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.

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.

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.

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.

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.

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.

Value of quantitative airspace disease measured on chest CT and chest radiography at initial diagnosis compared to clinical variables for prediction of severe COVID-19.

Purpose: Rapid prognostication of COVID-19 patients is important for efficient resource allocation. We evaluated the relative prognostic value of baseline clinical variables (CVs), quantitative human-read chest CT (qCT), and AI-read chest radiograph (qCXR) airspace disease (AD) in predicting severe COVID-19. Approach: We retrospectively selected 131 COVID-19 patients (SARS-CoV-2 positive, March to October, 2020) at a tertiary hospital in the United States, who underwent chest CT and CXR within 48 hr of initial presentation. CVs included patient demographics and laboratory values; imaging variables included qCT volumetric percentage AD (POv) and qCXR area-based percentage AD (POa), assessed by a deep convolutional neural network. Our prognostic outcome was need for ICU admission. We compared the performance of three logistic regression models: using CVs known to be associated with prognosis (model I), using a dimension-reduced set of best predictor variables (model II), and using only age and AD (model III). Results: 60/131 patients required ICU admission, whereas 71/131 did not. Model I performed the poorest ( AUC = 0.67 [0.58 to 0.76]; accuracy = 77 % ). Model II performed the best ( AUC = 0.78 [0.71 to 0.86]; accuracy = 81 % ). Model III was equivalent ( AUC = 0.75 [0.67 to 0.84]; accuracy = 80 % ). Both models II and III outperformed model I ( AUC difference = 0.11 [0.02 to 0.19], p = 0.01 ; AUC difference = 0.08 [0.01 to 0.15], p = 0.04 , respectively). Model II and III results did not change significantly when POv was replaced by POa. Conclusions: Severe COVID-19 can be predicted using only age and quantitative AD imaging metrics at initial diagnosis, which outperform the set of CVs. Moreover, AI-read qCXR can replace qCT metrics without loss of prognostic performance, promising more resource-efficient prognostication.

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.

Cytochrome c Oxidase Inhibition by ATP Decreases Mitochondrial ROS Production.

This study addresses the eventual consequence of cytochrome c oxidase (CytOx) inhibition by ATP at high ATP/ADP ratio in isolated rat heart mitochondria. Earlier, it has been demonstrated that the mechanism of allosteric ATP inhibition of CytOx is one of the key regulations of mitochondrial functions. It is relevant that aiming to maintain a high ATP/ADP ratio for the measurement of CytOx activity effectuating the enzymatic inhibition as well as mitochondrial respiration, optimal concentration of mitochondria is critically important. Likewise, only at this concentration, were the differences in ΔΨm and ROS concentrations measured under various conditions significant. Moreover, when CytOx activity was inhibited in the presence of ATP, mitochondrial respiration and ΔΨm both remained static, while the ROS production was markedly decreased. Consubstantial results were found when the electron transport chain was inhibited by antimycin A, letting only CytOx remain functional to support the energy production. This seems to corroborate that the decrease in mitochondrial ROS production is solely the effect of ATP binding to CytOx which results in static respiration as well as membrane potential.

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.

Dual-Energy Cone-Beam CT with Three-Material Decomposition for Bone Marrow Edema Imaging.

We investigate the feasibility of bone marrow edema (BME) detection using a kV-switching Dual-Energy (DE) Cone-Beam CT (CBCT) protocol. This task is challenging due to unmatched x-ray paths in the low-energy (LE) and high-energy (HE) spectral channels, CBCT non-idealities such as x-ray scatter, and narrow spectral separation between fat (bone marrow) and water (BME). We propose a comprehensive DE decomposition framework consisting of projection interpolation onto matching LE and HE view angles, fast Monte Carlo scatter correction with low number of tracked photons and Gaussian denoising, and two-stage three-material decompositions involving two-material (fat-Aluminium) Projection-Domain Decomposition (PDD) followed by image-domain three-material (fat-water-bone) base-change. Performance in BME detection was evaluated in simulations and experiments emulating a kV-switching CBCT wrist imaging protocol on a robotic x-ray system with 60 kV LE beam, 120 kV HE beam, and 0.5° angular shift between the LE and HE views. Cubic B-spline interpolation was found to be adequate to resample HE and LE projections of a wrist onto common view angles required by PDD. The DE decomposition maintained acceptable BME detection specificity (<0.2 mL erroneously detected BME volume compared to 0.85 mL true BME volume) over +/-10% range of scatter magnitude errors, as long as the scatter shape was estimated without major distortions. Physical test bench experiments demonstrated successful discrimination of ~20% change in fat concentrations in trabecular bone-mimicking solutions of varying water and fat content.

Feasibility of Dual-Energy Cone-Beam CT of Bone Marrow Edema Using Dual-Layer Flat Panel Detectors.

Purpose: We investigated the feasibility of detection and quantification of bone marrow edema (BME) using dual-energy (DE) Cone-Beam CT (CBCT) with a dual-layer flat panel detector (FPD) and three-material decomposition. Methods: A realistic CBCT system simulator was applied to study the impact of detector quantization, scatter, and spectral calibration errors on the accuracy of fat-water-bone decompositions of dual-layer projections. The CBCT system featured 975 mm source-axis distance, 1,362 mm source-detector distance and a 430 × 430 mm2 dual-layer FPD (top layer: 0.20 mm CsI:Tl, bottom layer: 0.55 mm CsI:Tl; a 1 mm Cu filter between the layers to improve spectral separation). Tube settings were 120 kV (+2 mm Al, +0.2 mm Cu) and 10 mAs per exposure. The digital phantom consisted of a 160 mm water cylinder with inserts containing mixtures of water (volume fraction ranging 0.18 to 0.46) - fat (0.5 to 0.7) - Ca (0.04 to 0.12); decreasing fractions of fat indicated increasing degrees of BME. A two-stage three-material DE decomposition was applied to DE CBCT projections: first, projection-domain decomposition (PDD) into fat-aluminum basis, followed by CBCT reconstruction of intermediate base images, followed by image-domain change of basis into fat, water and bone. Sensitivity to scatter was evaluated by i) adjusting source collimation (12 to 400 mm width) and ii) subtracting various fractions of the true scatter from the projections at 400 mm collimation. The impact of spectral calibration was studied by shifting the effective beam energy (± 2 keV) when creating the PDD lookup table. We further simulated a realistic BME imaging framework, where the scatter was estimated using a fast Monte Carlo (MC) simulation from a preliminary decomposition of the object; the object was a realistic wrist phantom with an 0.85 mL BME stimulus in the radius. Results: The decomposition is sensitive to scatter: approx. <20 mm collimation width or <10% error of scatter correction in a full field-of-view setting is needed to resolve BME. A mismatch in PDD decomposition calibration of ± 1 keV results in ~25% error in fat fraction estimates. In the wrist phantom study with MC scatter corrections, we were able to achieve ~0.79 mL true positive and ~0.06 mL false positive BME detection (compared to 0.85 mL true BME volume). Conclusions: Detection of BME using DE CBCT with dual-layer FPD is feasible, but requires scatter mitigation, accurate scatter estimation, and robust spectral calibration.

Slot-scan dual-energy bone densitometry using motorized X-ray systems.

PURPOSE: We investigate the feasibility of slot-scan dual-energy (DE) bone densitometry on motorized radiographic equipment. This approach will enable fast quantitative measurements of areal bone mineral density (aBMD) for opportunistic evaluation of osteoporosis. METHODS: We investigated DE slot-scan protocols to obtain aBMD measurements at the lumbar spine (L-spine) and hip using a motorized x-ray platform capable of synchronized translation of the x-ray source and flat-panel detector (FPD). The slot dimension was 5 × 20 cm2 . The DE slot views were processed as follows: (1) convolution kernel-based scatter correction, (2) unfiltered backprojection to tile the slots into long-length radiographs, and (3) projection-domain DE decomposition, consisting of an initial adipose-water decomposition in a bone-free region followed by water-CaHA decomposition with adjustment for adipose content. The accuracy and reproducibility of slot-scan aBMD measurements were investigated using a high-fidelity simulator of a robotic x-ray system (Siemens Multitom Rax) in a total of 48 body phantom realizations: four average bone density settings (cortical bone mass fraction: 10-40%), four body sizes (waist circumference, WC = 70-106 cm), and three lateral shifts of the body within the slot field of view (FOV) (centered and ±1 cm off-center). Experimental validations included: (1) x-ray test-bench feasibility study of adipose-water decomposition and (2) initial demonstration of slot-scan DE bone densitometry on the robotic x-ray system using the European Spine Phantom (ESP) with added attenuation (polymethyl methacrylate [PMMA] slabs) ranging 2 to 6 cm thick. RESULTS: For the L-spine, the mean aBMD error across all WC settings ranged from 0.08 g/cm2 for phantoms with average cortical bone fraction wcortical  = 10% to ∼0.01 g/cm2 for phantoms with wcortical  = 40%. The L-spine aBMD measurements were fairly robust to changes in body size and positioning, e.g., coefficient of variation (CV) for L1 with wcortical  = 30% was ∼0.034 for various WC and ∼0.02 for an obese patient (WC = 106 cm) changing lateral shift. For the hip, the mean aBMD error across all phantom configurations was about 0.07 g/cm2 for a centered patient. The reproducibility of hip aBMD was slightly worse than in the L-spine (e.g., in the femoral neck, the CV with respect to changing WC was ∼0.13 for phantom realizations with wcortical  = 30%) due to more challenging scatter estimation in the presence of an air-tissue interface within the slot FOV. The aBMD of the hip was therefore sensitive to lateral positioning of the patient, especially for obese patients: e.g., the CV with respect to patient lateral shift for femoral neck with WC = 106 cm and wcortical  = 30% was 0.14. Empirical evaluations confirmed substantial reduction in aBMD errors with the proposed adipose estimation procedure and demonstrated robust aBMD measurements on the robotic x-ray system, with aBMD errors of ∼0.1 g/cm2 across all three simulated ESP vertebrae and all added PMMA attenuator settings. CONCLUSIONS: We demonstrated that accurate aBMD measurements can be obtained on a motorized FPD-based x-ray system using DE slot-scans with kernel-based scatter correction, backprojection-based slot view tiling, and DE decomposition with adipose correction.

Mitochondrial respiration is controlled by Allostery, Subunit Composition and Phosphorylation Sites of Cytochrome c Oxidase: A trailblazer's tale - Bernhard Kadenbach.

In memoriam of Bernhard Kadenbach: Although the main focus of his research was the structure, function, and regulation of mitochondrial cytochrome c oxidase (CytOx), he earlier studied the mitochondrial phosphate carrier and found an essential role of cardiolipin. Later, he discovered tissue-specific and developmental-specific protein isoforms of CytOx. Defective activity of CytOx is found with increasing age in human muscle and neuronal cells resulting in mitochondrial diseases. Kadenbach proposed a theory on the cause of oxidative stress, aging, and associated diseases stating that allosteric feedback inhibition of CytOx at high mitochondrial ATP/ADP ratios is essential for healthy living while stress-induced reversible dephosphorylation of CytOx results in the formation of excessive reactive oxygen species that trigger degenerative diseases. This article summarizes the main discoveries of Kadenbach related to mammalian CytOx and discusses their implications for human disease.

Cementing technique for total knee arthroplasty in cadavers using a pastry bone cement.

BACKGROUND: In cemented primary total knee arthroplasty (TKA), aseptic loosening remains a major cause for failure. Cementing techniques and characteristics of a chosen cement play a key role for good fixation and implant survival. A pastry bone cement was developed to facilitate the cement preparation and to rule out most of preparation-associated application errors. The pastry bone cement was compared to a conventional polymethyl methacrylate cement in a TKA setting. METHODS: Standardized implantations of total knee endoprostheses were performed in bilateral knee cadavers to investigate handling properties, variables of cement application, working time, and temperature development. Mechanical aspects and cementation quality were assessed by pull-out trials and microscopic interface analysis. RESULTS: Both cements expressed similar characteristics during preparation and application, only the curing time of the pastry cement was about 3 min longer and the temperature peak was lower. Fractures of the conventional cement specimens differed from the pastry cement specimens in the tibial part, while no differences were found in the femoral part. Penetration depth of the pastry cement was similar (tibia) or deeper (femur) compared to the conventional cement. CONCLUSIONS: The pastry cement facilitates the feasibility of cemented TKA. The pre-clinical tests indicate that the pastry bone cement fulfills the requirements for bone cement in the field of knee arthroplasty. A clinical trial is needed to further investigate the approach and ensure patient safety.

Cholate Disrupts Regulatory Functions of Cytochrome c Oxidase.

Cytochrome c oxidase (CytOx), the oxygen-accepting and rate-limiting enzyme of mitochondrial respiration, binds with 10 molecules of ADP, 7 of which are exchanged by ATP at high ATP/ADP-ratios. These bound ATP and ADP can be exchanged by cholate, which is generally used for the purification of CytOx. Many crystal structures of isolated CytOx were performed with the enzyme isolated from mitochondria using sodium cholate as a detergent. Cholate, however, dimerizes the enzyme isolated in non-ionic detergents and induces a structural change as evident from a spectral change. Consequently, it turns off the "allosteric ATP-inhibition of CytOx", which is reversibly switched on under relaxed conditions via cAMP-dependent phosphorylation and keeps the membrane potential and ROS formation in mitochondria at low levels. This cholate effect gives an insight into the structural-functional relationship of the enzyme with respect to ATP inhibition and its role in mitochondrial respiration and energy production.

Development of a fluoroscopically guided robotic assistant for instrument placement in pelvic trauma surgery.

Purpose: A method for fluoroscopic guidance of a robotic assistant is presented for instrument placement in pelvic trauma surgery. The solution uses fluoroscopic images acquired in standard clinical workflow and helps avoid repeat fluoroscopy commonly performed during implant guidance. Approach: Images acquired from a mobile C-arm are used to perform 3D-2D registration of both the patient (via patient CT) and the robot (via CAD model of a surgical instrument attached to its end effector, e.g; a drill guide), guiding the robot to target trajectories defined in the patient CT. The proposed approach avoids C-arm gantry motion, instead manipulating the robot to acquire disparate views of the instrument. Phantom and cadaver studies were performed to determine operating parameters and assess the accuracy of the proposed approach in aligning a standard drill guide instrument. Results: The proposed approach achieved average drill guide tip placement accuracy of 1.57 ± 0.47 mm and angular alignment of 0.35 ± 0.32 deg in phantom studies. The errors remained within 2 mm and 1 deg in cadaver experiments, comparable to the margins of errors provided by surgical trackers (but operating without the need for external tracking). Conclusions: By operating at a fixed fluoroscopic perspective and eliminating the need for encoded C-arm gantry movement, the proposed approach simplifies and expedites the registration of image-guided robotic assistants and can be used with simple, non-calibrated, non-encoded, and non-isocentric C-arm systems to accurately guide a robotic device in a manner that is compatible with the surgical workflow.

Multiple Mechanisms Regulate Eukaryotic Cytochrome C Oxidase.

Cytochrome c oxidase (COX), the rate-limiting enzyme of mitochondrial respiration, is regulated by various mechanisms. Its regulation by ATP (adenosine triphosphate) appears of particular importance, since it evolved early during evolution and is still found in cyanobacteria, but not in other bacteria. Therefore the "allosteric ATP inhibition of COX" is described here in more detail. Most regulatory properties of COX are related to "supernumerary" subunits, which are largely absent in bacterial COX. The "allosteric ATP inhibition of COX" was also recently described in intact isolated rat heart mitochondria.