Flow diversion treatment: intra-aneurismal blood flow velocity and WSS reduction are parameters to predict aneurysm thrombosis

Background: To evaluate the haemodynamic changes induced by flow diversion treatment in cerebral aneurysms, resulting in thrombosis or persisting aneurysm patency over time. Method: Eight patients with aneurysms at the para-ophthalmic segment of the internal carotid artery were treated by flow diversion only. The clinical follow-up ranged between 6days and 12months. Computational fluid dynamics (CFD) analysis of pre- and post-treatment conditions was performed in all cases. True geometric models of the flow diverter were created and placed over the neck of the aneurysms by using a virtual stent-deployment technique, and the device was simulated as a true physical barrier. Pre- and post-treatment haemodynamics were compared, including mean and maximal velocities, wall-shear stress (WSS) and intra-aneurysmal flow patterns. The CFD study results were then correlated to angiographic follow-up studies. Results: Mean intra-aneurysmal flow velocities and WSS were significantly reduced in all aneurysms. Changes in flow patterns were recorded in only one case. Seven of eight aneurysms showed complete occlusion during the follow-up. One aneurysm remaining patent after 1year showed no change in flow patterns. One aneurysm rupturing 5days after treatment showed also no change in flow pattern, and no change in the maximal inflow velocity. Conclusions: Relative flow velocity and WSS reduction in and of itself may result in aneurysm thrombosis in the majority of cases. Flow reductions under aneurysm-specific thresholds may, however, be the reason why some aneurysms remain completely or partially patent after flow diversio

A new-generation, low-permeability flow diverting device for treatment of saccular aneurysms

Objectives: We report a preclinical comparative study of a 96-strand braided flow diverter. Methods: The 96-strand braided device was compared with the currently commercially available flow diverter with 48 strands. The devices were implanted across the neck of 12 elastase-induced aneurysms in New Zealand White rabbits and followed for 1 and 3months (n = 6 respectively). Aneurysm occlusion rates, parent artery stenosis and patency of jailed branch occlusions were assessed by angiography, histology and scanning electron microscopy studies. Results: It was feasible to navigate and implant the 96-strand device over the aneurysm orifice in all cases. At follow-up two aneurysms in the 48-strand vs. one in the 96-strand group were not occluded. This aneurysm from the 96-strand group however had a tracheal branch arising from the sac and showed a reverse remodelling of the vascular pouch at 3months. In the occluded aneurysms, the parent artery was always completely reconstructed and the aneurysm orifice was sealed with neointimal tissue. No in-stent stenosis or jailed branch artery occlusion was observed. Conclusions: The 96-strand flow diverter proved to be safe, biocompatible and haemodynamically effective, induced stable occlusion of aneurysms and led to reverse remodelling of the parent artery. Key points : • Flow diversion has been introduced to improve endovascular treatment of cerebral aneurysms • A new low-permeability flow diverter is feasible for parent artery reconstruction. • The Silk 96 flow diverter appears effective at inducing aneurysm healing. • The covered branches remained patent at follow-up

Flow diversion treatment: intra-aneurismal blood flow velocity and WSS reduction are parameters to predict aneurysm thrombosis

To evaluate the haemodynamic changes induced by flow diversion treatment in cerebral aneurysms, resulting in thrombosis or persisting aneurysm patency over time. Eight patients with aneurysms at the para-ophthalmic segment of the internal carotid artery were treated by flow diversion only. The clinical follow-up ranged between 6 days and 12 months. Computational fluid dynamics (CFD) analysis of pre- and post-treatment conditions was performed in all cases. True geometric models of the flow diverter were created and placed over the neck of the aneurysms by using a virtual stent-deployment technique, and the device was simulated as a true physical barrier. Pre- and post-treatment haemodynamics were compared, including mean and maximal velocities, wall-shear stress (WSS) and intra-aneurysmal flow patterns. The CFD study results were then correlated to angiographic follow-up studies. Mean intra-aneurysmal flow velocities and WSS were significantly reduced in all aneurysms. Changes in flow patterns were recorded in only one case. Seven of eight aneurysms showed complete occlusion during the follow-up. One aneurysm remaining patent after 1 year showed no change in flow patterns. One aneurysm rupturing 5 days after treatment showed also no change in flow pattern, and no change in the maximal inflow velocity. Relative flow velocity and WSS reduction in and of itself may result in aneurysm thrombosis in the majority of cases. Flow reductions under aneurysm-specific thresholds may, however, be the reason why some aneurysms remain completely or partially patent after flow diversion

Targeting Apoptotic Pathway of Cancer Cells with Phytochemicals and Plant-Based Nanomaterials

Apoptosis is the elimination of functionally non-essential, neoplastic, and infected cells via the mitochondrial pathway or death receptor pathway. The process of apoptosis is highly regulated through membrane channels and apoptogenic proteins. Apoptosis maintains cellular balance within the human body through cell cycle progression. Loss of apoptosis control prolongs cancer cell survival and allows the accumulation of mutations that can promote angiogenesis, promote cell proliferation, disrupt differentiation, and increase invasiveness during tumor progression. The apoptotic pathway has been extensively studied as a potential drug target in cancer treatment. However, the off-target activities of drugs and negative implications have been a matter of concern over the years. Phytochemicals (PCs) have been studied for their efficacy in various cancer cell lines individually and synergistically. The development of nanoparticles (NPs) through green synthesis has added a new dimension to the advancement of plant-based nanomaterials for effective cancer treatment. This review provides a detailed insight into the fundamental molecular pathways of programmed cell death and highlights the role of PCs along with the existing drugs and plant-based NPs in treating cancer by targeting its programmed cell death (PCD) network

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Repair of Iatrogenic Preterm Premature Rupture of Human Fetal Membranes

Preterm premature rupture of fetal membranes is a devastating complication of pregnancy with high risk of feto-maternal mortality and morbidity. Several attempts have been made to seal spontaneous and iatrogenic fetal membrane ruptures but none has made it to clinics. Persistent leakage of amniotic fluid following invasive surgical and diagnostic procedures jeopardize the benefit of such life saving interventions and draw the limits for the developing field of intrauterine fetal surgery. Efforts are directed to take action before the commencement of leakage of amniotic fluid rather than after the leakage in iatrogenic maneuver: one avenue of research focuses on prophylactic plugging of the fetoscopic lesion at the time of completion of the procedure, thus to increase the chance to prevent subsequent leakage of amniotic fluid. In order to design appropriate sealing strategies the knowledge of the mechanical and biological properties of intact and injured fetal membranes is indispensable. The objective of this thesis is on the one hand to develop regimen that allow the repair of fetal membranes by plugging membrane lesions with fetoscopical interventions. On the other hand, we concentrate on the description of biophysical parameters of the fetal membrane by establishing biomechanical test regimen. Towards a fetoscopic repair mechanism I have developed a method to decellularize amniotic membranes in order to produce a non-immunogenic material. These membranes proved to be stable enough for long term storage and for off-the-shelf use. In our animal trials using rabbit does, the material exhibited good handling properties as well as good sealing characteristics in absence of adverse biological effects. Although the plugs were at best marginally remodeled and populated with cells in these short term experiments in rabbits, the self locking features of the plugs and the predictably long term stability of the material might be a critically important for future clinical applications. Towards the mechanical characterization of the fetal membranes I have together with the group of Prof. Edoardo Mazza, Department for Mechanics, ETHZ worked on the establishment of a novel device, which allows the measurement of mechanical properties and the testing of membrane sealing regimen under near to physiological conditions. I have compared measurements of mechanical properties using this new generation device, which employs equibiaxial stretching with measurements performed with uniaxial stretching. These initial results indicate that the materials parameters can only be correctly estimated using biaxial stretching regimen and might add to the understanding of elastic and plastic features of biological membranes. Collectively a thorough understanding of mechanical and biological properties and the design of materials platforms that can be adapted to the tissue requirements might only approach the complexity of this problem. Although much more research is needed, we think that our results on the membrane repair and the mechanical properties presented in this thesis are promising starting points towards the establishment of appropriate treatment regimen for PPROM of fetal membranes. Der frühe vorzeitige Blasensprung (PPROM) ist eine gravierende Komplikation während der Schwangerschaft und ist mit einem grossen Risiko für feto-maternale Morbidität und Mortalität verbunden. Verschiedene Versuche wurden unternommen um spontane und iaterogene Rupturen der fetalen Membran zu verschliessen, bisher konnte jedoch keine dieser Methoden in die Klinik eingeführt werden. Der anhaltende Verlust von Amnionflüssigkeit infolge invasiver chirurgischer und diagnostischer Eingriffe gefährdet den Erfolg von potentiell lebensrettenden Interventionen, und limitiert daher die Weiterentwicklung der intrauterinen fetalen Chirurgie. Gegenwärtige Anstrengungen fokussieren darauf zu handeln, bevor die Amnionflüssigkeit austritt, anstatt das Ausrinnen nach einem iaterogenen Eingriff abzuwarten. So gilt eine Forschungsrichtung dem prophylaktischen Verschluss der fetoskopischen Wunde im Anschluss an den Eingriff, um das Risiko eines nachfolgenden Flüssigkeitsaustrittes zu vermeiden. Um geeignete Verschlussstrategien entwerfen zu können, sind Kenntnisse hinsichtlich biologischen und mechanischen Eigenschaften von intakten und verletzten fetalen Membranen unabdingbar. Das Ziel dieser Doktorarbeit ist einerseits eine Behandlung zu entwickeln, die die Reparatur von fetalen Membranen mittels Verstopfen der Membranläsion durch Fetoskopie erlaubt. Ein weiteres Ziel ist die Charakterisierung von biophysikalischen Parametern der fetalen Membranen, welches auch die Entwicklung einer biomechanischen Testprozedur beinhaltet. Bezüglich fetoskopischer Reparaturmechanismen habe ich eine Methode zur Dezellularisierung von Amnionmembranen entwickelt, um daraus ein nicht immunogenes Material zu gewinnen. Diese dezellularisierten Membranen sind für die Langzeit-Lagerung geeignet und können daher serienmässig produziert und eingesetzt zu werden. In unseren Versuchen mit trächtigen Kaninchen zeigte das Material gute Handhabungs- und Verschlusseigenschaften ohne nachteilige biologische Effekte aufzuweisen. Obwohl die Verschlusspfropfen in diesen Kurzzeit-Experimenten nur geringfügig umgebaut und durch Zellen besiedelt wurden, dürften die selbstverschliessenden Eigenschaften der Pfropfen und deren voraussichtlich gute Langzeit-Stabilität wichtige Voraussetzungen für mögliche klinische Anwendungen erfüllen. Um die fetalen Membranen mechanisch zu charakterisieren, habe ich in Zusammenarbeit mit der Gruppe von Prof. Eduardo Mazza, Departement für Mechanik, ETHZ an der Entwicklung eines neuen Gerätes gearbeitet. Dieses erlaubt die Messung von mechanischen Eigenschaften und das Testen von Verschlussmethoden der fetalen Membranen unter nahezu physiologischen Bedingungen. Ich habe in der Folge mechanische Parameter verglichen, die mit dem weiterentwickelten Testgerät unter equibiaxialer Dehnung oder mittels uniaxialer Dehnung erhoben wurden. Diese ersten Ergebnisse deuten darauf hin, dass die Materialparameter nur durch biaxiale Ausdehnung der Membranen korrekt erhoben werden können. Die in dieser Arbeit präsentierten Daten können unserem Verständnis für die elastischen und plastischen Eigenschaften von biologischen Membranen beitragen. Insgesamt scheinen Lösungen zu diesem komplexen Problem nur durch das gründliche Verständnis der mechanischen und biologischen Eigenschaften sowie Materialien die den Bedürfnissen des Gewebes angepasst werden können, möglich zu sein. Obwohl weitere Untersuchungen benötigt werden, denken wir, dass unsere Resultate bezüglich Reparatur und Mechanik der fetalen Membran ein vielversprechender Anfang zur Etablierung von Behandlungsmethoden von PPROM darstellen

Using Protein Dimers to Maximize the Protein Hybridization Efficiency with Multisite DNA Origami Scaffolds

<div><p>DNA origami provides a versatile platform for conducting ‘architecture-function’ analysis to determine how the nanoscale organization of multiple copies of a protein component within a multi-protein machine affects its overall function. Such analysis requires that the copy number of protein molecules bound to the origami scaffold exactly matches the desired number, and that it is uniform over an entire scaffold population. This requirement is challenging to satisfy for origami scaffolds with many protein hybridization sites, because it requires the successful completion of multiple, independent hybridization reactions. Here, we show that a cleavable dimerization domain on the hybridizing protein can be used to multiplex hybridization reactions on an origami scaffold. This strategy yields nearly 100% hybridization efficiency on a 6-site scaffold even when using low protein concentration and short incubation time. It can also be developed further to enable reliable patterning of a large number of molecules on DNA origami for architecture-function analysis.</p></div

The effect of a myocardial infarction on the normalized time-varying elastance curve

It has been suggested that the shape of the normalized time-varying elastance curve [E(n)(t(n))] is conserved in different cardiac pathologies. We hypothesize, however, that the E(n)(t(n)) differs quantitatively after myocardial infarction (MI). Sprague-Dawley rats (n = 9) were anesthetized, and the left anterior descending coronary artery was ligated to provoke the MI. A sham-operated control group (CTRL) (n = 10) was treated without the MI. Two months later, a conductance catheter was inserted into the left ventricle (LV). The LV pressure and volume were measured and the E(n)(t(n)) derived. Slopes of E(n)(t(n)) during the preejection period (alpha(PEP)), ejection period (alpha(EP)), and their ratio (beta = alpha(EP)/alpha(PEP)) were calculated, together with the characteristic decay time during isovolumic relaxation (tau) and the normalized elastance at end diastole (E(min)(n)). MI provoked significant LV chamber dilatation, thus a loss in cardiac output (-33%), ejection fraction (-40%), and stroke volume (-30%) (P < 0.05). Also, it caused significant calcium increase (17-fold), fibrosis (2-fold), and LV hypertrophy. End-systolic elastance dropped from 0.66 +/- 0.31 mmHg/microl (CTRL) to 0.34 +/- 0.11 mmHg/microl (MI) (P < 0.05). Normalized elastance was significantly reduced in the MI group during the preejection, ejection, and diastolic periods (P < 0.05). The slope of E(n)(t(n)) during the alpha(PEP) and beta were significantly altered after MI (P < 0.05). Furthermore, tau and end-diastolic E(min)(n) were both significantly augmented in the MI group. We conclude that the E(n)(t(n)) differs quantitatively in all phases of the heart cycle, between normal and hearts post-MI. This should be considered when utilizing the single-beat concept