Assessment of myocardial viability in a reperfused porcine model: evaluation of different MSCT contrast protocols in acute and subacute infarct stages in comparison with MRI

OBJECTIVE: To assess myocardial viability in acute and subacute infarcts using different multislice spiral computed tomography contrast protocols with magnetic resonance imaging (MRI) correlation. METHODS: Seven pigs were studied with 64-multislice spiral computed tomography and MRI (1.5 T) at a median of 1 and 21 days after temporary occlusion of the second diagonal branch. Computed tomography was performed at 3, 5, 10, and 15 minutes after injection of contrast medium. Contrast agent was applied either as a bolus (protocol 1; n = 7 for the first; n = 5 for the second scan) or as a bolus plus 30 mL of subsequent 0.1 mL/s low-flow (protocol 2; n = 7 for the first; n = 6 for the second scan). Finally, histological sections were obtained. Volumes of infarcted myocardium were assessed as the percentage of the left ventricle. Computed tomography attenuation values were obtained, and image quality was assessed. RESULTS: When compared with protocol 1, protocol 2 provided greater Hounsfield unit attenuation difference between viable and nonviable myocardium at 5, 10, and 15 minutes (P = 0.19; 0.003; 0.0006) and an additional significant contrast between nonviable myocardium and ventricular blood at 3 and 5 minutes (P < 0.001). Image quality was rated significantly higher with the use of protocol 2 at 5, 10, and 15 minutes (P < or = 0.027) and for all time points use of protocol 2 resulted in improved correlation of acute and subacute infarct size with MRI. CONCLUSIONS: Good correlation of infarct zones with MRI was achieved for both acute and subacute infarcts. With the use of a bolus/low-flow protocol, image quality was substantially improved by means of a higher tissue contrast.     

Sixty-four-slice CT in the assessment of global and regional left ventricular function: Comparison with MRI in a porcine model of acute and subacute myocardial infarction

The purpose was to assess 64-slice CT in the analysis of global and regional ventricular function, using a model of acute and subacute myocardial infarction in comparison with cine-MRI. Seven pigs underwent standard MSCT and MRI examination a median 1 and 21 days following creation of reperfused myocardial infarction. Endocardial and epicardial contours were manually defined and ventricular volumes calculated according to Simpson’s method. Results were compared by Pearson’s correlation coefficient and Blant-Altman analysis. Wall motion was assessed on cine-images and evaluated by kappa statistics. MSCT revealed a strong correlation with cine-MRI regarding quantification of end-diastolic volume (EDV; r = 0.97), end-systolic volume (ESV; r = 0.97), stroke volume (SV; r = 0.94), ejection fraction (EF; r = 0.95) or myocardial mass (MM; r =0.94 ). Minor overestimation was observed for EDV and ESV (bias −1.7 ml; −1.5 ml; P=0.095; 0.025), whilst the mean difference for EF was found to be negligible (bias 0.9%; P = 0.18). Both modalities showed a 96.2% segmental agreement in regional wall motion (weighted-kappa 0.91 for 238 segments). This was true for both acute and subacute infarct phase and MSCT, and thereby enabled accurate intraindividual follow-up of segmental dysfunction. Sixty-four-slice CT allows for reliable analysis of global cardiac function and, moreover, provides accurate evaluation of wall motion in acute and subacute myocardial infarct. Scheule and Kopp both contributed equally. This study was funded by an institutional “Fortune Grant” (project no. 1500-0-0). There is no conflict of interest.     

Pain perception is altered by a nucleotide polymorphism in SCN9A

The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the A allele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype.     

Clinical, genetic, and cardiac magnetic resonance imaging findings in primary desminopathies

We report the clinical, genetic and cardiac magnetic resonance imaging (MRI) findings in 11 German patients with heterozygous E245D, D339Y, R350P and L377P desmin mutations and without cardiac symptoms. Clinical evaluation revealed a marked variability of skeletal muscle, respiratory and cardiac involvement even between patients with identical mutations, ranging from asymptomatic to severely affected. While echocardiography did not show any pathological findings in all 11 patients, cine MRI revealed focal left ventricular hypertrophy in 2 patients and MR delayed enhancement imaging displayed intramyocardial fibrosis in the left ventricle in 4 patients indicating early myocardial involvement. Our data argue against distinct genotype-phenotype correlations and suggest that comprehensive cardiac MRI is superior to conventional echocardiography for the detection of early and clinically asymptomatic stages of cardiomyopathy in desminopathy patients. Therefore, cardiac MRI may serve as a screening tool to identify patients at risk, which might benefit from early pharmacological and/or interventional (e.g. implantable cardioverter-defibrillator devices) therapy.     

The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo

In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anticancer barrier in early human tumorigenesis leading to apoptosis or cellular senescence. DDR mutations may promote tumor formation, but their impact on treatment outcome remains unclear. In this study, we generated ataxia telangiectasia mutated (Atm)-proficient and -deficient B-cell lymphomas in Emu-myc transgenic mice to examine the role of DDR defects in lymphomagenesis and treatment sensitivity. Atm inactivation accelerated development of lymphomas, and their DNA damage checkpoint defects were virtually indistinguishable from those observed in Atm+/+-derived lymphomas that spontaneously inactivated the proapoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species (ROS). Importantly, acquisition of DDR defects, but not selection against the ARF pathway, could be prevented by lifelong exposure to the ROS scavenger N-acetylcysteine (NAC) in vivo. Following anticancer therapy, DDR-compromised lymphomas displayed apoptotic but, surprisingly, no senescence defects and achieved a much poorer long-term outcome when compared with DDR-competent lymphomas treated in vivo. Hence, Atm eliminates preneoplastic lesions by converting oncogenic signaling into apoptosis, and selection against an Atm-dependent response promotes formation of lymphomas with predetermined treatment insensitivity.     

Contact areas of the tibiotalar joint.

The contact areas between the articular surfaces of the talus and tibia are essential for understanding the mobility of the ankle joint. The purpose of our study was to reveal the contact area among the superior articular surface of the trochlea tali (target surface T) and the inferior articular surface of the tibia (query surface Q) under non-weight-bearing conditions in plantar flexion and dorsiflexion. Twenty cadaveric foot specimens were dissected and scanned by a three-dimensional (3D) laser scanner to obtain data point sets. These point sets were triangulated and a registration procedure performed to avoid any intersection of the two joint surfaces. For all points of the query surface Q, the closest distance to T was measured. In 11 of the 20 ankle joints, the contact area was larger in plantar flexion, in 5 it was nearly of equal size, and in 4 the two surfaces were found in a better congruence in dorsiflexion. The two articular surfaces can be in point or line contact and cause different motions while T is gliding on Q, so the original geometry of ligaments must be carefully reconstructed after injury or during total ankle replacement.     

A comparative assessment of the roles of CD8 and CD2 in the functions of activated murine CD8+ T lymphocytes.

Both CD8 and CD2 are T cell surface receptors involved in physical cell interaction and in transmembrane signalling. The present paper addresses their role in the induction of two different functions of the cloned murine cytotoxic T cell C196: target cell lysis and IFN-gamma production. These functions were induced in C196 either by stimulation with the specific stimulator/target cell P815 or, bypassing specific recognition, by the aCD3 hybridoma 145-2C11 or by solid phase aTCR antibodies. These responses were tested for their susceptibility to inhibition/enhancement by a panel of aCD8 and aCD2 mAb. In addition, CD8 deficient and CD8/CD2 double-deficient variants of C196 were transfected with the CD8 and CD2 genes and the resulting cell lines were analysed for their functional capacities. The following results were obtained: (i) CD8 is primarily important in the specific recognition process of activated CTL; (ii) transmembrane signalling of activated CTL through the TCR does not require CD8, nor is it sensitive to modification through CD8; (iii) CTL can nevertheless be directly activated through CD8; however, this is restricted to induction of cytotoxicity but does not result in IFN-gamma production; (iv) CD2 does not seem to be important in any of these responses.