Percutaneous Large-Bore Pulmonary Thrombectomy with the FlowTriever Device: Initial Experience in Intermediate-High and High-Risk Patients.

OBJECTIVES: This retrospective cohort study investigates outcomes of patients with intermediate-high and high-risk pulmonary embolism (PE) who were treated with transfemoral mechanical thrombectomy (MT) using the large-bore Inari FlowTriever aspiration catheter system. MATERIAL AND METHODS: Twenty-seven patients (mean age 56.1 ± 15.3 years) treated with MT for PE between 04/2021 and 11/2021 were reviewed. Risk stratification was performed according to European Society of Cardiology (ESC) guidelines. Clinical and hemodynamic characteristics before and after the procedure were compared with the paired Student's t test, and duration of hospital stay was analyzed with the Kaplan-Meier estimator. Procedure-related adverse advents were assessed. RESULTS: Of 27 patients treated, 18 were classified as high risk. Mean right-to-left ventricular ratio on baseline CT was 1.7 ± 0.6. After MT, a statistically significant reduction in mean pulmonary artery pressures from 35.9 ± 9.6 to 26.1 ± 9.0 mmHg (p = 0.002) and heart rates from 109.4 ± 22.5 to 82.8 ± 13.8 beats per minute (p < 0.001) was achieved. Two patients died of prolonged cardiogenic shock. Three patients died of post-interventional complications of which a paradoxical embolism can be considered related to MT. One patient needed short cardiopulmonary resuscitation during the procedure due to clot displacement. Patients with PE as primary driver of clinical instability had a median intensive care unit (ICU) stay of 2 days (0.5-3.5 days). Patients who developed PE as a complication of an underlying medical condition spent 11 days (9.5-12.5 days) in the ICU. CONCLUSION: In this small study population of predominantly high-risk PE patients, large-bore MT without adjunctive thrombolysis was feasible with an acceptable procedure-related complication rate.

Impact of angiogenic activation and inhibition on miRNA profiles of human retinal endothelial cells.

BACKGROUND: Human retinal microvascular endothelial cells (HRMVECs) are involved in the pathogenesis of retinopathy of prematurity. In this study, the microRNA (miRNA) expression profiles of HRMVECs were investigated under resting conditions, angiogenic stimulation (VEGF treatment) and anti-VEGF treatment. MATERIALS AND METHODS: The miRNA profiles of HRMVECs under resting and angiogenic conditions (VEGF treatment), as well as after addition of aflibercept, bevacizumab or ranibizumab were evaluated by analyzing the transcriptome of small non-coding RNAs. Differentially expressed miRNAs were validated using qPCR and classified using Gene Ontology enrichment analysis. RESULTS: Ten miRNAs were found to be significantly changed more than 2-fold. Seven of these miRNAs were changed between resting conditions and angiogenic stimulation. Four of these miRNAs (miR-139-5p/-3p and miR-335-5p/-3p) were validated by qPCR in independent experiments and were found to be associated with angiogenesis and cell migration in Gene Ontology analysis. In addition, analysis of the most abundant miRNAs in the HRMVEC miRNome (representing at least 1% of the miRNome) was conducted and identified miR-21-5p, miR-29a-3p, miR-100-5p and miR-126-5p/-3p to be differently expressed by at least 15% between resting conditions and angiogenic conditions. These miRNAs were found to be associated with apoptotic signaling, regulation of kinase activity, intracellular signal transduction, cell surface receptor signaling and positive regulation of cell differentiation in Gene Ontology analysis. No differentially regulated miRNAs between angiogenic stimulation and angiogenic stimulation plus anti-VEGF treatment were identified. CONCLUSION: In this study we characterized the miRNA profile of HRMVECs under resting, angiogenic and anti-angiogenic conditions and identified several miRNAs of potential pathophysiologic importance for angioproliferative retinal diseases. Our results have implications for possible miRNA-targeted angiomodulatory approaches in diseases like diabetic retinopathy or retinopathy of prematurity.

Spontaneous decision of organ donation in patients signing informed consent for liver transplantation.

The shortage of postmortem donor organs is a well-known problem in Germany. Willingness in the general population is 80%, but less than 14% have an organ donor card. We evaluated the free decision of liver transplant candidates who filled out a donor card before signing the informed consent for the transplant procedure. We analyzed 122 patients of mean age 55.9 years (range, 15.4-74.1) who signed an informed consent for liver transplantation between January 10, 2007, and January 24, 2012. The patients received the original text of the German organ donor card with tick boxes on the informed consent form for liver transplantation. All patients were informed that their decision had no impact on further management. Patients were able to choose between (1) becoming a donor, (2) refusal, (3) transfer of the decision to another person, or (4) no decision. All patients signed the informed consent to be listed for liver transplantation: 73.8% (n = 90) chose to become a donor; 5.7% (n = 7) refused; 5.7% (n = 7) transferred the decision to another person; and 14.8% (n = 18) did not come to a decision. Interestingly, not all candidates for liver transplantation were willing to become an organ donor in the time of expressed consent. However, willingness to sign the donor card was much higher among liver transplant candidates compared with the general population.

Does the processing fluency of a syllabus affect the forecasted grade and course difficulty?

Processing fluency is known to affect a variety of cognitive assessments, but most research has not examined such effects in the context of a real-life experience. In the first experiment, college students, enrolled in either a statistics or cognitive psychology course, read a course syllabus which varied in the clarity of its font and frequency of its vocabulary. Based on the syllabus, students then forecasted their final course grade and the course's difficulty. Despite methodological similarity to other fluency experiments and adequate statistical power, there were no significant differences in forecasts across fluency conditions. Fluency may be discounted in a task which provides information that affects people's lives. This interpretation was bolstered by a second experiment whose participants were students in a statistics course. These students read the cognitive course's syllabus and forecasted better grades and less difficulty in the cognitive course when the font of the syllabus was more clear than unclear.

Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker.

Deregulation of the ErbB (proto-oncogene B of the avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib [BIBW 2992; N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide] is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group. It was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here, we show by X-ray crystallography the covalent binding of afatinib to wild-type epidermal growth factor receptor (EGFR) and by mass spectrometry the covalent interaction with EGFR, EGFRL858R/T790M, human epidermal growth factor receptor 2 (HER2), and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC50=1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butanamide (BI 37781), a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFRL858R, but less or no detectable activity on cells expressing EGFRL858R/T790M HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients who are resistant to antibody or kinase inhibitor therapy because of secondary mutations or ErbB receptor "reprogramming."

Mortality salience and symbols of cultural worldview affect the desirability of a stressful job: the ironic consequences of terror management.

In a study of terror management theory, participants first responded to prompts asking them to imagine their own death or dental pain and later rated the desirability of a generic job described explicitly as extremely stressful. The job description included either an American or foreign company logo. As predicted by terror management theory, the participants shown an American logo ironically desired the stressful job more, having been prompted with reminders of death than with reminders of dental pain. This study is the first to examine terror management theory's prediction of the influence of symbols of cultural worldview on health-related decisions. The authors discuss possible implications of the findings for making unintentionally stress-inducing decisions and for public health campaigns.

Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression.

Polybrominated diphenyl ethers (PBDEs) accumulate in the environment and in humans. PBDEs are developmental neurotoxicants, disturb the endocrine system and induce tumors in rodents. However, underlying mechanisms of PBDE toxicity are still insufficiently understood. Some reports demonstrated activation but also inhibition of the aryl hydrocarbon receptor (AhR) by PBDEs based on expression of its target gene cyp1A1. In the present study, we used different PBDE congeners (BDE47, 99, 153 and 209) and analyzed their effects on AhR signaling in various cell lines and zebrafish embryos. Furthermore, we performed microarray experiments in rat hepatoma cells to compare changes in gene expression induced by either BDE47 or the AhR agonist 2,3,7,8-tetrabromo-dibenzofuran (TBDF). PBDEs did not activate but rather inhibited AhR signaling and specifically induced malformations in zebrafish embryos, which differ from those provoked by AhR agonists. Furthermore, BDE47 and TBDF differentially regulated global gene expression in hepatoma cells. Hence, PBDEs and AhR agonists trigger different toxicity and target gene expression. Several novel target genes of BDE47 and TBDF were identified and verified by RT-PCR. TBDF induced expression of the transcriptional regulators Sim2 and RevErbbeta whereas BDE47 specifically deregulated expression of two subunits of the cytochrome c oxidase complex, cox6a2 and cox4i2, which might be linked to its toxicity.

Caffeine's effects on true and false memory.

Caffeine's effects on recall of word lists were investigated using the Deese-Roediger-McDermott (DRM) paradigm. College students were administered either 200 mg of caffeine or a 250-mg lactose placebo; after 30 min., they were tested on recall using six word lists. Words of each list were semantically related to a single word (a "critical lure") that was not presented in the list. Participants administered caffeine recalled more list words and more critical lures than participants administered lactose. Recall of list words was negatively correlated with recall of critical lures. Caffeine appears to intensify the strength of connections among list words and critical lures, thereby enhancing both true and false memory.

[MMP- and FAP-mediated non-inflammation-related destruction of cartilage and bone in rheumatoid arthritis]. / MMP- und FAP-vermittelte inflammationsunabhängige Destruktion von Knochen und Knorpel in der rheumatoiden Arthritis.

INTRODUCTION: Due to morphological similarities of high-grade synovitis in rheumatoid Arthritis (RA) and mesenchymal, semimalignant tumors and the hypothesis that RA progression is not only inflammation-related, but also determined by tumor-like mechanisms, a comparison was made between expression profiles of RA, giant cell tumor of bone (GCT) and normal synovium (ND). METHODS: Array data of selected genes were validated through immunohistochemical staining of paraffin-embedded and deep frozen tissue samples of GCT, RA and normal synovium. RESULTS: With microarray analysis, CCR1, CCR5, MMP-1, MMP-2, MMP-3, MMP-9, MMP-14 and FAP were found to be significantly upregulated in RA and GCT compared to ND. A significant upregulation in RA and GCT compared to ND could be validated by immunohistochemistry for MMP-1, MMP-9, MMP-14 and FAP. DISCUSSION: For MMPs, and MMP-9 in particular, an important role in early cartilage destruction of RA was suggested. The presence of FAP in RA and in stroma of a semimalignant tumor indicates tumor-like tissue destruction in chronic synovitis associated with RA.

A technical mixture of 2,2',4,4'-tetrabromo diphenyl ether (BDE47) and brominated furans triggers aryl hydrocarbon receptor (AhR) mediated gene expression and toxicity.

Polybrominated diphenyl ethers (PBDE) are found as ubiquitous contaminants in the environment, e.g., in sediments and biota as well as in human blood samples and mother's milk. PBDEs are neuro- and developmental toxins, disturb the endocrine system and some are even carcinogenic. Structural similarities of PBDEs with dioxin-like compounds, e.g., 2,3,7,8-tetrachloro-dibenzodioxin (TCDD), have raised concern about a possible "dioxin-like" action of PBDEs. TCDD exerts its toxicity via binding to and activation of the aryl hydrocarbon receptor (AhR). AhR ligands are in contrast to PBDEs usually coplanar compounds. Thus, PBDEs are not likely to be strong AhR agonists. The aim of this study was to analyze the effects of the most abundant PBDE congener, 2,2',4,4'-tetrabromo diphenyl ether (BDE47), on AhR activity and signaling. Initially, we measured cytochrome P450 1A1 (Cyp1A1) induction as a readout for AhR activation by BDE47. Low grade purified BDE47 increased CYP1A1 levels in transformed and primary rat hepatocytes and human hepatoma cells. Chemical analysis of the BDE47 sample identified trace contaminations with brominated furans such as 2,3,7,8-tetrabromo dibenzodioxin (TBDF), which most likely were responsible for the observed activation of AhR. Subsequently, the BDE47 mixture was studied for its effect on AhR mediated toxicity and global gene expression. Indeed, in rat hepatoma cells and in zebrafish embryos the BDE47 mixture provoked changes in gene expression and toxicity similar to known AhR agonists. In addition to the dioxin-like actions, the BDE47 sample enhanced Cyp2B and Cyp3A expression suggesting that commercial PBDE mixtures, which also often contain brominated furans, may disturb cellular homeostasis at multiple levels.

Life-threatening bite injury of the lower lip after use of metamizole.

INTRODUCTION: Bite wounds of the oral mucosa heal after eliminating the causative irritant, but there are serious exceptions from the rule. We present the case of a 37-year-old woman with an ulcer of the mucosa of the lower lip, which had been present for 10 days, and leucopenia. DISCUSSION: Agranulocytosis after the use of metamizole is part from leukaemia and lues, a rare reason for non-healing ulcers of the mucosa of the oral cavity without fulminant signs for inflammation. CONCLUSION: As this is a life-threatening disease, medical therapy must begin immediately.

Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts.

PURPOSE: Invasion and metastasis of malignant epithelial cells into normal tissues is accompanied by adaptive changes in the mesenchyme-derived supporting stroma of the target organs. Altered gene expression in these nontransformed stromal cells provides potential targets for therapy. The present study was undertaken to determine the antitumor effects of an antibody-conjugate against fibroblast activation protein-alpha, a cell surface protease of activated tumor fibroblasts. EXPERIMENTAL DESIGN: A novel antibody-maytansinoid conjugate, monoclonal antibody (mAb) FAP5-DM1, was developed to target a shared epitope of human, mouse, and cynomolgus monkey fibroblast activation protein-alpha, enabling preclinical efficacy and tolerability assessments. We have used stroma-rich models in immunodeficient mice, which recapitulate the histotypic arrangement found in human epithelial cancers. RESULTS: Treatment with mAb FAP5-DM1 induced long-lasting inhibition of tumor growth and complete regressions in xenograft models of lung, pancreas, and head and neck cancers with no signs of intolerability. Analysis of chemically distinct conjugates, resistance models, and biomarkers implicates a unique mode of action, with mitotic arrest and apoptosis of malignant epithelial cells coupled to disruption of fibroblastic and vascular structures. CONCLUSIONS: We show that mAb FAP5-DM1 combines excellent efficacy and tolerability and provides a first assessment of the mode of action of a novel drug candidate for tumor stroma targeting, thus encouraging further development toward clinical testing of this treatment paradigm.

[Expression analyses for rheumatoid arthritis]. / Expressionsanalysen bei der rheumatoiden Arthritis.

Inflammatory rheumatic diseases with their unclear aetiology are a challenge for the routine clinical practice. The dominating inflammatory processes with many facets of autoimmune phenomena have been extensively studied during the last decades. Modern high throughput technologies provide for the first time the opportunity to obtain an insight into the many different molecular aspects in one patient in parallel. Step by step, concepts can be developed to understand the relationships and interdependencies of the molecular processes and to place them in order of importance for each individual separately. Thus, studies have demonstrated that the risk of disease severity can be estimated and the response to therapy can be objectified based on molecular investigations. Exemplarily, the potential has been demonstrated that the therapeutic outcome towards a defined treatment may be predicted. Despite the high cost, it is becoming more and more obvious that an extensive increase of knowledge depends on the detection of a multitude of parameters, a task which will need to be accomplished in the near future.

Molecular coronary MR imaging of human thrombi using EP-2104R, a fibrin-targeted contrast agent: experimental study in a swine model.

PURPOSE: The aim of this study was to investigate the use of a fibrin-specific contrast agent (EP-2104R, EPIX Pharmaceuticals, Lexington, Massachusetts, USA) for targeted molecular magnetic resonance (MR) imaging of human clot material removed from patients in a model of coronary thrombosis in swine. MATERIALS AND METHODS: Freshly ex vivo engineered clots from human blood and human in situ developed clots removed from patients were delivered into the coronary arteries of nine domestic swine. For MR imaging a navigator-gated, free-breathing, cardiac-triggered 3D inversion recovery black-blood gradient echo sequence was performed prior to clot delivery (baseline), after clot delivery but prior to contrast media administration, and two hours after systemic (i.v.) injection of 4 micromol/kg EP-2104R. MR images were analyzed by two investigators and the contrast-to-noise ratio and Gadolinium (Gd) concentration in the clots were assessed. RESULTS: On baseline images and prior to contrast media application no thrombi were visible. Post contrast administration all 10 coronary emboli (five ex vivo engineered clots and five human clots removed from patients) were selectively visualized as white spots with a mean contrast-to-noise ratio to the blood pool and the surrounding tissue of >12 and a mean Gd concentration of >100 microM. CONCLUSION: Molecular MR imaging using the fibrin-targeted contrast agent EP-2104R allows selective visualization of human clot material in a model of coronary thrombosis in swine.

[Imaging of the abdominal wall: combination of tissue-harmonic-imaging and extended field-of-view sonography]. / Ultraschall der Bauchdecke: Kombination von Tissue-Harmonic-Imaging und Panorama-Ultraschall.

PURPOSE: To evaluate the combined use of extended field-of-view sonography and tissue harmonic imaging (THI) for assessment of the abdominal wall. MATERIALS AND METHODS: In 32 patients (25 patients without and 7 patients with abdominal wall pathologies) extended field-of-view sonography of the abdominal wall was performed with and without THI using a 7.5 MHz ultrasound transducer. Images with a scan length of 60 cm were acquired above and below the arcuate line. The images were independently assessed by two observers regarding visibility of the anatomic structures and delineation of pathological changes using a 4-point grading scale. Furthermore, the influence of the extent of the subcutaneous fat on the image quality was assessed. For statistical analysis, kappa coefficients, Fisher"s exact test and a repeated measurement analysis of variance (ANOVA) were applied. RESULTS: In all patients, delineation of the abdominal wall was possible with diagnostic image quality. Abdominal wall pathologies were concurrently diagnosed for extended field-of-view sonography with and without utilization of THI. Image quality was rated better with THI when compared to extended field-of-view B-Mode sonography. In comparison to extended field-of-view B-Mode sonography, the agreement between both readers regarding image quality was markedly improved using extended field-of-view sonography in combination with THI. With increasing thickness of the subcutaneous fat layer, image quality was rated significantly better using THI than B-Mode ultrasound. CONCLUSION: Combined use of extended field-of-view sonography and THI improves image quality and documentation of ultrasound examinations. Especially in obese patients, the use of THI is advantageous. Therefore, abdominal wall ultrasound gains additional value in the preoperative planning.

Improved in-stent magnetic resonance angiography with high flip angle excitation.

RATIONALE AND OBJECTIVES: To optimize the intraluminal signal intensity of a nitinol stent by performing contrast-enhanced three-dimensional magnetic resonance angiography (CE-MRA) with varying flip angles (FAs). METHODS: Contrast-enhanced magnetic resonance angiography at 1.5 T and FAs of 30 degrees, 100 degrees, and 150 degrees was performed on five sheep with 10 iliac nitinol stents (Memotherm-FLEXX). Maximum-intensity projections (MIPs) and composite images of MIPs were performed and compared. RESULTS: Reconstructed MIPs at an FA of 150 degrees showed a slightly disturbed lumen visibility inside the stent accompanied by low-grade lumen visibility outside the stent and vice versa for an FA of 30 degrees. Composite images of a 30 degrees MIP added to a 150 degrees MIP resulted in improved image quality compared with the standard MIP of a single FA. CONCLUSIONS: Signal loss due to radiofrequency shielding inside nitinol stents imaged by CE-MRA can be reduced by applying high FAs. Composite MIP images allow simultaneous visualization of the lumen inside as well as outside the stent.