cardiovascular system and early stages of the big three diseases based on low-dose CT imaging. This information can be finally integrated into personalized precision health strategies in the general population.     

Public Preferences for Lung Cancer Screening Policies

Background

Because early detection of lung cancer can substantially improve survival, there is increasing attention for lung cancer screening.