Utility of FRET in studies of membrane protein oligomerization: The concept of the effective dissociation constant.

The activity of many membrane receptors is controlled through their lateral association into dimers or higher-order oligomers. Although Förster resonance energy transfer (FRET) measurements have been used extensively to characterize the stability of receptor dimers, the utility of FRET in studies of larger oligomers has been limited. Here we introduce an effective equilibrium dissociation constant that can be extracted from FRET measurements for EphA2, a receptor tyrosine kinase (RTK) known to form active oligomers of heterogeneous distributions in response to its ligand ephrinA1-Fc. The newly introduced effective equilibrium dissociation constant has a well-defined physical meaning and biological significance. It denotes the receptor concentration for which half of the receptors are monomeric and inactive, and the other half are associated into oligomers and are active, irrespective of the exact oligomer size. This work introduces a new dimension to the utility of FRET in studies of membrane receptor association and signaling in the plasma membrane.

The efficacy of receptor tyrosine kinase EphA2 autophosphorylation increases with EphA2 oligomer size.

The receptor tyrosine kinase (RTK) EphA2 is expressed in epithelial and endothelial cells and controls the assembly of cell-cell junctions. EphA2 has also been implicated in many diseases, including cancer. Unlike most RTKs, which signal predominantly as dimers, EphA2 readily forms high-order oligomers upon ligand binding. Here, we investigated if a correlation exists between EphA2 signaling properties and the size of the EphA2 oligomers induced by multiple ligands, including the widely used ephrinA1-Fc ligand, the soluble monomeric m-ephrinA1, and novel engineered peptide ligands. We used fluorescence intensity fluctuation (FIF) spectrometry to characterize the EphA2 oligomer populations induced by the different ligands. Interestingly, we found that different monomeric and dimeric ligands induce EphA2 oligomers with widely different size distributions. Our comparison of FIF brightness distribution parameters and EphA2 signaling parameters reveals that the efficacy of EphA2 phosphorylation on tyrosine 588, an autophosphorylation response contributing to EphA2 activation, correlates with EphA2 mean oligomer size. However, we found that other characteristics, such as the efficacy of AKT inhibition and ligand bias coefficients, appear to be independent of EphA2 oligomer size. Taken together, this work highlights the utility of FIF in RTK signaling research and demonstrates a quantitative correlation between the architecture of EphA2 signaling complexes and signaling features.

Vidian Canal as a Transcranial Landmark: Anatomy, Technique, and Illustrative Cases.

Objective The vidian nerve can be accessed in transcranial approaches in carefully selected patients to ensure its preservation and to serve as a landmark for sphenoid sinus entry. This report is to review a technique, evaluate it in laboratory settings, and present two illustrative cases. Design The study involves cadaveric dissection and illustrative cases. Setting The study conducted in a cadaveric dissection laboratory. Participants The object of the study is one cadaveric head and two illustrative clinical cases. Main Outcome Measures Two cases using this approach were illustrated, and a cadaver dissection was performed in a step-by-step fashion. Results: The vidian canal can be accessed by drilling the anterolateral triangle. Two illustrated cases were presented; in one, the vidian nerve was used as part of a corridor to access the sphenoid sinus for tumor delivery, and in the other, the technique was used to find and preserve the vidian nerve during transcranial resection. Conclusion Careful identification of the vidian canal in transcranial surgery is a beneficial technique in carefully selected cases which allows identification of the nerve both for its preservation in selected cases and to create the vidian-maxillary corridor for tumor resection. Knowing the anatomy and pneumatization variants is important in the surgical approach.

Utility of machine learning algorithms in degenerative cervical and lumbar spine disease: a systematic review.

Machine learning is a rapidly evolving field that offers physicians an innovative and comprehensive mechanism to examine various aspects of patient data. Cervical and lumbar degenerative spine disorders are commonly age-related disease processes that can utilize machine learning to improve patient outcomes with careful patient selection and intervention. The aim of this study is to examine the current applications of machine learning in cervical and lumbar degenerative spine disease. A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of PubMed, Embase, Medline, and Cochrane was conducted through May 31st, 2020, using the following terms: "artificial intelligence" OR "machine learning" AND "neurosurgery" AND "spine." Studies were included if original research on machine learning was utilized in patient care for degenerative spine disease, including radiographic machine learning applications. Studies focusing on robotic applications in neurosurgery, navigation, or stereotactic radiosurgery were excluded. The literature search identified 296 papers, with 35 articles meeting inclusion criteria. There were nine studies involving cervical degenerative spine disease and 26 studies on lumbar degenerative spine disease. The majority of studies for both cervical and lumbar spines utilized machine learning for the prediction of postoperative outcomes, with 5 (55.6%) and 15 (61.5%) studies, respectively. Machine learning applications focusing on degenerative lumbar spine greatly outnumber the current volume of cervical spine studies. The current research in lumbar spine also demonstrates more advanced clinical applications of radiographic, diagnostic, and predictive machine learning models.

Spontaneous coronary artery dissection in cutis laxa.

We describe the case of a 21-year-old female with Cutis Laxa presenting with an acute coronary syndrome. A CT coronary angiogram (CTCA) diagnosed spontaneous coronary artery dissection (SCAD) of the right coronary artery, which was successfully managed with medical therapy. Cutis Laxa is a rare connective-tissue disorder in which the skin becomes inelastic. Lax, redundant skin hangs in folds give a prematurely aged appearance and several forms of the disease have been described. Although certain cardiovascular complications are recognised in Cutis Laxa, to our knowledge SCAD has not been previously described. SCAD is an uncommon cause of acute coronary syndrome and sudden cardiac death. The condition particularly affects young females, those with connective tissue diseases, arteriopathies, pregnant females, contraceptive use and cocaine use. Atherosclerotic risk factors are seldom reported. The condition is underdiagnosed as symptoms may not generate a high index of clinical suspicion in this demographic. Diagnosis is traditionally made on invasive coronary angiogram although the procedure carries risks in SCAD and non-invasive CTCA should be considered in appropriately selected patient cohorts or as an adjunctive measure to assess for extracoronary vascular abnormalities. Our patient was diagnosed on CTCA, avoiding the need for invasive catheter angiogram.

Robotics in spine surgery: A systematic review.

Robotic systems to assist with pedicle screw placement have recently emerged in the field of spine surgery. Here, the authors systematically reviewed the literature for evidence of these robotic systems and their utility. Thirty-four studies that reported the use of spinal instrumentation with robotic assistance and met inclusion criteria were identified. The outcome measures gathered included: pedicle screw accuracy, indications for surgery, rates of conversion to an alternative surgical method, radiation exposure, and learning curve. In our search there were five different robotic systems identified. All studies reported accuracy and the most commonly used accuracy grading scale was the Gertzbein Robbins scale (GRS). Accuracy of clinically acceptable pedicle screws, defined as < 2 mm cortical breech, ranged from 80% to 100%. Many studies categorized indications for robotic surgery with the most common being degenerative entities. Some studies reported rates of conversion from robotic assistance to manual instrumentation due to many reasons, with robotic failure as the most common. Radiation exposure data revealed a majority of studies reported less radiation using robotic systems. Studies looking at a learning curve effect with surgeon use of robotic assistance were not consistent across the literature. Robotic systems for assistance in spine surgery have continued to improve and the accuracy of pedicle screw placement remains superior when compared to free-hand technique, however rates of manual conversion are significant. Currently, these systems are successfully employed in various pathological entities where trained spine surgeons can be safe and accurate regardless of robotic training.

Beyond the balloon: excimer coronary laser atherectomy used alone or in combination with rotational atherectomy in the treatment of chronic total occlusions, non-crossable and non-expansible coronary lesions.

AIMS: To establish success and complication rates of excimer laser coronary atherectomy (ELCA) in a contemporary series of patients with balloon failure during percutaneous coronary intervention (PCI) of both chronic total occlusions (CTO) and lesions with distal TIMI 3 flow. METHODS AND RESULTS: We identified 58 cases of balloon failure treated with ELCA±rotational atherectomy (RA) over four years, representing 0.84% of all PCI performed in our centre during this period. Balloon failures were classified according to: (i) mechanism of balloon failure; and (ii) whether this occurred in the context of treating a CTO. ELCA was performed following balloon failure using the CVX-300 Excimer Laser System and a 0.9 mm catheter with saline flush. For the entire cohort, procedure success was achieved in 91% (with ELCA successful: alone in 76.1%, after RA failure in 6.8% and in combination with RA for 8.6%). Only in one case did RA succeed where ELCA had failed. There were four procedure-related complications, including transient no-reflow, side branch occlusion and two coronary perforations, of which one was directly attributable to ELCA and led to subsequent mortality. CONCLUSIONS: ELCA provides safe and effective adjunctive therapy in contemporary PCI to treat lesions associated with balloon failure due to an inability either to cross the lesion or to expand a balloon sufficiently to permit stenting. ELCA was successful in the majority of these selected cases when used independently with further effectiveness achieved when combined with RA or after RA failure.

Treatment of coronary aneurysms with covered stents: a review with illustrated case.

Coronary aneurysms are found in approximately 5% of patients undergoing coronary angiography. Most coronary artery aneurysms (CAAs) are associated with significant stenosis of the coronary lumen; however, there is no common consensus on the treatment of coronary aneurysms. A large aneurysm in the coronary artery makes the blood flow turbulent and predisposes to thrombus formation and coronary artery obstruction even without the presence of significant stenosis. Despite this important anatomical abnormality of the coronary artery, the treatment options are poorly understood and present a therapeutic challenge to the interventional cardiologist. While treating CAAs with percutaneous implantation of covered stents offers a less invasive option compared to surgical correction, the short- and long-term outcomes are unknown. In this article, we have reviewed the literature and discussed the pathophysiology, clinical importance, and treatment options for CAAs. The illustrated case demonstrates a difficult situation in the management of CAA with interesting images, including coronary angiography, intravascular ultrasound, and transesophageal echocardiography of the complication encountered in this particular case.

A spontaneous coronary arterial dissection associated with a calcineurin inhibitor.

We present the case of a 55-year-old lady presenting 5 months after a liver transplant with acute coronary syndrome. She was on maintenance-dose tacrolimus. An angiogram diagnosed a spontaneous coronary artery dissection, which was successfully stented. This is the third case in the literature associating a calcineurin inhibitor with a spontaneous coronary arterial dissection. The detrimental effect of calcineurin inhibitors on vasculature is well recognised. This report highlights their potentially serious side-effects. It should be appreciated that calcineurin inhibitors have the potential to cause or contribute to this rare vascular phenomenon and the diagnosis should therefore be considered in those taking such drugs.

How should I treat severe calcific coronary artery disease?

BACKGROUND: An 80-year-old man with limiting angina pectoris. INVESTIGATION: Physical examination, laboratory tests, echocardiography, exercise ECG, coronary arteriography, pressure wire assessment. DIAGNOSIS: Single severe calcific coronary artery disease. TREATMENT: Elective percutaneous coronary intervention (PCI) for calcific mid-vessel stenosis with rotational and excimer laser atherectomy.

Use of a novel pericardial covered stent to seal an iatrogenic coronary perforation.

Iatrogenic coronary perforation complicates 0.1-0.8% of percutaneous coronary interventional (PCI) procedures. The incidence is higher if atheroablative therapy is used. When coronary perforation occurs, it may rapidly result in cardiac tamponade, myocardial infarction or death, hence prompt treatment is required. PTFE-covered stents have been used to seal coronary perforations, but these are bulky devices that lack flexibility, and rapid deployment in calcified or tortuous vessels can be difficult, particularly in emergency situations. Furthermore, difficulties in achieving adequate stent expansion and the prospect of delayed re-endothelialization have led to concern about the increased potential for stent thrombosis or restenosis. We present the first report of the successful use of a novel, highly deliverable pericardial covered stent to treat an iatrogenic coronary perforation during PCI, with angiographic follow up.

A novel strategy for managing clopidogrel-induced adverse skin reactions.

AIMS: We conducted a prospective observational study using a course of steroids and antihistamines to treat a cohort of patients who developed skin reactions to clopidogrel, to assess whether dual antiplatelet therapy could be continued in an outpatient setting. METHODS AND RESULTS: This study included 2,701 patients who underwent percutaneous coronary intervention (PCI) at our centre over a 23 month period. Patients with skin reactions to clopidogrel were identified and then commenced on five days oral prednisolone (30 mg/od) and chlorpheniramine (4 mg/tds) for seven days. A subsequent telephone survey was performed to evaluate a number of variables. The probability of the adverse reaction being secondary to clopidogrel was assessed using the Naranjo adverse drug reaction probability scale. Twenty (0.7%) patients were identified who developed adverse skin reactions to clopidogrel. There was complete resolution seen in the majority (89%) of patients within an average of 3.2 days following treatment. One patient had partial resolution, and one had no response to treatment, but both were able to continue clopidogrel. CONCLUSIONS: We propose a novel, safe and effective way of managing clopidogrel-induced skin reactions using a short course of prednisolone and chlorpheniramine, without stopping or substituting clopidogrel.

Malignancy: an unrecognized risk factor for coronary stent thrombosis?

Stent thrombosis is a potentially catastrophic complication of coronary artery stenting. There have been particular concerns about the incidence of stent thrombosis following insertion of drug-eluting stents. We report a series of cases in which stent thrombosis occurred in association with malignancy and describe the potential mechanisms behind such an association. We speculate that this association merits further investigation as it raises the possibility that known malignancy may be a risk factor for stent thrombosis and that unexplained stent thrombosis, particularly if recurrent, should stimulate a search for occult malignancy.

Thrombolytics: prospects for new agents.

Thrombolytic therapy revolutionised the management of acute myocardial infarction (AMI). The ability to re-establish coronary artery patency with intravenous thrombolytic drugs has transformed our therapeutic approach, despite patency failures and re-occlusions. However, the established agents are not perfect and a number of novel thrombolytic drugs have consequently been developed and evaluated. This article reviews the currently available agents, discusses available adjunctive therapies and examines the future developments that may affect the application of this therapy.