CFD analysis in an anatomically realistic coronary artery model based on non-invasive 3D imaging: comparison of magnetic resonance imaging with computed tomography

Computational fluid dynamics (CFD) methods based on in vivo three-dimensional vessel reconstructions have recently been shown to provide prognostically relevant hemodynamic data. However, the geometry reconstruction and the assessment of clinically relevant hemodynamic parameters may depend on the used imaging modality. This study compares geometric reconstruction and calculated wall shear stress (WSS) values based on magnetic resonance imaging (MRI) and computed tomography (CT). Both imaging methods were applied to a same 2.5-fold upscale silicon model of the left coronary artery (LCA) main bifurcation. The original model is an optically digitized post mortem vessel cast. This digitized geometry is considered as a “gold standard” or original geometry for the MRI versus CT comparative study. The use of the upscale model allowed generating a high resolution CT raw data set with voxel size of 0.156 × 0.156 × 0.36 mm³ and a high resolution MRI data set with an equivalent voxel size of 0.196 × 0.196 × 0.196 mm³ for corresponding in vivo conditions. MRI based reconstruction achieved a mean Hausdorff surface distance of 0.1 mm to the original geometry. This is 2.5 times better than CT based reconstruction with mean Hausdorff surface distance of 0.252 mm. A comparison of the calculated mean WSS shows good correlation (r = 0.97) and good agreement among the three modalities with a WSS of 0.65 Pa in the original model, of 0.68 Pa in the CT based model and of 0.67 Pa in the MRI based model.     

High prevalence of urogenital infection/inflammation in patients with azoospermia does not impede surgical sperm retrieval

Considering infection/inflammation to be an important risk factor in male infertility, the aim of this study was to make a comprehensive evaluation of the prevalence of urogenital tract infection/inflammation and its potential impact on sperm retrieval in azoospermic patients. In this prospective study, 71 patients with azoospermia were subjected to an extensive andrological workup including comprehensive microbiological diagnostics (2‐glass test, semen, testicular swab and testicular tissue analysis) and testicular biopsy/testicular sperm extraction (TESE). Medical history suggested urogenital tract infection/inflammation in 7% of patients, 11% harboured STIs, 14% showed significant bacteriospermia, 15% had seminal inflammation, 17% fulfilled the MAGI definition, and 27% had relevant pathogens. At the testicular level, 1 patient had a swab positive for bacteria, no viruses were detected, tissue specimens never indicated pathogens, whereas histopathology revealed focal immune cell infiltrates in 23% of samples. Testicular sperm retrieval rate was 100% in obstructive and 46% in nonobstructive azoospermia. None of the infection/inflammation‐related variables was associated with the success of sperm retrieval or inflammatory lesions in the testis. The high prevalence of urogenital infection/inflammation among azoospermic men underpins their role as significant aetiologic factors in male infertility. However, this observation does not refer to the chances of sperm retrieval at the time of surgery/TESE.     

Altered expression of cell–cell adhesion molecules β-catenin/E-cadherin and related Wnt-signaling pathway in sporadic and syndromal keratocystic odontogenic tumors

Differential diagnosis of the keratocystic odontogenic tumor (KCOT) still represents a challenging problem especially if compared with the dentigerous cyst, which is similar in clinical and radiological course. Histological assessment of this entity may therefore draw crucial attention since various radical procedures are recommended for such lesions in contrast to dentigerous cysts. Since recent reports could prove the involvement of wingless(Wnt)-signaling pathway and β-catenin in the pathogenesis of many odontogenic and neoplastic lesions indicating impairment of cell–cell adhesion, we investigated the expression of two Wnt-signaling pathways, Wnt-1 and Wnt-10A as well as β-catenin and E-cadherin along with other related proteins in both lesions. We found a significant down-regulation in the expression of cell adhesion proteins β-catenin and E-cadherin along with alteration of Wnt-1 and Wnt-10A expression in the epithelium of KCOT. We assessed a specific focal distribution pattern of p63 in the suprabasal cell layer and a significant up-regulation of cyclin D1. Furthermore, laminin α-2 was a characteristic marker labelling only the basement membrane of dentigerous cysts. These results provide a new hypothesis explaining a molecular mechanism to understand initiating and development of KCOTs and an alternative therapeutic approach, especially for syndromal patients, where these multilocal lesions may involve and destroy wide orofacial bony structures.     

Challenges and Opportunities for Real-World Evidence in Metastatic Luminal Breast Cancer

BackgroundThe therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data.SummaryTo develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas.Key MessagesThis article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.     

Propofol and Sevoflurane in Subanesthetic Concentrations Act Preferentially on the Spinal Cord: Evidence from Multimodal Electrophysiological Assessment

Background: Animal experiments in recent years have shown that attenuation of motor responses by general anesthetics is mediated at least partly by spinal mechanisms. Less is known about the relative potency of anesthetic drugs in suppressing cortical and spinal electrophysiological responses in vivo in humans, particularly those, but not only those, connected with motor responses. Therefore, we studied the effects of sevoflurane and propofol in humans using multimodal electrophysiological assessment.

Methods: We studied nine healthy volunteers in two sessions during steady state sedation with 0.5, 1.0, and 1.5 [mu]g/l (targeted plasma concentration) propofol or 0.2 and 0.4 vol% (end-tidal) sevoflurane. Following a 15-min equilibration period, motor responses to transcranial magnetic stimulation and peripheral (H-reflex, F-wave) stimulation were recorded, while electroencephalography and auditory evoked responses were recorded in parallel.

Results: At concentrations corresponding to two thirds of C50 awake, motor responses to transcranial magnetic stimulation were reduced by approximately 50%, H-reflex amplitude was reduced by 22%, F-wave amplitude was reduced by 40%, and F-wave persistence was reduced by 25%. No significant differences between sevoflurane and propofol were found. At this concentration, the Bispectral Index was reduced by 7%, and the middle-latency auditory evoked responses were attenuated only mildly (Nb latency increased by 11%, amplitude PaNb did not change). In contrast, the postauricular reflex was suppressed by 77%.     

Development of a perfusion chamber assay to study in real time the kinetics of thrombosis and the antithrombotic characteristics of antiplatelet drugs

ABSTRACT: BACKGROUND: Arterial thrombosis triggered by vascular injury is a balance between thrombus growth and thrombus fragmentation (dethrombosis). Unbalance towards thrombus growth can lead to vascular occlusion, downstream ischemia and tissue damage. Here we describe the development of a simple methodology that allows for continuous real time monitoring and quantification of both processes during perfusion of human blood under arterial shear rate conditions. Using this methodology, we have studied the effects of antiplatelet agents targeting COX-1 (aspirin), P2Y12 (2-MeSAMP, clopidogrel), GP IIb-IIIa (eptifibatide) and their combinations on the kinetics of thrombosis over time. RESULTS: Untreated samples of blood perfused over type III collagen at arterial rates of shear promoted the growth of stable thrombi. Modulation by eptifibatide affected thrombus growth, while that mediated by 2-MeSAMP and aspirin affected thrombus stability. Using this technique, we confirmed the primacy of continuous signaling by the ADP autocrine loop acting on P2Y12 in the maintenance of thrombus stability. Analysis of the kinetics of thrombosis revealed that continuous and prolonged analysis of thrombosis is required to capture the role of platelet signaling pathways in their entirety. Furthermore, studies evaluating the thrombotic profiles of 20 healthy volunteers treated with aspirin, clopidogrel or their combination indicated that while three individuals did not benefits from either aspirin or clopidogrel treatments, all individuals displayed marked destabilization profiles when treated with the combination regimen. CONCLUSIONS: These results show the utility of a simple perfusion chamber technology to assess in real time the activity of antiplatelet drugs and their combinations. It offers the opportunity to perform pharmacodynamic monitoring of arterial thrombosis in clinical trials and to investigate novel strategies directed at inhibiting thrombus stability in the management of cardiovascular disease.     

Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2

Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, shape, and mobility. Here we demonstrate that CD4+ T lymphocytes express the EphA1 and EphA4 receptors and that these cells bind the ligand ephrin-A1. Further we show ephrin-A1 expression in vivo on high endothelial venule (HEV) endothelial cells. Ephrin-A1 binding to CD4+ T cells stimulates both stromal cell-derived factor 1alpha (SDF-1alpha)- and macrophage inflammatory protein 3beta (MIP3beta)-mediated chemotaxis. In line with the increased chemotactic response, increased actin polymerization is observed in particular with the combination of ephrin-A1 and SDF-1alpha. Signaling through EphA receptors induces intracellular tyrosine phosphorylation. In particular, proline-rich tyrosine kinase 2 (PYK2) is phosphorylated on tyrosine residues 402 and 580. Ephrin-A1-induced chemotaxis and intracellular tyrosine phosphorylation, including EphA1 and Pyk2, was inhibited by Tyrphostin-A9. In conclusion, ligand engagement of EphA receptors on CD4+ T cells stimulates chemotaxis, induces intracellular tyrosine phosphorylation, and affects actin polymerization. This, together with our finding that ephrin-A1 is expressed by HEV endothelial cells, suggests a role for Eph receptors in transendothelial migration.     

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca(2+) permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca(2+) influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans.     

Cardiovascular Reactivity in Patients with Essential or Renal Hypertension under Standardized Mental Stress

Introduction. Patients with essential hypertension react more strongly to mental stress than normotensives. This may be related to the type of stress coping or to increased reactivity associated with the disease. The aim of our study was to examine whether patients with essential or secondary hypertension differ in their reaction to mental stress. Methods. Seventeen patients with essential hypertension (EH), 9 patients with renal hypertension (RH), and 22 normotensive controls (N) with no circulatory disorders were subjected to a psychophysiological examination under mental stress. Blood pressure (BP), heart rate (HR) and electrodermal activity (EDA) were measured. Results. The two hypertensive groups differed in their BP reaction to mental stress from the control group but not from each other. The product of heart rate and systolic blood pressure during the matrix test was significantly higher in essential than renal hypertensives (EH median: 13344; RH median: 12154.5; p?=?0.04). This also holds true for the number of spontaneous fluctuations of EDA in the resting phase after the experiment (EH. median: 3.2; RH. median: 1.3; p?=?0.01). Conclusion. The results suggest that not only a high blood pressure level but also the sympathetic nervous tone are responsible for the blood pressure response to mental stress. Due to very different (perhaps psychosocially triggered) conditions, essential hypertension leads to a stronger cardiovascular reaction under mental stress than renal hypertension.     

Risk factors for recurrence after acute colonic diverticulitis: a systematic review

Purpose

Several factors may influence the risk of recurrence after an episode of acute colonic diverticulitis. Until now, a comprehensive systematic overview and evaluation of relevant risk factors have not been presented. This review aimed at assembling and evaluating current evidence on risk factors for recurrence after conservatively treated acute colonic diverticulitis.

Methods

PubMed, Embase, and Cochrane databases were searched for studies evaluating risk factors for recurrence after acute diverticulitis treated non-surgically defined as antibiotic treatment, percutaneous abscess drainage, or by observation. Randomized clinical trials and observational studies were included. Analyzed outcome variables were extracted and grouped. No meta-analysis was performed due to low inter-study comparability. Variables were rated according to their likelihood of causing recurrence (no/low, medium, high).

Results

Of 1153 screened records, 35 studies were included, enrolling 396,676 patients with acute diverticulitis. A total of 50,555 patients experienced recurrences. Primary diverticulitis with abscess formation and young age increased the risk of recurrence. Readmission risk was higher within the first year after remission. In addition, the risk of subsequent diverticulitis more than doubled after two earlier episodes of diverticulitis and the risk increased further for every episode.

Conclusions

The best treatment strategy for recurrent diverticulitis is undetermined. However, the risk of a new recurrence seemed to increase after each recurrence making elective resection a viable option at some point after multiple recurrences depending on patient risk factors and preferences.