Retrograde Delivery Research Articles

Virus-mediated neuron-specific retrograde gene delivery in spinal cord injury

To support neuronal function and restoration, virus-mediated neuron-specific retrograde transport is an effective tool for determining the localization of neuronal somas, identifying interneuronal connections, and facilitating the retrograde delivery of therapeutic transgenes. In experimental spinal cord injury, the retrograde transport of therapeutic transgenes offers several advantages over other more common delivery methods, such as targeted transfer of genetic constructs to specific types of spinal neuron somas, low invasiveness, relatively low risk of inflammatory response, and potential for repeated injections. Research on retrograde transport has extensively focused on enhancing its efficiency through capsid modification and application of novel promoters. This review presents a detailed examination of the outcomes of virus-mediated neuron-specific retrograde transduction of transgenes after intramuscular injection of genetic constructs. In retrograde delivery technology, the ability to choose between monosynaptic and polysynaptic transports, depending on the specific viral vector used, was a positive aspect. The review also addresses the effects of virus-mediated retrograde transduction on both spinal motoneurons and interneurons, which collectively form motor neuronal networks. By delivering transgenes through retrograde transport along axons from the periphery to the perikarya of spinal neurons, not only localized effects within the spinal cord but also in supraspinal structures can be anticipated, a crucial aspect in restoring extensive neural connections.

Unloading the left ventricle in VA-ECMO: a comparative analysis of outcomes

Abstract Funding Acknowledgements None. Introduction Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) has radically changed the way we see and treat cardiogenic shock, despite the challenges it presents. The retrograde delivery of oxygenated blood to the aorta via the arterial cannula imposes increased afterload on an already strained left ventricle (LV). Unloading techniques aim to reduce the preload and afterload caused by VA-ECMO on the LV. Purpose Our study aims to compare the clinical outcomes of patients on VA-ECMO where additional invasive techniques were employed to unload the LV, against those without unloading strategies. Methods Patients treated with VA-ECMO in our hospital since 2012 were categorized into two groups: the Venting Group (VG) that received LV unloading interventions and the Non-Venting Group (NVG) without such interventions. We collected comprehensive clinical data, including demographics, baseline characteristics, ECMO-related parameters, in-hospital complications, and patient outcomes. Statistical analyses involved chi-square tests for categorical variables and independent samples t-tests for continuous variables to assess the impact of unloading strategies on patient outcomes. Results Our hospital treated 100 patients with VA-ECMO (mean age 58.4 ± 11.9 years, 60% male). Approximately 39% of patients received LV unloading support. The choice of unloading device was guided by our center's expertise. Most commonly, Intra-Aortic Balloon Pump (IABP) was used (61.5%), followed by Impella CP (23.1%), percutaneous atrial septostomy (2.6%) and surgical LV venting (12.8%). Unloading techniques were implemented either concurrently with VA-ECMO cannulation (58.9%), before (17.9%), or after its insertion (23.2%). Most patients (68%) received inotropic drugs, predominantly dobutamine. The mean duration of venting device use was 4.2 ± 3.8 days. Airway bleeding (3.3% NVG vs. 17.9% VG, p=0.032) and thromboembolic complications (19.7% NVG vs. 41.0% VG, p=0.036) were significantly more prevalent in the VG. There were no significant differences in the others reported ECMO-related complications. No significant differences were observed in the mean duration of support with VA-ECMO (3 days NVG vs. 4 days VG, p=0.147) or in the mean duration of hospitalization (13 days NVG vs. 12 VG, p=0.619) between the two groups. The 30-day survival rates were 42% (95% CI, 0.30-0.59) in NVG and 29% (95% CI, 0.18-0.49) in VG, which did not display statistical significance, p=0.24 [Figure 1]. Conclusions In our cohort, incorporating unloading devices alongside VA-ECMO did not yield major differences in survival rates, yet led to a considerable increase in airway bleeding and thromboembolic complications. The precocity of unloading device implantation occurred either as an initial strategy or to prevent increased afterload in hearts with limited contractile reserve.Characteristics and Clinical OutcomesSurviving Curves VG vs. NVG

Disruption of axonal transport in neurodegeneration.

Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.

First in Human Implantation of the Thoracoflo Graft: A New Hybrid Device for Thoraco-Abdominal Aortic Repair

Despite a high rate of success when performed in specialised centres, current techniques for thoraco-abdominal aortic repair are associated with serious complications. The problem of spinal cord ischaemia remains unsolved. The new hybrid graft for thoraco-abdominal aortic repair was developed based on the frozen elephant trunk principle. The device consists of a proximal stent graft for transabdominal retrograde delivery to the descending thoracic aorta, combined with a distal six branched abdominal device for open aortic repair. An additional seventh branch is provided for possible lumbar artery re-implantation. Because the stent graft is implanted via a transabdominal approach, it avoids the need for thoracotomy and extracorporeal circulation. A 56 year old patient with Loeys-Dietz syndrome was placed in a supine position. The aorto-iliac axis was exposed via a midline transperitoneal approach. Following an end to side anastomosis of the iliac branch to the left common iliac artery, the stent graft portion was inserted into the thoracic aorta via the coeliac trunk ostium. After stent implantation and graft de-airing by needle puncture, retrograde blood flow to the abdominal aortic segment, and the lumbar and visceral arteries was established via the end to side iliac anastomosis creating an extra-anatomic bypass. Subsequently, the visceral and renal arteries were anastomosed to the branches. Finally, the aorta was opened and surgical graft attached via the collar. The reconstruction ended with end to end anastomoses of both common iliac arteries to the graft branches. The first and successful implantation of the new Thoracoflo hybrid device via a novel surgical technique is reported, eliminating the need for thoracotomy and extracorporeal circulation for thoraco-abdominal aortic repair.

Two approaches in the treatment of malignant obstructive jaundice using nitinol stents

The article presents our experience of observing two different approaches for endoscopic retrograde drainage in patients with malignant pathology of the pancreatobiliary zone, complicated by the bile duct obstruction. In one case, in case of dysfunction of the installed uncovered stent as a result of incrustation with bile salts and/or tumor invasion, stent-to-stent restenting was performed. In the second case, if it was impossible to pass the guidewire retrogradely beyond the area of the tumor narrowing, an alternative method was used – bringing it down by percutaneous transhepatic access towards the endoscope to install a retrograde stent delivery system along it using the "Rendezvous" method.

Recombinant Adenoviruses for Delivery of Therapeutics Following Spinal Cord Injury.

The regeneration of nerve tissue after spinal cord injury is a complex and poorly understood process. Medication and surgery are not very effective treatments for patients with spinal cord injuries. Gene therapy is a popular approach for the treatment of such patients. The delivery of therapeutic genes is carried out in a variety of ways, such as direct injection of therapeutic vectors at the site of injury, retrograde delivery of vectors, and ex vivo therapy using various cells. Recombinant adenoviruses are often used as vectors for gene transfer. This review discusses the advantages, limitations and prospects of adenovectors in spinal cord injury therapy.

Objective Content Validation of the Hemodynamic and Technical Parameters of the OrpheusTM Cardiopulmonary Bypass Simulator.

The utilization of simulators for training is increasing in the professions associated with cardiac surgery. Before applying these simulators to high-stakes assessment, the simulator's output data must be validated. The aim of this study is to validate a Cardiopulmonary Bypass (CPB) simulator by comparing the simulated hemodynamic and technical outputs to published clinical norms. Three Orpheus™ CPB simulators were studied and compared to a published reference of physiologic and technical metrics that are managed during clinical CPB procedures. The limits of the simulators user modifiable variables were interrogated across their full range and the results were plotted against the published clinical norms. The data generated with the simulator conforms to validated clinical parameters for patients between 50 and 110 kg. For the pre- and post-CPB periods, the independent variables of central venous pressure (CVP), heart rate (HR), contractility, and systemic vascular resistance (SVR) must be operated between the limits of 7 and 12 mmHg, 65 and 110 beats/min, 28% and 65%, and 6 and 32 units respectively. During full CPB the arterial pump flows should be maintained between 3.5 and 5.5 LPM and SVR between 18 and 38 units. Validated technical parameters during cardioplegia delivery are expected at solution flow rates between 250 and 400 mL/min and 100 and 225 mL/min for antegrade and retrograde delivery routes, respectively. We have identified the limits for user-modifiable settings that produce data conforming to the physiologic and technical parameter limits reported in the peer reviewed literature. These results can inform the development of simulation scenarios used for high stakes assessments of personnel, equipment, and technical protocols.

Re-dosing of del Nido cardioplegia in adult cardiac surgery requiring prolonged aortic cross-clamp.

OBJECTIVESFew data exist on the use of del Nido cardioplegia in adults, specifically during operations requiring prolonged aortic cross-clamp. In this pilot study, we evaluate outcomes of patients undergoing surgery with cross-clamp time >3 h based on re-dosing strategy, using either full dose (FD; 1:4 blood to crystalloid ratio) or dilute (4:1 blood to crystalloid ratio) solution.METHODSConsecutive adult patients (>18 years) undergoing cardiac surgery from 2012 to 2018 with cross-clamp time >3 h were reviewed. Patients were excluded if del Nido cardioplegia was not used. Patients were categorized into FD or dilute groups based on re-dosing solution. Propensity score matching was used to control for baseline differences between groups. The primary endpoint was in-hospital mortality. Other outcomes examined included: postoperative mechanical support, arrhythmia, stroke, dialysis and cardiac function.RESULTSIncluded for analysis were 173 patients (115 male) with median age of 63.8 (interquartile range 53.9–73.1). Major comorbidities included diabetes (45), cerebrovascular disease (34), hypertension (131), atrial fibrillation (52) and previous cardiac surgery (83). There were 108 patients (62%) who received FD re-dosing, while 65 (38%) received dilute. A greater proportion of patients in the dilute group received retrograde delivery, for both induction (32/108 vs 39/65, P < 0.001) and re-dose (50/108 vs 53/65, P < 0.001). After propensity score matching, in-hospital mortality was not different between groups (6/48 vs 1/48, P = 0.131). There were no differences in rates of postoperative mechanical circulatory support, stroke, left ventricular ejection fraction or right ventricle dysfunction.CONCLUSIONSDel Nido cardioplegia has been used in complex cardiac surgery requiring prolonged cross-clamp. Re-dosing can be performed with either FD or dilute del Nido solution with no statistical difference in outcomes.

Chemogenetic inhibition of corticostriatal circuits reduces cued reinstatement of methamphetamine seeking.

Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.

Gene therapy for ischaemic heart disease and heart failure.

Gene therapy has been expected to become a novel treatment method since the structure of DNA was discovered in 1953. The morbidity from cardiovascular diseases remains remarkable despite the improvement of percutaneous interventions and pharmacological treatment, underlining the need for novel therapeutics. Gene therapy-mediated therapeutic angiogenesis could help those who have not gained sufficient symptom relief with traditional treatment methods. Especially patients with severe coronary artery disease and heart failure could benefit from gene therapy. Some clinical trials have reported improved myocardial perfusion and symptom relief in CAD patients, but few trials have come up with disappointing negative results. Translating preclinical success into clinical applications has encountered difficulties in successful transduction, study design, endpoint selection, and patient selection and recruitment. However, promising new methods for transducing the cells, such as retrograde delivery and cardiac-specific AAV vectors, hold great promise for myocardial gene therapy. This review introduces gene therapy for ischaemic heart disease and heart failure and discusses the current status and future developments in this field.

Antegrade Hybrid Chimney TEVAR Endograft in a Patient with Blunt Aortic Injury: A Challenging Case with Technical Success but Unfavorable Result

Thoracic Endovascular Aortic Repair (TEVAR) has modified aortic medicine, particularly in patients with traumatic aortic injury (TAI). Conventional repair of TAI in the aortic arch is technically demanding as it requires cardiopulmonary bypass and deep hypothermic arrest with still a significant number of complications. Despite recent improvements in endovascular techniques, many patients have been excluded from endovascular repair due to unfavorable anatomy. To increase the feasibility of endovascular repair, adjunctive open extra-anatomical bypasses may be required to provide an adequate proximal landing zone. Several methods, for instance, chimney technique, hybrid technique, and fenestrated or branched stent-grafts, have been proposed as options to preserve the supra-aortic branches, each with its own advantages and disadvantages. We herein present a patient with complex anatomical features and blunt aortic injury, who underwent antegrade chimney stent-graft deployment through the ascending aorta, not otherwise amenable to standard retrograde delivery because of severe peripheral artery disease. The remarkable aspect, in this case, is that both stents were placed antegrade, through the ascending aorta.

Combined kinesin-1 and kinesin-3 activity drives axonal trafficking of TrkB receptors in Rab6 carriers.

SummaryNeurons depend on proper localization of neurotrophic receptors in their distal processes for their function. The Trk family of neurotrophin receptors controls neuronal survival, differentiation, and remodeling and are well known to function as retrograde signal carriers transported from the distal axon toward the cell body. However, the mechanism driving anterograde trafficking of Trk receptors into the axon is not well established. We used microfluidic compartmental devices and inducible secretion assay to systematically investigate the retrograde and anterograde trafficking routes of TrkB receptor along the axon in rat hippocampal neurons. We show that newly synthesized TrkB receptors traffic through the secretory pathway and are directly delivered into axon. We found that these TrkB carriers associate and are regulated by Rab6. Furthermore, the combined activity of kinesin-1 and kinesin-3 is needed for the formation of axon-bound TrkB secretory carriers and their effective entry and processive anterograde transport beyond the proximal axon.

Second-Generation Spider-Graft: Development of the Novel Hybrid Thoracoabdominal Aorticdevice in a Porcine Model

Introduction - The SPIDER-graft was developed to avoid thoracotomy, extracorporeal circulation (ECC) and to reduce cross-clamping during thoracoabdominal aortic (TAA) repair time. The first generation reversed Frozen Elephant Trunk with proximal stentgraft for retrograde delivery to the descending thoracic aorta (DTA) and distal abdominal prostheses for open repair with four visceral and two iliac branches was further optimized (modification of the visceral branches and the introducer system) and compared to open aortic repair (OAR) in a pig model. Methods - Retroperitoneal access to the TAA was performed in 6 pigs per group (75-85kg). For OAR TAA exposure was required. After crossclamping proximal and distal aortic anastomosis were performed and successively celiac trunk (CT), superior mesenteric artery (SMA), right and left renal arteries (RA) and finally iliac arteries were implanted. For Spider-graft, retroperitoneal exposure of the infradiaphragmaitc aorta was performed. The right iliac branch was first temporarily anastomosed end-to-side to the distal aorta maintaining periprocedural retrograde visceral and antegrade aortoiliac blood flow. Proximal stent-grafted part was deployed in the DTA via the CT ostium. Visceral and renal arteries were successively anastomosed to the side-branches of the graft and lumbar arteries were reimplanted. Technical feasibility, operating and clamping time, blood flow and tissue perfusion in the related organs were evaluated before implantation and 3, and six hours after implantation using transit-time flow measurement (TTFM) and fluorescent microspheres (FM). After 6 hours observation, final angiography, post-procedural CT-angiography and histology was performed. Results - Graft deployment was successful in all 6 animals in both groups. All pigs were hemodynamically stable during the entire procedure. Total aortic clamping time was 88.3±16.3min during OAR and 4.2±1min during SPIDER-graft. Selective ischemic times of related organs were significantly longer during OAR. TTFM and FM confirmed clinical findings. Angiography and CT-scan confirmed successful graft implantation in both groups. Conclusion - Conclusion: SPIDER-graft can reduce crossclamping time, ischemic time, and avoid ECC and thoracotomy during TAA repair in a pig model. Hemodynamic stability can be achieved easier with less blood loss compared to OAR. The SPIDER-graft will be further modified to improve the handling and to enable reimplantation of lumbar arteries.

Unmodified autologous stem cells at point of care for chronic myocardial infarction.

BACKGROUNDNumerous studies investigated cell-based therapies for myocardial infarction (MI). The conflicting results of these studies have established the need for developing innovative approaches for applying cell-based therapy for MI. Experimental studies on animal models demonstrated the potential of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) for treating acute MI. In contrast, studies on the treatment of chronic MI (CMI; > 4 wk post-MI) with UA-ADRCs have not been published so far. Among several methods for delivering cells to the myocardium, retrograde delivery into a temporarily blocked coronary vein has recently been demonstrated as an effective option.AIMTo test the hypothesis that in experimentally-induced chronic myocardial infarction (CMI; > 4 wk post-MI) in pigs, retrograde delivery of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) into a temporarily blocked coronary vein improves cardiac function and structure.METHODSThe left anterior descending (LAD) coronary artery of pigs was blocked for 180 min at time point T0. Then, either 18 × 106 UA-ADRCs prepared at “point of care” or saline as control were retrogradely delivered via an over-the-wire balloon catheter placed in the temporarily blocked LAD vein 4 wk after T0 (T1). Effects of cells or saline were assessed by cardiac magnetic resonance (CMR) imaging, late gadolinium enhancement CMR imaging, and post mortem histologic analysis 10 wk after T0 (T2).RESULTSUnlike the delivery of saline, delivery of UA-ADRCs demonstrated statistically significant improvements in cardiac function and structure at T2 compared to T1 (all values given as mean ± SE): Increased mean LVEF (UA-ADRCs group: 34.3% ± 2.9% at T1 vs 40.4 ± 2.6% at T2, P = 0.037; saline group: 37.8% ± 2.6% at T1 vs 36.2% ± 2.4% at T2, P > 0.999), increased mean cardiac output (UA-ADRCs group: 2.7 ± 0.2 L/min at T1 vs 3.8 ± 0.2 L/min at T2, P = 0.002; saline group: 3.4 ± 0.3 L/min at T1 vs 3.6 ± 0.3 L/min at T2, P = 0.798), increased mean mass of the left ventricle (UA-ADRCs group: 55.3 ± 5.0 g at T1 vs 71.3 ± 4.5 g at T2, P < 0.001; saline group: 63.2 ± 3.4 g at T1 vs 68.4 ± 4.0 g at T2, P = 0.321) and reduced mean relative amount of scar volume of the left ventricular wall (UA-ADRCs group: 20.9% ± 2.3% at T1 vs 16.6% ± 1.2% at T2, P = 0.042; saline group: 17.6% ± 1.4% at T1 vs 22.7% ± 1.8% at T2, P = 0.022).CONCLUSIONRetrograde cell delivery of UA-ADRCs in a porcine model for the study of CMI significantly improved myocardial function, increased myocardial mass and reduced the formation of scar tissue.

Ministernotomy aortic valve surgery in patients with prior patent mammary artery grafts after coronary artery bypass grafting.

Patients with patent internal thoracic artery (ITA) grafts after prior coronary artery bypass grafting surgery who require aortic valve replacement (AVR) pose unique technical challenges for safe and optimal myocardial protection. The purpose of this study is to review our short- and long-term outcomes with redo minimally invasive AVR in patients with patent in situ ITA grafts. From 2008 to 2016, 48 patients with at least 1 patent in situ mammary artery graft underwent minimally invasive AVR. Preoperative computed tomography was performed in all patients to evaluate the relationship of patent grafts to the sternum. Retrograde coronary sinus and pulmonary vent catheters were placed via the right internal jugular vein. The in situ ITA grafts were not clamped during AVR. Transverse aortotomy, taking care to avoid the grafts arising from the aorta, was performed to expose the aortic valve. The median age of the patients was 78 years [Quartile 1 (Q1)-Quartile 3 (Q3): 71-81]. Thirty-nine (81%) patients were men, and 46 (96%) patients had aortic stenosis. The median cardiopulmonary bypass and cross-clamp times were 124 (Q1-Q3: 108-164) and 92 (Q1-Q3: 83-116) min, respectively. Moderate hypothermia at 28-30°C was used in all patients. Most patients received cold blood cardioplegia with antegrade induction and continuous retrograde delivery. Four patients received only retrograde delivery due to some degree of aortic insufficiency. Thirty-day mortality was 4% (2 of 48 patients). There was no conversion to full sternotomy, and no reoperations were performed for postoperative bleeding or sternal wound infection. Excluding the 2 patients who died in the hospital, the median postoperative length of stay was 7 days (Q1-Q3: 5-8). Overall survival at 1, 5 and 10 years was 94%, 87% and 44%, respectively. Percutaneous retrograde cardioplegia combined with antegrade cardioplegia and moderate hypothermia, without interruption of ITA flow, is a safe and reliable strategy in patients with patent ITA grafts undergoing aortic valve replacement. This strategy combined with a minimally invasive approach may reduce surgical trauma, and is a safe and effective technique in these challenging patients.

Iatrogenic Injuries during Retrograde Delivery of Cardioplegia- Prevention, Diagnosis and Management: A Collective Review

Iatrogenic Injuries during Retrograde Delivery of Cardioplegia- Prevention, Diagnosis and Management: A Collective Review

Is ureteral stent an effective way to deliver drugs such as bacillus Calmette-Guérin to the upper urinary tract? An experimental study.

Background:We aim to evaluate the distribution in the upper urinary tract of intravesical-delivered fluids, after inducing vesicoureteral reflux (VUR) with a double J stent.Methods:In group 1 (n = 35) patients were maintained in a 20° Trendelenburg position and were evaluated after immediate insertion of ureteral stent, while in group 2 (n = 16) patients were evaluated after several days with ureteral stent placement. Patients in both groups were submitted to a cystogram with progressive volumes of iodine contrast and were evaluated according to VUR of contrast medium to the renal pelvis. Additionally, in group 2 visual confirmation was performed by endoscopic inspection of upper tract mucosal impregnation with methylene blue.Results:In group 1, after immediate insertion of ureteral stent reflux occurred in 51.4% (n = 18/35), and after several days with ureteral stent placement reflux was observed in 87.5% (n = 14/16) of patients. Reflux was progressively more frequent according to increasing bladder volume (p < 0.001). At 60 ml bladder volume no reflux was observed, while at 120 ml, 180 ml, 240 ml, 300 ml and 360 ml bladder volume reflux was observed in 14%, 25%, 41%, 55% and 63% of patients, respectively.Conclusion:Retrograde delivery of fluids such as bacillus Calmette-Guérin to the upper urinary tract through double J stents can be effective; however, it is mainly effective after several days with ureteral stent and relatively large volumes might be instilled into the bladder.

EP06 ANTEGRADE TRANSAPICAL TEVAR IN ACUTE AORTIC RUPTURE

Background and Aim: TEVAR has become the first choice treatment of thoracic aortic rupture. However, in some cases standard retrograde delivery can be prevented by severe aorto-ilio-femoral vascular disease. For these high-risk patients, left ventricular apex can be a valid alternative to achieve vascular access for stent-graft antegrade delivery. Here we report our experience and mid-term results with trans-apical TEVAR (Ta-TEVAR) in case of thoracic aortic rupture Methods: Since 2012 we performed Ta-TEVAR in six patients with acute aortic syndrome. Indication for urgent/emergent TEVAR was post-traumatic aortic injury in 2 patients, contained rupture in 3 patients and penetrating aortic ulcer with signs of impeding rupture in the last patient. In five patients standard retrograde delivery was prevented by severe and calcific ilio-femoral occlusive disease and in one patient with traumatic aortic transection due to severe polytrauma, by acute ischemia of both lower limbs following Resuscitative Endovascular Balloon Occlusion of the Aorta. Antegrade TEVAR through left ventricular apex in left anterior minithoracotomy was performed in all cases. Results: Successful deployment of the stent graft was achieved in all patients. No case of hemodynamic instability or bleeding from the cardiac apex was noted during the procedures. No case endo-leak or aorta-related mortality was noted during the follow-up (range 9–68 months). Conclusion: In patient with thoracic aortic rupture and unfeasible standard retrograde TEVAR, the trans-apical approach can be used safely even in an emergency setting. Study with bigger cohorts and longer follow up are necessary to further evaluate this alternative approach.

Del Nido cardioplegia for minimally invasive aortic valve replacement

We analyzed the impact and safety of del Nido Cardioplegia (DNC) in patients undergoing minimally invasive aortic valve replacement (MIAVR). We analyzed all isolated MIAVR replacements from 5/2013-6/2015 excluding re-operative patients. The approach was a hemi-median sternotomy in all patients. Patients were divided into two cohorts, those who received 4:1 crystalloid:blood DNC solution and those in whom standard 1:4 Buckberg-based cardioplegia (WBC) was used. One-to-one propensity case matching of DNC to WBC was performed based on standard risk factors and differences between groups were analyzed using chi-square and non-parametric methods. MIAVR was performed in 181 patients; DNC was used in 59 and WBC in 122. Case matching resulted in 59 patients per cohort. DNC was associated with reduced re-dosing (5/59 (8.5%) versus 39/59 (61.0%), P < 0.001) and less total cardioplegia volume (1290 ± 347 mL vs 2284 ± 828 mL, P < 0.001). Antegrade cardioplegia alone was used in 89.8% (53/59) of DNC patients versus 33.9% (20/59) of WBC patients (P < 0.001). Median bypass and aortic cross-clamp times were similar. Clinical outcomes were similar with respect to post-operative hematocrit, transfusion requirements, need for inotropic/pressor support, duration of intensive care unit stay, re-intubation, length of stay, new onset atrial fibrillation, and mortality. Del Nido cardioplegia usage during MIAVR minimized re-dosing and the need for retrograde delivery. Patient safety was not compromised with this technique in this group of low-risk patients undergoing MIAVR.

The pUL37 tegument protein guides alpha-herpesvirus retrograde axonal transport to promote neuroinvasion.

A hallmark property of the neurotropic alpha-herpesvirinae is the dissemination of infection to sensory and autonomic ganglia of the peripheral nervous system following an initial exposure at mucosal surfaces. The peripheral ganglia serve as the latent virus reservoir and the source of recurrent infections such as cold sores (herpes simplex virus type I) and shingles (varicella zoster virus). However, the means by which these viruses routinely invade the nervous system is not fully understood. We report that an internal virion component, the pUL37 tegument protein, has a surface region that is an essential neuroinvasion effector. Mutation of this region rendered herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) incapable of spreading by retrograde axonal transport to peripheral ganglia both in culture and animals. By monitoring the axonal transport of individual viral particles by time-lapse fluorescence microscopy, the mutant viruses were determined to lack the characteristic sustained intracellular capsid motion along microtubules that normally traffics capsids to the neural soma. Consistent with the axonal transport deficit, the mutant viruses did not reach sites of latency in peripheral ganglia, and were avirulent. Despite this, viral propagation in peripheral tissues and in cultured epithelial cell lines remained robust. Selective elimination of retrograde delivery to the nervous system has long been sought after as a means to develop vaccines against these ubiquitous, and sometimes devastating viruses. In support of this potential, we find that HSV-1 and PRV mutated in the effector region of pUL37 evoked effective vaccination against subsequent nervous system challenges and encephalitic disease. These findings demonstrate that retrograde axonal transport of the herpesviruses occurs by a virus-directed mechanism that operates by coordinating opposing microtubule motors to favor sustained retrograde delivery of the virus to the peripheral ganglia. The ability to selectively eliminate the retrograde axonal transport mechanism from these viruses will be useful in trans-synaptic mapping studies of the mammalian nervous system, and affords a new vaccination paradigm for human and veterinary neurotropic herpesviruses.