Surgical Ablation of Permanent Atrial Fibrillation: Age, LV Dilatation, Obesity.

OBJECTIVES: Although concomitant surgical ablation can help to reach freedom from atrial fibrillation (FREEAF) even in patients with permanent atrial fibrillation (AF), some cardiac surgeons hesitate to perform concomitant ablation to avoid perioperative risk escalation. Here, we investigated outcome and predicators of therapeutic success of concomitant surgical ablation in an all-comers study. METHODS: Ablation-naïve patients with formerly accepted permanent AF (FAP, n = 41) or paroxysmal AF (parAF, n = 24) underwent concomitant epicardial bipolar radio frequency ablation and implantable loop recorder (ILR) at two surgical departments. Follow-up examination for 24 months included electrocardiogram, ILR readout, 24h Holter monitoring, echocardiography, and blood sampling. RESULTS: Eighty-six percent of parAF and 70% of FAP patients reached FREEAF (month 24). Mortality was low (parAF/FAP: 5.3 ± 0.2%/4.1 ± 0.3%; p < 0.05; EuroScoreII; 6.1 ± 0.7%/6.4 ± 0.4%, p = ns) and no strokes occurred. FREEAF induced atrial reverse remodeling (left atrial [LA] diameter: -6.7 ± 2.2 mm) and improved cardiac function (left ventricular ejection fraction [LVEF]: +7.3 ± 2.8%), while AF resulted in further atrial dilation (+8.0 ± 1.0 mm, p < 0.05) and LVEF reduction (-7.0 ± 1.3%, p < 0.05). Higher LV (odds ratio [OR]: 1.164) and LA diameter (OR: 1.218), age (OR: 1.180) and body mass index (BMI) (OR: 1.503) increased the risk factors of AF recurrence. Patients remaining in sinus rhythm (SR) demonstrated a decrease in BMI, while AF recurrence was associated with stable overweight. Further aging did not reduce FREEAF. CONCLUSIONS: Long-term SR is achievable by concomitant surgical ablation even in FAP patients. Therefore, it should be offered routinely. Obesity influences therapeutic long-term success but may also offer addressable therapeutic targets to reach higher FREEAF rates.

Urinary TIMP-2 and IGFBP-7 protein levels as early predictors of acute kidney injury after cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication associated with on-pump cardiac surgery. Early recognition may alter their prognosis. Therefore, the urinary concentrations of TIMP-2 (tissue inhibitor of metalloproteinases-2) and IGFBP7 (insulin-like growth factor-binding protein) as predictors for AKI were studied. METHODS: Repetitive blood and urine samples were collected consecutively from 50 patients. Demographic, intra-, and postoperative data were recorded prospectively. To calculate the production of the TIMP-2 and IGFBP-7 protein concentrations, urinary samples were taken preoperatively, intraoperatively at 30 and 60 min after aortic clamping and at 0, 6, 12, and 24 h after admission to the intensive care unit (ICU). RESULTS: AKI occurred in 14 patients (28%), all of them at Kidney Disease: Improving Global Outcomes stage 1. Predictive value for [TIMP-2] × [IGFBP7] was shown at 0 and 24 h after admission to ICU. At 0 h, the sensitivity was 84.6% and the specificity 55.6% for an ideal calculated cutoff at 0.07. After 24 h, the ideal cutoff amounted to 0.35 with a sensitivity of 53.8% and a specificity of 88.2%. The receiver operating characteristic curves demonstrated areas under the curve of 0.725 and 0.718. The suggested cutoffs of 0.3 and 2.0 could not be confirmed. The serum creatinine was reached to the peak median within 48 h after admission to ICU. CONCLUSION: Postoperative risk assessment for the development of AKI can be established by [ TIMP - 2 ] × [ IGFBP 7 ] . Previously suggested cutoff values could not be confirmed. A correlation with urinary dilution parameters may enable the identification of more universal cutoffs.

Influence of cardioplegic solution on incidence of delirium after CABG surgery: Use of Calafiore blood cardioplegia versus HTK - Bretschneider - solution in a single-center retrospective analysis from 2017 to 2021.

BACKGROUND: Purpose of the present study is an evaluation of postoperative incidence for delirium after coronary artery bypass surgery (CABG). Study addressed whether application of Histidine-Tryptophan-Ketoglutarate (HTK) solution (Bretschneider) or blood cardioplegia (Calafiore) is associated with increased of postoperative delirium cases. MATERIALS AND METHODS: In a retrospective, single center evaluation a total number of 273 patients were enrolled in the study from January 2017 to October 2021. There were 124 patients assigned to the Calafiore group blood cardioplegic solution (BCC) and 149 patients were included in the Bretschneider group (HTK). The primary endpoint was the postoperative delirium rate in its frequency of occurrence. Definition of the dilirium status was performed using the Confusion Assessment Method in the Intensive Care Unit (CAM-ICU) score during the first three postoperative days. Secondary endpoints were the time intervals of intensive care duration of stay, mechanical ventilation, total extracorporeal circulation, ischemia and reperfusion. Serum levels of the electrolytes Sodium, Potassium, ionized Calcium, and Chloride were monitored. RESULTS: Although no significant difference in delirium status between the groups were noticed, on third postoperative day, delirium rate dependent on cardioplegia solution used (HTK 12.0%; BCC 3.0%; p = .024) and duration of intensive care stay differed (HTK 4.5 vs. BCC 3.0 days; p = .001). Although Ischemic time (HTK 73.0 vs. BCC 83.0 min; p < .001) and reperfusion time (HTK 35.0 vs. Calafiore 24.0 min; p < .001) were extended in the BCC group less cases of delirium were diagnosed. Serum sodium levels after HTK cardioplegic infusion were decreased (HTK 129.68 vs. BCC 138.96 mmol/l; p < .001). The significant difference persists up to the hundredth extracorporeal circulation circuit min (p = .005). CONCLUSION: The present data suggest an impact of the cardioplegic solution used upon postoperative delirium rates. Optimization of cardiac arrest protocols is needed. Present data encourage further prospective studies regarding the impact of cardioplegic solutions on electrolyte imbalance for postoperative delirium rates in CABG surgery.

Prediction of stroke reconvalescence after coronary bypass surgery indicated by CT scan parameters.

BACKGROUND: Stroke in the postoperative time course after heart surgery remains a serious risk. Cranial computer tomography (CCT) is the first line option to detect severe intracranial damage. However, only few data are available to predict neurological outcome. Using visual rating scales (VRSs), this study addresses reliability and effectivity to indicate neurological status and likelyhood of improvement. METHODS: In a single-center retrospective evaluation, 3719 patients underwent coronary bypass surgery. Because of a delayed recovery phase and neurologic deficits after cardiac surgery 109 patients had a cranial CT scan in the early postoperative period. The incidence of clinically relevant findings within the imaging was rated by an experienced neuroradiologist using two VRS, that is, the age-related white matter changes (ARWMCs) and the Mendes-Ribeiro visual rating scale (MRVRS). Both are computer-assisted measurement schemes to detect stroke-related intracranial damage. Follow-up was investigated with regard to clinical outcome and patient-related risk profiles. RESULTS: Of 109 patients with postoperative cranial CT scans due to prolonged recovery phases or proven neurological damage 44.5% had one cerebral defect in CCT imaging scans only. The others showed multiple defects. During hospital stay, 92.3% experienced neurological improvement exposing reduced ARWMC, while 7.1% had no improvement and correlating high scores. Of both scales, the ARWMC-VRS demonstrated superior accuracy and discrimination. The preoperative ejection fraction (EF), arteriosclerotic degeneration of carotid arteries, and reduced glomerular filtration rate were found to have a high correlation (r = 0.0005) with the latter group. In-hospital mortality of this cohort was 8.18%. CONCLUSION: Both the ARWMC and MRVRS were found to be appropriate. They reliably discriminate the groups of stroke patients after coronary artery bypass grafting (CABG)  in the analysis of CCT images. When applied at the onset of neurological symptoms both scales are able to predict neurological reconvalescence upon hospital dismission. The ARWMC scale appeared superior as it demonstrated better accuracy and discrimination. The use of both VRS in patients with suspected stroke after CABG surgery can give insightful information toward a progression of neurological dysfunction or postoperative improvement.

Role of matrix metalloproteinases in mitral valve regurgitation: Association between the of MMP-1, MMP-9, TIMP-1, and TIMP-2 expression, degree of mitral valve insufficiency, and pathologic etiology.

BACKGROUND: The pathogenesis of mitral valve insufficiency is not yet fully understood. Several studies stressed the role of matrix metalloproteinases (MMPs) in the emergence of valvular pathologies. The primary objective of the present study is to analyze the role of selected MMPs and their inhibitors in mitral valve insufficiency. PATIENTS AND METHODS: Eighty patients (33 female/47 male, mean age 67 years) underwent cardiopulmonary bypass surgery for mitral valve reconstruction between 2007 and 2015. All patients suffered from mitral insufficiency (MI) Stages iii and iv. When tissue resection was acquired specimens were taken immediately frozen and used for histological examination. Expression of MMP-1, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 was examined immunohistochemically and distribution was analyzed in regard to preoperative clinical, echocardiographic, and histopathological findings. RESULTS: A clear correlation between the MMP expression and the MI degree of severity could be shown. The expression of MMPs proved to be high in relation to mild insufficiencies and relatively weak in the case of severe ones. Additionally, the etiology of the MI was considered in the analysis and a significant difference in the expression of MMPs between the mitral valves with endocarditis and the ones featuring a degenerative disease could be shown. Within the group of valves with degenerative diseases, no significant difference could be established between the subgroups (myxoid and sclerosed valves). CONCLUSION: The increased expression of MMPs and their inhibitors in mild insufficiencies could prove that the molecular changes in the valve precede the macroscopical and thus the echocardiographically diagnosable changes. Hence, new options for early diagnosis and therapy of MIs should be examined in further studies, respectively. Herein, the correlation of the MMP blood levels with MMP tissue expression should be addressed for surgical therapeutical decisions.

Protamine Sulfate Induces Mitochondrial Hyperpolarization and a Subsequent Increase in Reactive Oxygen Species Production.

Protamine sulfate (PS) is widely used in heart surgery as an antidote for heparin, albeit its pharmacological effects are not fully understood and applications are often accompanied by unwanted side effects. Here we show the effect of PS on mitochondrial bioenergetics profile resulting in mitochondrial reactive oxygen species (ROS) production. Polarographic measurements were performed in parallel to membrane potential and ROS measurements by FACS analyzer using tetramethylrhodamine ethyl ester and MitoSOX fluorescent dyes, respectively. PS inhibited intact rat heart mitochondrial respiration (stimulated by ADP) to 76% (P < 0.001) from the baseline of 51.6 ± 6.9 to 12.4 ± 2.3 nmol O2⋅min-1⋅ml-1 The same effect was found when respiration was inhibited by antimycin A (101.0 ± 8.9 vs. 38.0 ± 9.9 nmol O2 ⋅min-1⋅ml-1, P < 0.001) and later stimulated by substrates of cytochrome oxidase (CytOx) i.e., ascorbate and tetramethyl phenylene diamine, suggesting that PS exerted its effect through inhibition of CytOx activity. Furthermore, the inhibition of mitochondrial respiration by PS was concentration dependent and accompanied by hyperpolarization of the mitochondrial membrane potential (Δψ m), i.e., 18% increase at 50 µg/ml and an additional 3.3% increase at 250 µg/ml PS compared with control. This effect was associated with a strong consequent increase in the production of ROS, i.e., 85% and 88.6% compared with control respectively. We propose that this excessive increase in ROS concentrations results in mitochondrial dysfunction and thus might relate to the "protamine reaction," contributing to the development of various cardiovascular adverse effects.

Mitochondrial active and relaxed state respiration after heat shock mRNA response in the heart.

Induction of Heat Shock Proteins results in cytoprotection. Beneficial effect results from transcription and translational cellular components' involvement that defends metabolism and thus induce ischemic protection of the tissue. Mitochondrial respiration is also involved in stress- induced conditions. It is not a uniform process. Cytochrome c Oxidase (CytOx) representing complex IV of the Electron Transfer Chain (ETC) has a regulatory role for mitochondrial respiratory activity, which is tested in our study after hsp induction. Moreover, protein translation for mitochondrial components was probed by the detection of MT-CO1 for Subunit 1 of CytOx neosynthesis. Wistar rats were subjected to whole-body hyperthermia at 42.0-42.5 °C for 15 min followed by a normothermic recovery period. Heat shock response was monitored time dependent from LV biopsies of all control and heat treated animals with PCR-analysis for hsp 32, 60, 70.1, 70.2, 90 and MT-CO1 expression at 15, 30, 45, 60, 120 and 360 min recovery (n = 5 in each group), respectively. Enzymatic activity of CytOx were evaluated polarographically. High energy phosphates were detected by chromatographic analysis. The mRNA expression of MT-CO1 peaked at 60 min and was accompanied by hsp 32 (r = 0.457; p = 0.037) and hsp 70.2 (r = 0.615; p = 0.003) upregulation. With hsp induction, mitochondrial respiration was increased initially. Enzymatic activity reconciled from active into relaxed status wherein CytOx activity was completely inhibited by ATP. Myocardial ATP content increased from stress induced point i.e. < 1 µmol g-1 protein w/w to finally 1.5 ±â€¯0.53 µmol g-1 protein w/w at 120 min recovery interval. Hyperthermic, myocardial hsp- induction goes along with increased CytOx activity representing an increased "active" mitochondrial respiration. In parallel, de -novo holoenzyme assembly of CytOx begins as shown by MT-CO1 upregulation at 60 min recovery time crossing with a final return to the physiological "relaxed" state and ATP -inhibited respiration.

Revisiting Kadenbach: Electron flux rate through cytochrome c-oxidase determines the ATP-inhibitory effect and subsequent production of ROS.

Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel, is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to CytOx, causing inhibition. In times of stress, ATP-dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased.

Early Results of Surgical Simultaneous Therapy for Significant Carotid Artery Stenosis and Heart Disease.

BACKGROUND: The purpose of this single-center, retrospective study was to review the early outcome with defined endpoints of myocardial infarction, brain injury, and death after coronary bypass grafting and simultaneous carotid endarterectomy with or without combined valve replacement. METHODS: During the preoperative investigation 52 (44 males, 8 females) patients were examined by cardiac catheterization within the scope of their coronary status. In addition, all patients underwent echocardiography, CT angiography of the supra-aortic vessels, and full description of their neurologic status. Included were all patients with the need of coronary revascularization, valve disease, and either symptomatic or asymptomatic carotid artery stenosis with a maximal narrowing of >70%. RESULTS: There was one (2%) patient with a perioperative stroke and paresis of the upper limb. One (2%) patient experienced PRIND (2%). Eighteen (35%) patients suffered symptomatic transitory psychotic syndrome that fully recovered in all patients. One (2%) patient incurred a perioperative myocardial infarction that could be cured by percutaneous coronary stent implantation. Overall mortality was 4%. CONCLUSION: Simultaneous coronary bypass grafting as a single procedure or in combination with valve replacement and endarterectomy of severe carotid lesions with or without patients' history of previous stroke can be performed with a calculated low surgical risk. The complication rate for neurologic and myocardial events is low compared with the hazard of a single surgical repair. The in-hospital mortality is not significantly different to isolated procedures. The concomitant appearance of coronary stenosis and carotid artery disease is reasonable due to the nature of arteriosclerosis. In our opinion these patients benefit from a combined surgical approach.

A Newly Developed mm-Wave Sensor for Detecting Plaques of Arterial Vessels.

BACKGROUND: Microcalcifications within the fibrous cap of the arteriosclerotic plaques lead to the accrual of plaque-destabilizing mechanical stress. New techniques for plaque screening with small detectors and the ability to differentiate between the smooth and hard elements of plaque formation are necessary. METHOD: Vascular plaque formations are characterized as calcium phosphate containing structures organized as hydroxylapatite resembling the mineral whitlockite. In transmission and reflexion studies with a simple millimeter wave (mm-wave)-demonstrator, we found that there is a narrow window for plaque detection in arterial vessels because of the tissue water content, the differentiation to fatty tissue, and the dielectric property of air or water, respectively. RESULT: The new sensor is based on a sensing oscillator working around 27 GHz. The open-stub capacitance determines the operating frequency of the sensor oscillator. The capacitance depends on the dielectric properties of the surrounding material. The sensor components were completely built up in surface mount technique. CONCLUSION: Completed with a catheter, the sensor based on microwave technology appears as a robust tool ready for further clinical use.

Mitochondrial cytochrome c oxidase is inhibited by ATP only at very high ATP/ADP ratios.

In the past, divergent results have been reported based on different methods and conditions used for enzymatic activity measurements of cytochrome c oxidase (CytOx). Here, we analyze in detail and show comparable and reproducible polarographic activity measurements of ATP-dependent inhibition of CytOx kinetics in intact and non-intact rat heart mitochondria and mitoplasts. We found that this mechanism is always present in isolated rat heart mitochondria and mitoplasts; however, it is measurable only at high ATP/ADP ratios using optimal protein concentrations. In the kinetics assay, measurement of this mechanism is independent of presence or absence of Tween-20 and the composition of measuring buffer. Furthermore, the effect of atractyloside on intact rat heart mitochondria confirms that (i) ATP inhibition occurs under uncoupled conditions [in the presence of carbonly cyanide m-chlorophenyl hydrazone (CCCP)] when the classical respiratory control is absent and (ii) high ATP/ADP ratios in the matrix as well as in the cytosolic space are required for full ATP inhibition of CytOx. Additionally, ATP inhibition measured in intact mitochondria extends in the presence of oligomycin, thus indicating further that the problem to measure the inhibitory effect of ATP on CytOx is apparently due to the lack of very high ATP/ADP ratios in isolated mitochondria.

Iterative image reconstruction techniques for CT coronary artery calcium quantification: comparison with traditional filtered back projection in vitro and in vivo.

PURPOSE: To investigate in vitro and in vivo the use of image-based and raw data-based iterative reconstruction algorithms for quantification of coronary artery calcium by using the Agatston score and subsequent cardiac risk stratification. MATERIALS AND METHODS: In vitro data were obtained by using a moving anthropomorphic cardiac phantom containing calcium inserts of different concentrations and sizes. With institutional review board approval and HIPAA compliance, coronary calcium imaging data of 110 consecutive patients (mean age ± standard deviation, 58.2 years ± 9.8; 48 men) were reconstructed with filtered back projection (FBP), iterative reconstruction in image space (IRIS), and sinogram-affirmed iterative reconstruction (SAFIRE). Image noise was measured and the Agatston score was obtained for all reconstructions. Assignment to Agatston scores and percentile-based cardiac risk categories was compared. Statistical analysis included the Cohen κ coefficient and Friedman and Wilcoxon testing. RESULTS: In vitro, mean Agatston scores ± standard deviation for FBP (638.9 ± 9.6), IRIS (622.7 ± 15.2), and SAFIRE (631.4 ± 17.6) were comparable (P = .30). The smallest phantom calcifications were more frequently detected when iterative reconstruction techniques were used. The Agatston scores in the patient cohort were not significantly different among FBP, IRIS, and SAFIRE in paired comparisons (median Agatston score [25th and 75th percentiles]: 76.0 [20.6, 243.9], 76.4 [22, 249.3], and 75.7 [21.5, 49.1], respectively; P = .20 each). Comparison of categorization based on Agatston score percentiles showed excellent agreement for both IRIS and SAFIRE with FBP (κ = 0.975 [0.942-1.00] and κ = 0.963 [0.922-1.00], respectively). The mean effective dose was 1.02 mSv ± 0.51. Mean image noise was significantly (P < .001) higher with FBP than that with iterative reconstructions. CONCLUSION: In comparison with FBP, iterative reconstruction techniques do not have a profound effect on the reproducible quantification of coronary calcium according to Agatston score and subsequent cardiac risk classification, although risk reclassification may occur in a small subset of subjects.

The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation.

AIMS: The conditions of hypoxia are suggested to induce permanent atrial fibrillation (AF). The regulation of COX4I2 and COX4I1 depends on oxygen availability in tissues. A role of COX4I2 in the myocardium of AF patients is supposed for pathogenesis of AF and subsequent alterations in the electron transfer chain (ETC) under hypoxia. METHODS AND RESULTS: In vitro, influence of hypoxia on HeLa 53 cells was studied and elevated parts of COX 4I2 were confirmed. Myocardial biopsies were taken ex vivo from the patients' Right Atria with SR (n = 31) and AF (n = 11), respectively. RT- PCR for mRNA expresson, mitochondrial respiration by polarography and the protein content of cytochrome c oxidase (CytOx) subunit 4I1 and CytOx subunit 4I2 by ELISA were studied. Clinical data were correlated to the findings of gene expressions in parallel. Patients with permanent AF had a change in isoform 4I2/4I1 expression along with a decrease of isoform COX 4I1 expression. The 4I2/4I1 ratio of mRNA expression was increased from 0.630 to 1.058 in comparison. However, the protein content of CytOx subunit 4 was much lower in the AF group, whereas the respiration/units enzyme activity in both groups remained the same. CONCLUSIONS: This study describes a possible molecular correlate for the development of AF. Due to the known functional significance of COX 4I2, mitochondrial dysfunction can be assumed as a part of the pathogenesis of AF.

The Role of Matrix Metalloproteinases in Thoracic Aortic Disease: Are They Indicators for the Pathogenesis of Dissections?

The pathogenesis of aortic aneurysm and dissection continues to be under discussion. Extracellular matrix (ECM) remodeling processes in the aortic wall are hypothesized to be involved in the development of the disorders. Therefore, in a histological study, we investigated the expression of metalloproteases 1 and 9 (MMP1 and MMP9) and their inhibitors (TIMP 1 and TIMP 2) in cardiac surgery patients. In parallel, we studied the aortic roots by echocardiography. Clinical reports of 111 patients (30 women and 81 men) who suffered from aortic aneurysms and aortic dissection were evaluated and studied by transesophageal echocardiography. Seven patients who had coronary heart disease served as "healthy controls". All patients underwent the necessary surgical procedure according to the diagnosed aortic disease in the period from 2007 to 2015. A tissue sample of the aortic biopsies was collected from each patient during surgery. Immunohistochemical staining was performed for MMP1 and MMP9 and TIMP1 and TIMP2 as well. Vascularization was monitored by a CD 31 antibody. In direct comparison, the expressions are not homogeneous. We found the smallest changes in the intima area at all. TIMP 1 and TIMP 2 distribution increases from the lumen of the vessel outward in the wall layers of the aorta. In the case of arteriosclerotic changes, intima had a capillarization, but not in the media. An opposite pattern was found in the dissected aortas. There are differences in the vascularization between the aneurysm and dissection and the different layers, respectively. A different remodeling process of the ECM in comparison to the vascular layers must be hypothesized. Reading the patterns of staining and with regard to the known inhibitory effect of MMP9 on ECM remodeling, but especially TIMP 2 on neoangiogenesis, disturbed nutrition, and dysfunctional vasa vasorum remodeling must be assumed as causes of dissection.

Feasibility of bone marrow edema detection using dual-energy cone-beam computed tomography.

BACKGROUND: Dual-energy (DE) detection of bone marrow edema (BME) would be a valuable new diagnostic capability for the emerging orthopedic cone-beam computed tomography (CBCT) systems. However, this imaging task is inherently challenging because of the narrow energy separation between water (edematous fluid) and fat (health yellow marrow), requiring precise artifact correction and dedicated material decomposition approaches. PURPOSE: We investigate the feasibility of BME assessment using kV-switching DE CBCT with a comprehensive CBCT artifact correction framework and a two-stage projection- and image-domain three-material decomposition algorithm. METHODS: DE CBCT projections of quantitative BME phantoms (water containers 100-165 mm in size with inserts presenting various degrees of edema) and an animal cadaver model of BME were acquired on a CBCT test bench emulating the standard wrist imaging configuration of a Multitom Rax twin robotic x-ray system. The slow kV-switching scan protocol involved a 60 kV low energy (LE) beam and a 120 kV high energy (HE) beam switched every 0.5° over a 200° angular span. The DE CBCT data preprocessing and artifact correction framework consisted of (i) projection interpolation onto matched LE and HE projections views, (ii) lag and glare deconvolutions, and (iii) efficient Monte Carlo (MC)-based scatter correction. Virtual non-calcium (VNCa) images for BME detection were then generated by projection-domain decomposition into an Aluminium (Al) and polyethylene basis set (to remove beam hardening) followed by three-material image-domain decomposition into water, Ca, and fat. Feasibility of BME detection was quantified in terms of VNCa image contrast and receiver operating characteristic (ROC) curves. Robustness to object size, position in the field of view (FOV) and beam collimation (varied 20-160 mm) was investigated. RESULTS: The MC-based scatter correction delivered > 69% reduction of cupping artifacts for moderate to wide collimations (> 80 mm beam width), which was essential to achieve accurate DE material decomposition. In a forearm-sized object, a 20% increase in water concentration (edema) of a trabecular bone-mimicking mixture presented as ∼15 HU VNCa contrast using 80-160 mm beam collimations. The variability with respect to object position in the FOV was modest (< 15% coefficient of variation). The areas under the ROC curve were > 0.9. A femur-sized object presented a somewhat more challenging task, resulting in increased sensitivity to object positioning at 160 mm collimation. In animal cadaver specimens, areas of VNCa enhancement consistent with BME were observed in DE CBCT images in regions of MRI-confirmed edema. CONCLUSION: Our results indicate that the proposed artifact correction and material decomposition pipeline can overcome the challenges of scatter and limited spectral separation to achieve relatively accurate and sensitive BME detection in DE CBCT. This study provides an important baseline for clinical translation of musculoskeletal DE CBCT to quantitative, point-of-care bone health assessment.

Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation.

Cytochrome c (Cytc) and cytochrome c oxidase (COX) catalyze the terminal reaction of the mitochondrial electron transport chain (ETC), the reduction of oxygen to water. This irreversible step is highly regulated, as indicated by the presence of tissue-specific and developmentally expressed isoforms, allosteric regulation, and reversible phosphorylations, which are found in both Cytc and COX. The crucial role of the ETC in health and disease is obvious since it, together with ATP synthase, provides the vast majority of cellular energy, which drives all cellular processes. However, under conditions of stress, the ETC generates reactive oxygen species (ROS), which cause cell damage and trigger death processes. We here discuss current knowledge of the regulation of Cytc and COX with a focus on cell signaling pathways, including cAMP/protein kinase A and tyrosine kinase signaling. Based on the crystal structures we highlight all identified phosphorylation sites on Cytc and COX, and we present a new phosphorylation site, Ser126 on COX subunit II. We conclude with a model that links cell signaling with the phosphorylation state of Cytc and COX. This in turn regulates their enzymatic activities, the mitochondrial membrane potential, and the production of ATP and ROS. Our model is discussed through two distinct human pathologies, acute inflammation as seen in sepsis, where phosphorylation leads to strong COX inhibition followed by energy depletion, and ischemia/reperfusion injury, where hyperactive ETC complexes generate pathologically high mitochondrial membrane potentials, leading to excessive ROS production. Although operating at opposite poles of the ETC activity spectrum, both conditions can lead to cell death through energy deprivation or ROS-triggered apoptosis.

GAPDH: the missing link between glycolysis and mitochondrial oxidative phosphorylation?

The main function of glycolysis and oxidative phosphorylation is to produce cellular energy in the form of ATP. In the present paper we propose a link between both of these energy-regulatory processes in the form of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and CytOx (cytochrome c oxidase). GAPDH is the sixth enzyme of glycolysis, whereas CytOx is the fourth complex of the mitochondrial oxidative phosphorylation system. In MS analysis, GAPDH was found to be associated with a BN-PAGE (blue native PAGE)-isolated complex of CytOx from bovine heart tissue homogenates. Both GAPDH and CytOx are highly regulated under normal energy metabolic conditions, but both of these enzymes are highly deregulated in the presence of oxidative stress. The interaction of GAPDH with CytOx could be the point of interest as it has already been shown that GAPDH protein damage results in a marked decrease in cellular ATP levels. On the other hand, decreasing the ATP/ADP ratio may ultimately result in switching off the allosteric ATP inhibition of CytOx leading to increased ROS (reactive oxygen species), cytochrome c release and apoptosis. Moreover, we have previously reported that allosteric ATP inhibition of CytOx is responsible for keeping the membrane potential at low healthy values, thus avoiding the production of ROS and this allosteric ATP inhibition is switched on at a high ATP/ADP ratio. So, in the present paper, we propose a scheme that could prove to be a link between these two enzymes and their role in the prevalence of diseases.

Creep and fatigue behavior of a novel 2-component paste-like formulation of acrylic bone cements.

The fatigue and creep performance of two novel acrylic bone cement formulations (one bone cement without antibiotics, one with antibiotics) was compared to the performance of clinically used bone cements (Osteopal V, Palacos R, Simplex P, SmartSet GHV, Palacos R+G and CMW1 with Gentamicin). The preparation of the novel bone cement formulations involves the mixing of two paste-like substances in a static mixer integrated into the cartridge which is used to apply the bone cement. The fatigue performance of the two novel bone cement formulations is comparable to the performance of the reference bone cements. The creep compliance of the bone cements is significantly influenced by the effects of physical ageing. The model parameters of Struik's creep law are used to compare the creep behavior of different bone cements. The novel 2-component paste-like bone cement formulations are in the group of bone cements which exhibit a higher creep resistance.

T4 Lung Carcinoma with Infiltration of the Thoracic Aorta: Indication and Surgical Procedure.

Lung carcinomas infiltrate the aorta mostly on the left side and are altogether rare. As an initial step, complete staging is performed and the results are evaluated in an interdisciplinary tumor board. If the patient's general condition including cardiopulmonary reserves is sufficient, and if there is neither distant metastasis nor an N2 situation, surgical resection may be indicated. The option for neoadjuvant chemotherapy should always be taken into consideration. Depending on the anatomic tumor location, partial lung resection and resection of the affected aortic wall are performed employing a cardiopulmonary bypass. The resected aortic wall is replaced by a vascular prosthesis. In recent years, this proven procedure has partly been replaced by an alternative one, avoiding extracorporeal circulation. An endoaortic stent is implanted in the affected area followed by partial lung resection and resection of the diseased aortic wall. This new procedure has significantly reduced perioperative mortality and morbidity. With proper patient selection, long-term survival can be improved even in this complex malignoma.

Daptomycin-Impregnated PMMA Cement against Vancomycin-Resistant Germs: Dosage, Handling, Elution, Mechanical Stability, and Effectiveness.

BACKGROUND: The number of periprosthetic joint infections caused by vancomycin-resistant pathogens is increasing. Currently, no PMMA cement is commercially available to cover VRE. Daptomycin shows promising results in treating infection, offering a good safety profile and a reduced risk of developing resistance. The purpose of this in vitro study was to investigate the mechanical stability, handling properties, elution behavior, and antimicrobial effectiveness of PMMA cement loaded with three different daptomycin concentrations in comparison to commercially available antibiotic-loaded bone cement (ALBC). METHODS: Mechanical properties and handling characteristics (ISO 5833, DIN 53435), HPLC elution, antimicrobial effectiveness with proliferation assay (DIN 17025), and inhibition zone testing were investigated. RESULTS: All tested daptomycin concentrations met the ISO and DIN standards for mechanical strength. Loading of 40 g of PMMA cement with 0.5 g of daptomycin did not show any antimicrobial effectiveness, in contrast to 1.0 g and 1.5 g. PMMA cement with 1.5 g of daptomycin was the best in terms of elution and effectiveness, and it showed good ISO mechanical strength; ISO doughing was sticky for a little longer and setting was faster compared to the vancomycin-containing reference cement. CONCLUSION: PMMA cement containing 0.5 g of gentamicin and 1.5 g of daptomycin could be a good alternative to the already established COPAL® (Wehrheim, Germany) G+V for the treatment of PJIs caused by VRE.