Multimodal nonlinear imaging of atherosclerotic plaques differentiation of triglyceride and cholesterol deposits

Cardiovascular diseases in general and atherothrombosis as the most common of its individual disease entities is the leading cause of death in the developed countries. Therefore, visualization and characterization of inner arterial plaque composition is of vital diagnostic interest, especially for the early recognition of vulnerable plaques. Established clinical techniques provide valuable morphological information but cannot deliver information about the chemical composition of individual plaques. Therefore, spectroscopic imaging techniques have recently drawn considerable attention. Based on the spectroscopic properties of the individual plaque components, as for instance different types of lipids, the composition of atherosclerotic plaques can be analyzed qualitatively as well as quantitatively. Here, we compare the feasibility of multimodal nonlinear imaging combining two-photon fluorescence (TPF), coherent anti-Stokes Raman scattering (CARS) and second-harmonic generation (SHG) microscopy to contrast composition and morphology of lipid deposits against the surrounding matrix of connective tissue with diffraction limited spatial resolution. In this contribution, the spatial distribution of major constituents of the arterial wall and atherosclerotic plaques like elastin, collagen, triglycerides and cholesterol can be simultaneously visualized by a combination of nonlinear imaging methods, providing a powerful label-free complement to standard histopathological methods with great potential for in vivo application

Affective regulation of cognitive-control adjustments in remitted depressive patients after acute tryptophan depletion

Negative affect in healthy populations regulates the appraisal of demanding situations, which tunes subsequent effort mobilization and adjustments in cognitive control. In the present study, we hypothesized that dysphoria in depressed individuals similarly modulates this adaptation, possibly through a neural mechanism involving serotonergic regulation. We tested the effect of dysphoria induced by acute tryptophan depletion (ATD) in remitted depressed patients on conflict adaptation in a Simon task. ATD temporarily lowers the availability of the serotonin precursor L-Tryptophan and is known to increase depressive symptoms in approximately half of remitted depressed participants. We found that depressive symptoms induced by ATD were associated with increased conflict adaptation. Our finding extends recent observations implying an important role of affect in regulating conflict-driven cognitive control

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^(pro). In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics

Left atrial endocarditis as a rare complication of mitral valve endocarditis: a clinical case

Abstract Background Infective Endocarditis (IE) is considered as a multifaceted problem in every aspect from etiology and presentation to diagnosis and management. Early recognition of this disease and especially its complications, remain a critical task for the cardiologist. Atrial endocarditis is a rare and sometimes unrecognized complication of mitral valve endocarditis. Case presentation We present a 48 year-old male patient who was admitted to our clinic because of recent onset of malaise, fever, jaundice and peripheral edema. Important physical findings were peripheral stigmata of IE in addition to holosystolic murmur over the left sternal border. Transthoracic and transesophageal echocardiophy revealed a severe eccentric MR due to a flailed posterior mitral valve caused by IE. The presence of atrial septal endocarditis caused by jet streaming was also observed. Blood culture was positive for streptococcus oralis and antibiotic therapy was immediately initiated. Considering the large burden of infective tissue, the patient was planned for an early surgical intervention. A minimally invasive resection of the atrial mass, direct closure of the defect, resection of the diseased portions of mitral leaflets and implantation of a biological mitral valve prosthesis was performed. Intra-operative and histological findings confirmed provisional diagnosis by echocardiography. Conclusions Together with comprehensive echocardiographic evaluation, attention should be placed on mural vegetations and excluded among all cases of mitral valve endocarditis, particularly those with severe eccentric regurgitant jets.</p

Rapid clinical evaluation: an early warning cardiac surgical scoring system for hand-held digital devices

The purpose of this study was to develop a new scoring system for the prompt recognition of clinical deterioration and early treatment in postoperative cardiac surgical patients. All consecutive adult patients undergoing cardiac surgery between 1st January 2007 and 31st December 2010 were included. The new score was calculated daily until intensive care unit (ICU) discharge. The score consists of 11 variables representing six different organ systems. Performance was assessed using receiver-operating characteristic (ROC) curves and calibration tests. A total of 5207 patients with a mean age of 67.2 +/- 10.9 years were admitted to the ICU after cardiac surgery. The operations performed covered the whole spectrum of cardiac surgery. ICU mortality was 5.9%. The mean length of ICU stay was 4.6 +/- 7.0 days. The new score had an excellent discrimination with areas under the ROC curves between 0.91 and 0.96. Calibration was also excellent reflected by observed/expected mortality ratios ranging between 1.0 and 1.26. The new score is a simple and reliable scoring system to assess organ dysfunction in cardiac intensive care patients. It is designed especially for personal digital assistants to simplify and accelerate the process of risk stratification in cardiac surgical ICUs

Mortality Prediction after Cardiac Surgery: Blood Lactate Is Indispensible

BackgroundBlood lactate is accepted as a mortality risk marker in intensive care units (ICUs), especially after cardiac surgery. Unfortunately, most of the commonly used ICU risk stratification scoring systems did not include blood lactate as a variable. We hypothesized that blood lactate alone can predict the risk of mortality after cardiac surgery with an accuracy that is comparable to those of other complex models. We therefore evaluated its accuracy at mortality prediction and compared it with that of other widely used complex scoring models statistically. MethodsWe prospectively collected data of all consecutive adult patients who underwent cardiac surgery between January 1, 2007, and December 31, 2009. By using (2) statistics, a blood lactate-based scale (LacScale) with only four cutoff points was constructed in a developmental set of patients (January 1, 2007, and May 31, 2008). LacScale included five categories: 0 ( 1.7 mmol/L); 1 (1.8-5.9 mmol/L), 2 (6.0-9.3 mmol/L), 3 (9.4-13.3 mmol/L), and 4 ( 13.4 mmol/L). Its accuracy at predicting ICU mortality was evaluated in another independent subset of patients (validation set, June 1, 2008, and December 31, 2009) on both study-population level (calibration analysis, overall correct classification) and individual-patient-risk level (discrimination analysis, ROC statistics). The results were then compared with those obtained from other widely used postoperative models in cardiac surgical ICUs (Sequential Organ Failure Assessment [SOFA] score, Simplified Acute Physiology Score II [SAPS II], and Acute Physiology and Chronic Health Evaluation II [APACHE II] score). ResultsICU mortality was 5.8% in 4,054 patients. LacScale had a reliable calibration in the validation set (2,087 patients). It was highly accurate in predicting ICU mortality with an area under the ROC curve (area under curve [AUC]; discrimination) of 0.88. This AUC was significantly larger than that of all the other models (SOFA 0.83, SAPS II: 0.79 and APACHE II: 0.76) according to DeLong's comparison. Integrating the LacScale in those scores further improved their accuracy by increasing their AUCs (0.88, 0.81, and 0.80, respectively). This improvement was also highly significant. ConclusionBlood lactate accurately predicts mortality at both individual patient risk and patient cohort levels. Its precision is higher than that of other commonly used complex scoring models. The proposed LacScale is a simple and highly reliable model. It can be used (at bedside without electronic calculation) as such or integrated in other models to increase their accuracy