Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation.

OBJECTIVE: We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR. SUMMARY BACKGROUND DATA: Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist. METHODS: Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups. RESULTS: Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups. CONCLUSIONS: Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.

Preoperative ß-blocker use correlates with worse outcomes in patients undergoing aortic valve replacement.

OBJECTIVES: ß-Blocker use is associated with fewer cardiac complications in patients undergoing noncardiac surgery and is a quality metric for coronary artery bypass grafting. We sought to determine the influence of preoperative ß-blocker administration before aortic valve replacement (AVR). METHODS: All patients undergoing isolated AVR from 2002 to 2016 were extracted from a multi-institutional, statewide database composed of Society of Thoracic Surgeons data. Patients were propensity score matched by preoperative and operative variables, and the effects of preoperative ß-blockers on outcomes were assessed. RESULTS: Of 7380 eligible patients, 53% received a preoperative ß-blocker. After propensity matching, a total of 4592 patients were well matched (1:1) with minimal baseline differences between groups. Within the matched cohort, the operative mortality rate (ß-blocker: 2.8% vs no ß-blocker: 2.4%; P = .454) and rate of major morbidity (14.4% vs 12.7%; P = .101) were similar between groups. The rates of cardiac arrest (2.1% vs 1.3%; P = .034), renal failure requiring dialysis (1.7% vs 0.9%; P = .007), and postoperative transfusion (38.2% vs 33.8%; P = .002) after AVR were significantly greater in the cohort receiving preoperative ß-blockade. Postoperative atrial fibrillation was also more prevalent in patients receiving a preoperative ß-blocker (26.9% vs 23.4%; P = .007). Finally, preoperative ß-blocker use was associated with longer postoperative intensive care unit stays (45.2 vs 47.0 hours; P = .001), but clinically similar hospital length of stay. CONCLUSIONS: Preoperative ß-blocker administration is not associated with improved outcomes after AVR but instead is associated with increased postoperative morbidity. Routinely initiating preoperative ß-blockade is not supported in patients undergoing AVR.

Assessment of miR-98-5p, miR-152-3p, miR-326 and miR-4289 Expression as Biomarker for Prostate Cancer Diagnosis.

Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide, accounting for almost 1 in 5 new cancer diagnoses in the US alone. The current non-invasive biomarker prostate specific antigen (PSA) has lately been presented with many limitations, such as low specificity and often associated with over-diagnosis. The dysregulation of miRNAs in cancer has been widely reported and it has often been shown to be specific, sensitive and stable, suggesting miRNAs could be a potential specific biomarker for the disease. Previously, we identified four miRNAs that are significantly upregulated in plasma from PCa patients when compared to healthy controls: miR-98-5p, miR-152-3p, miR-326 and miR-4289. This panel showed high specificity and sensitivity in detecting PCa (area under the curve (AUC) = 0.88). To investigate the specificity of these miRNAs as biomarkers for PCa, we undertook an in depth analysis on these miRNAs in cancer from the existing literature and data. Additionally, we explored their prognostic value found in the literature when available. Most studies showed these miRNAs are downregulated in cancer and this is often associated with cancer progression and poorer overall survival rate. These results suggest our four miRNA signatures could potentially become a specific PCa diagnostic tool of which prognostic potential should also be explored.

Pulmonary-Systemic Pressure Ratio Correlates with Morbidity in Cardiac Valve Surgery.

OBJECTIVES: Pulmonary hypertension portends worse outcomes in cardiac valve surgery; however, isolated pulmonary artery pressures may not reflect patients' global cardiac function accurately. To better account for the interventricular relationship, the authors hypothesized that patients with greater pulmonary-systemic ratios (mean pulmonary arterial pressure)/(mean systemic arterial pressure) would correlate with worse outcomes after valve surgery. DESIGN: Retrospective cohort study. SETTING: Single academic hospital. PARTICIPANTS: The study comprised 314 patients undergoing valve surgery with or without coronary artery bypass grafting (2004-2016) with Society of Thoracic Surgeons predicted risk scores and preoperative right heart catheterization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pulmonary-systemic ratio was calculated as follows: mean pulmonary arterial pressure/mean systemic arterial pressure. Patients were stratified by pulmonary-systemic ratio quartile. Logistic regression was used to assess the risk-adjusted association between pulmonary-systemic ratio or mean pulmonary arterial pressure. Median pulmonary-systemic ratio was 0.33 (Q1-Q3: 0.23-0.65); median pulmonary arterial pressure was 29 (21-30) mmHg. Patients with the highest pulmonary-systemic ratio had the highest rates of morbidity and mortality (p < 0.0001). A high pulmonary-systemic ratio was associated with longer duration in the intensive care unit (p < 0.0001) and hospital (p < 0.0001). After risk-adjustment, pulmonary-systemic ratio and pulmonary arterial pressure were independently associated with morbidity and mortality, but the pulmonary-systemic ratio (odds ratio 23.88, p = 0.008, Wald 7.1) was more strongly associated than the pulmonary arterial pressure (odds ratio 1.035, p = 0.011, Wald 6.5). CONCLUSIONS: The pulmonary-systemic ratio is more strongly associated with risk-adjusted morbidity and mortality in valve surgery than pulmonary arterial pressure. By integrating ventricular interactions, this metric may better characterize the risk of valve surgery.

An experimental study to investigate design and assessment criteria: What is important for communication between pedestrians and automated vehicles?

In the near future, more vehicles will have automated functions. The traffic system will be a shared space of automated and manually driven vehicles. In our study we focused on the perspective of vulnerable road users, namely pedestrians, in cooperative situations with automated vehicles. Established communication methods, such as eye-contact between pedestrians and drivers, may no longer work when automated vehicles represent the interaction partner. Therefore, we evaluated several human-machine-interfaces (HMI) in order to implement smooth and comfortable communication. We conducted a two-stage study consisting of an explorative focus group discussion with naïve pedestrians (n = 6), followed by an experimental video simulation study (n = 25) based on the results of the focus group discussion. From the focus group we sought member opinion about various HMI, upon presentation of acoustic and visual communication systems such as projections, displays and LED light strips, in addition to portable communication systems, specifically smart watches. On the basis of the focus group discussion, an evaluation criteria was derived. For the video simulation study, HMI designs were created with variations in position, type and coding of the message, and technology. These were assessed by 25 subjects according to the focus discussion derived evaluation criteria: recognizability, unambiguousness, interaction comfort and intuitive comprehensibility. The results show that direct instructions to cross the street are preferred over status information of the vehicle and that large-scale text-based messages from the vehicle to the pedestrian, deliver better results. Design recommendations for HMIs for communication between automated vehicles are derived, and the extent external HMIs may supplement informal communication strategies such as vehicle movement or braking maneuvers, is discussed.

Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion.

BACKGROUND: Sphingosine-1-phosphate regulates endothelial barrier integrity and promotes cell survival and proliferation. We hypothesized that upregulation of sphingosine-1-phosphate during ex vivo lung perfusion would attenuate acute lung injury and improve graft function. METHODS: C57BL/6 mice (n = 4-8/group) were euthanized, followed by 1 hour of warm ischemia and 1 hour of cold preservation in a model of donation after cardiac death. Subsequently, mice underwent 1 hour of ex vivo lung perfusion with 1 of 4 different perfusion solutions: Steen solution (Steen, control arm), Steen with added sphingosine-1-phosphate (Steen + sphingosine-1-phosphate), Steen plus a selective sphingosine kinase 2 inhibitor (Steen + sphingosine kinase inhibitor), or Steen plus both additives (Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor). During ex vivo lung perfusion, lung compliance and pulmonary artery pressure were continuously measured. Pulmonary vascular permeability was assessed with injection of Evans Blue dye. RESULTS: The combination of 1 hour of warm ischemia, followed by 1 hour of cold ischemia created significant lung injury compared with lungs that were immediately harvested after circulatory death and put on ex vivo lung perfusion. Addition of sphingosine-1-phosphate or sphingosine kinase inhibitor alone did not significantly improve lung function during ex vivo lung perfusion compared with Steen without additives. However, group Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor resulted in significantly increased compliance (110% ± 13.9% vs 57.7% ± 6.6%, P < .0001) and decreased pulmonary vascular permeability (33.1 ± 11.9 µg/g vs 75.8 ± 11.4 µg/g tissue, P = .04) compared with Steen alone. CONCLUSIONS: Targeted drug therapy with a combination of sphingosine-1-phosphate + sphingosine kinase inhibitor during ex vivo lung perfusion improves lung function in a murine donation after cardiac death model. Elevation of circulating sphingosine-1-phosphate via specific pharmacologic modalities during ex vivo lung perfusion may provide endothelial protection in marginal donor lungs leading to successful lung rehabilitation for transplantation.

Cardiothoracic surgery training grants provide protected research time vital to the development of academic surgeons.

BACKGROUND: The Ruth L. Kirschstein Institutional National Research Service Award (T32) provides institutions with financial support to prepare trainees for careers in academic medicine. In 1990, the Cardiac Surgery Branch of the National Heart, Lung and Blood Institute (NHLBI) was replaced by T32 training grants, which became crucial sources of funding for cardiothoracic (CT) surgical research. We hypothesized that T32 grants would be valuable for CT surgery training and yield significant publications and subsequent funding. METHODS: Data on all trainees (past and present) supported by CT T32 grants at two institutions were obtained (T32), along with information on trainees from two similarly sized programs without CT T32 funding (Non-T32). Data collected were publicly available and included publications, funding, degrees, fellowships, and academic rank. Non-surgery residents and residents who did not pursue CT surgery were excluded. RESULTS: Out of 76 T32 trainees and 294 Non-T32 trainees, data on 62 current trainees or current CT surgeons (T32: 42 vs Control: 20) were included. Trainees who were supported by a CT T32 grant were more likely to pursue CT surgery after residency (T32: 40% [30/76] vs Non-T32: 7% [20/294], P < .0001), publish manuscripts during residency years (P < .0001), obtain subsequent NIH funding (T32: 33% [7/21] vs Non-T32: 5% [1/20], P = .02), and pursue advanced fellowships (T32: 41% [9/22] vs Non-T32: 10% [2/20], P = .02). CONCLUSIONS: T32 training grants supporting CT surgery research are vital to develop academic surgeons. These results support continued funding by the NHLBI to effectively develop and train the next generation of academic CT surgeons.

Transcatheter interventions for functional mitral regurgitation.

Mitral regurgitation is considered the most prevalent valve disease in the United States and its incidence is increasing due to the aging population. Surgical mitral valve repair and replacement are effective at reducing regurgitation due to ischemia, but many patients with secondary mitral regurgitation do not undergo surgery because they are too high risk. Transcatheter devices that mimic surgical techniques are rapidly being developed to reduce the risks traditionally associated with surgical mitral valve repair and replacement. Despite the challenges posed by complex anatomy and multiple etiologies of mitral valve pathology, early results of transcatheter mitral repair and replacement indicate that they have the potential to increase the number of patients with secondary MR who are candidates for intervention.

Contemporary outcomes in reoperative mitral valve surgery.

OBJECTIVE: Data suggest that redo mitral valve surgery is being performed in increasing numbers, possibly with superior results according to single-centre studies. The purpose of this study is to describe outcomes of redo mitral valve surgery and identify risk-adjusted predictors of poor outcomes. METHODS: All (11 973) open mitral valve cases were evaluated (2002-2016) from a regional Society of Thoracic Surgery (STS) database. Patients were stratified by primary versus redo mitral valve surgery. Mixed effects logistic regression models including hospital as a random effect were used to identify risk factors for patients undergoing redo mitral valve surgery. RESULTS: Of all mitral valve cases, 1096 (9.7%) had a previous mitral operation. Redo patients had higher rates of valve replacement and preoperative comorbidities resulting in more complications, operative mortalities (11.1%vs6.5%, p<0.0001) and higher resource utilisation. Several factors independently increased risk for composite STS major morbidity and 30-day mortality, including cardiogenic shock (OR 10.3, p=0.0001), severe tricuspid insufficiency (OR 2.3, p=0.001), urgent/emergent status (OR 1.8, p=0.001) and concurrent coronary artery bypass grafting (OR 2.4, p=0.002). The volume of redo mitral valve surgery increased 10% per year and the observed-to-expected ratios (O/E) for operative mortality in redo mitral surgery improved from 1.44 early in the study period to 0.72 in the most recent era. CONCLUSIONS: Redo mitral valve surgery accounts for approximately 10% of mitral valve operations and is associated with increased risk and resource utilisation. However, as the volume of redo mitral surgery increases, outcomes have dramatically improved and are now better than predicted.

In vivo lung perfusion rehabilitates sepsis-induced lung injury.

BACKGROUND: Sepsis is the leading cause of lung injury in adults and can lead to acute respiratory distress syndrome (ARDS). Using a novel technique of isolated in vivo lung perfusion (IVLP), we hypothesized that normothermic IVLP will improve oxygenation and compliance in a porcine model of sepsis-induced lung injury. METHODS: Mature adult swine (n = 8) were administered lipopolysaccharide (LPS; 50 µg/kg over 2 hours) via the external jugular vein, followed by sternotomy and central extracorporeal membrane oxygenation (ECMO) cannulation (right atrium to ascending aorta). The left pulmonary artery (inflow) and left superior and inferior pulmonary veins (outflow) were dissected out and cannulated to deliver isolated perfusion to the left lung. After 4 hours of normothermic IVLP with Steen solution, the left lung then underwent 4 hours of reperfusion after IVLP decannulation. Airway pressures and lung-specific pulmonary vein blood gases from the right lung (LPS control) and left lung (LPS + IVLP) of the same animal were compared. RESULTS: All animals demonstrated a significant reduction in the ratio of partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) (P/F ratio) and total lung compliance at 2 hours after the start of LPS infusion (mean, 469 ± 19.7 mm Hg vs 222.2 ± 21.4 mm Hg; P < .0001). After reperfusion, 6 animals (75%) exhibited improved lung function, allowing for ECMO decannulation. Lung-specific oxygenation was superior in the left lung after 4 hours of reperfusion (mean, 310.5 ± 54.7 mm Hg vs 201.1 ± 21.7 mm Hg; P = .01). Similarly, total lung compliance improved after IVLP of the left lung. The lung wet weight to dry weight ratio demonstrated reduced edema in rehabilitated left lungs (mean, 6.5 ± 0.3 vs 7.5 ± 0.4; P = .04). CONCLUSIONS: IVLP successfully rehabilitated LPS-injured lungs compared to ECMO support alone in this preclinical porcine model.

Mitral Valve Repair: The French Correction Versus the American Correction.

Degenerative mitral valve disease causing mitral regurgitation is the most common organic valve pathology and is classified based on leaflet motion. The "French correction" mitral valve repair method restores normal valvular anatomy with extensive leaflet resection, chordal manipulation, and rigid annuloplasty. The American correction attempts to restore normal valve function through minimal leaflet resection, flexible annuloplasty, and use of artificial chordae. These differing methods of mitral valve repair reflect an evolution in principles, but both require understanding of the valve pathology and correction of leaflet prolapse and annular dilatation. Adhering to those unifying principles and ensuring that no patient leaves the operating room with significant persistent mitral regurgitation produces durable results and satisfactory patient outcomes.

Ex Vivo Lung Perfusion Rehabilitates Sepsis-Induced Lung Injury.

BACKGROUND: Sepsis is the number one cause of lung injury in adults. Ex vivo lung perfusion (EVLP) is gaining clinical acceptance for donor lung evaluation and rehabilitation and may expand the use of marginal organs for transplantation. We hypothesized that 4 hours of normothermic EVLP would improve compliance and oxygenation in a porcine model of sepsis-induced lung injury. METHODS: We used intravenous lipopolysaccharide (LPS) to induce a systemic inflammatory response in a porcine model of lung injury. Two groups of 4 animals each received a 2-hour infusion of LPS through the external jugular vein. Serial measurements of blood gases were performed every 30 minutes until the partial pressure of oxygen/fraction of inspired oxygen ratio dropped below 150 on two consecutive readings. Lungs were then randomized to treatment with 4 hours of normothermic EVLP with STEEN Solution (XVIVO Perfusion Inc, Englewood, CO) or 4 additional hours of in vivo perfusion (control). Airway pressures and blood gases were recorded for calculation of dynamic lung compliance and partial pressure of oxygen/fraction of inspired oxygen ratios. EVLP was performed with hourly recruitment maneuvers and oxygen challenge. RESULTS: All animals reached a partial pressure of oxygen/fraction of inspired oxygen ratio of less than 150 mm Hg within 3 hours after start of the LPS infusion. Oxygenation and compliance in the control animals continued to decline during the 4-hour in vivo perfusion period, and 3 of the 4 animals died of severe hypoxia within 4 hours. The EVLP group demonstrated significant improvements hour 1 to hour 4 in oxygenation (365.8 ± 53.0 vs 584.4 ± 21.0 mm Hg, p = 0.02) and dynamic compliance (9.0 ± 2.8 vs 15.0 ± 3.6, p = 0.02 mL/cm H2O). CONCLUSIONS: EVLP successfully rehabilitated LPS-induced lung injury in this preclinical porcine model and may thus provide a means to rehabilitate many types of acute lung injury.

A New Intraoperative Protocol for Reducing Perioperative Transfusions in Cardiac Surgery.

BACKGROUND: Perioperative anemia and blood product transfusion increases short-term and long-term morbidity and mortality during cardiac surgery. We hypothesized that streamlined cardiopulmonary bypass circuit and rotational thromboelastometry (ROTEM) would reduce blood product usage and improve outcomes. METHODS: All patients with Society of Thoracic Surgeons risk scores at our institution from January 2013 to June 2015 were included. Individuals were chronologically stratified into 2 groups according to institutional changes to a streamlined bypass circuit and ROTEM-guided transfusion. Blood product transfusion, hematocrit, and observed to expected outcomes (O/E) were compared between the groups. RESULTS: Patients were defined as either control group (533 patients, 12 months) or intervention group (804 patients, 18 months). The intervention group was further subdivided into streamlined circuit (290 patients, 6 months) and ROTEM (514 patients, 12 months). Use of streamlined bypass circuit correlated with significantly reduced intraoperative transfusion of packed red blood cells (pRBCs) (23.8% versus 17.9%; p = 0.05) and platelets (28.0% versus 19.3; p = 0.01) with improvement in lowest intraoperative hematocrit (26.0 versus 26.9; p = 0.02). ROTEM was associated with a further reduction in intraoperative pRBCs (17.9% versus 11.28%; p = 0.01) and postoperative transfusion pRBCs (38.3% versus 23.5%; p = 0.02). The combination was associated with reduced intraoperative (44.6% versus 34.1; p < 0.001) and postoperative transfusions (45.6% versus 40.1; p < 0.001) in the intervention group, while maintaining a higher hematocrit at discharge (28.1 versus 29.1; p < 0.001). Finally, the intervention was associated with a statistically significant reduction in the O/E for reoperation (p = 0.003). CONCLUSIONS: Use of streamlined cardiopulmonary bypass circuit and ROTEM may reduce transfusion and reoperation rates and improve perioperative anemia in cardiac surgical patients. This study demonstrates reproducible intraoperative methods for reducing blood product usage and improving outcomes.

The Effectiveness of Eye Movement Desensitization and Reprocessing Therapy to Treat Symptoms Following Trauma in Timor Leste.

The effectiveness of eye movement desensitization and reprocessing (EMDR) therapy for treating trauma symptoms was examined in a postwar/conflict, developing nation, Timor Leste. Participants were 21 Timorese adults with symptoms of posttraumatic stress disorder (PTSD), assessed as those who scored ≥2 on the Harvard Trauma Questionnaire (HTQ). Participants were treated with EMDR therapy. Depression and anxiety symptoms were assessed using the Hopkins Symptom Checklist. Symptom changes post-EMDR treatment were compared to a stabilization control intervention period in which participants served as their own waitlist control. Sessions were 60-90 mins. The average number of sessions was 4.15 (SD = 2.06). Despite difficulties providing treatment cross-culturally (i.e., language barriers), EMDR therapy was followed by significant and large reductions in trauma symptoms (Cohen's d = 2.48), depression (d = 2.09), and anxiety (d = 1.77). At posttreatment, 20 (95.2%) participants scored below the HTQ PTSD cutoff of 2. Reliable reductions in trauma symptoms were reported by 18 participants (85.7%) posttreatment and 16 (76.2%) at 3-month follow-up. Symptoms did not improve during the control period. Findings support the use of EMDR therapy for treatment of adults with PTSD in a cross-cultural, postwar/conflict setting, and suggest that structured trauma treatments can be applied in Timor Leste.

Natural history of coexistent mitral regurgitation after aortic valve replacement.

OBJECTIVES: The long-term evolution of coexistent mitral regurgitation (MR) after aortic valve replacement (AVR) for aortic stenosis remains poorly defined. Prior studies have demonstrated that acute improvement in MR after AVR is modest, and more aggressive approaches have been advocated. This study examines the evolution of MR after AVR and identifies prognostic indicators for MR improvement. METHODS: We retrospectively evaluated demographic and echocardiographic data of 423 patients who underwent primary isolated AVR for aortic stenosis with coexistent mild (n = 314) or moderate (n = 109) MR at our institution, from 2004 to 2013. For each patient, preoperative and postoperative MR was extracted from 903 echocardiograms and graded on a 0 to 4+ scale. Hierarchic linear models were used to estimate postoperative residual MR over a 5-year follow-up period. Patients were then stratified by improvement in MR, and preoperative risk factors and survival were compared between groups. Cox proportional hazards regression was used to assess the association between survival and preoperative and postoperative MR. RESULTS: The overall acute reduction in MR was -0.23 degrees per patient. Patients with moderate MR had a -0.53 degree reduction in MR, whereas patients with mild MR had only a -0.13 degree reduction in MR (P < .001). Residual MR, however, worsened over time and regressed back to baseline, particularly in patients with preoperative moderate MR. At last follow-up, 70 (17%) patients returned to 2+ or worse MR. Residual MR at last echocardiographic follow-up was not affected by left ventricular ejection fraction, severity of preoperative aortic valve gradient (AVG), magnitude of reduction of AVG, or other comorbidities. Degree of preoperative MR did not affect midterm survival. Patients whose MR improved after AVR demonstrated a trend toward improved survival (75% vs 65% 5-year survival; P = .06), compared with those without MR whose survival remained unchanged or worsened. CONCLUSIONS: Coexistent MR modestly improves after AVR, but eventually regresses back to baseline or worsens over time in many patients. Preoperative AVG, reduction of AVG, heart failure, or atrial fibrillation was not predictive of residual MR. Moderate preoperative MR did not adversely affect 5-year survival. Patients with improvement in MR, however, demonstrated a trend toward improved survival at 5 years. More aggressive approaches for coexistent moderate MR should be considered in patients who need AVR for aortic stenosis.

Mutational analysis of the CYP7B1, PNPLA6 and C19orf12 genes in autosomal recessive hereditary spastic paraplegia.

The hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative diseases. Here, we evaluated the spectrum and frequency of mutations in the CYP7B1, PNPLA6 and C19orf12 genes (causative for the subtypes SPG5A, SPG39 and SPG43, respectively) in a cohort of 63 unrelated HSP patients with suspected autosomal recessive inheritance. Two novel homozygous mutations (one frameshift and one missense mutation) were detected in CYP7B1 (SPG5A), while no disease-causing mutation was identified for SPG39 or SPG43.

Early outcomes of pulmonary valve replacement with the mitroflow bovine pericardial bioprosthesis.

BACKGROUND: Bovine pericardial valves are often used for pulmonary valve replacement (PVR) in patients with previously repaired congenital heart disease. Attention has recently focused on the safety of the Mitroflow (Sorin Group USA, Arvada, CO) bovine pericardial valve after a national alert describing several cases of sudden valve failure in young patients. In response, we reviewed our experience using the Mitroflow bioprosthesis for PVR. METHODS: Medical records were reviewed for all patients who underwent PVR using a Mitroflow valve at our center (2008-2013). RESULTS: The cohort included 84 patients with a median age of 18.3 years (range, 0.8-62.1 years) and weight of 48.4 kg (range, 5.7-167.8 kg). Indications for surgical intervention included native outflow tract insufficiency (59 patients), valved conduit failure (20 patients), and isolated prosthetic valve failure (5 patients). Median length of stay was 3 days (range, 2-13 days). There were no hospital deaths. Median follow-up was 2.4 years (range, 0.2-5.6 years). Pulmonary valve insufficiency and peak gradient increased with time. At latest follow-up, freedom from insufficiency greater than or equal to a moderate degree was 83%, and freedom from a peak gradient greater than or equal to 50 mm Hg was 92%. Reintervention was required in 4 patients. One patient experienced endocarditis and underwent surgical PVR (0.6 years after initial intervention). Three patients underwent transcatheter treatment for valve stenosis including PVR (at 4.2 and 4.4 years in 2 patients) and balloon valvuloplasty (at 5.2 years in the third patient). Kaplan-Meier freedom from reintervention at 5 years was 81%. CONCLUSIONS: Early outcomes using the Mitroflow bovine pericardial valve for PVR in children and adults with repaired congenital heart disease appear acceptable and similar to reported outcomes for other tissue valve options. Valve failure from premature structural deterioration was not observed.

Left anterior descending coronary artery blood flow and left ventricular unloading during extracorporeal membrane oxygenation support in a swine model of acute cardiogenic shock.

The impact of extracorporeal membrane oxygenation (ECMO) support on coronary blood flow and left ventricular unloading is still debated. This study aimed to further characterize the influence of ECMO on coronary artery blood flow and its ability to unload the left ventricle in a short-term model of acute cardiogenic shock. Seven anesthetized pigs were intubated and then underwent median sternotomy and cannulation for venoarterial (VA) ECMO. Flow in the left anterior descending (LAD) artery, left atrial pressure (LAP), left ventricular end-diastolic pressure (LVEDP), and mean arterial pressure (MAP) were measured before and after esmolol-induced cardiac dysfunction and after initiating VA-ECMO support. Induction of acute cardiogenic shock was associated with short-term increases in LAP from 8 ± 4 mm Hg to 18 ± 14 mm Hg (P = 0.9) and LVEDP from 5 ± 2 mm Hg to 13 ± 17 mm Hg (P = 0.9), and a decrease in MAP from 63 ± 16 mm Hg to 50 ± 24 mm Hg (P = 0.3). With VA-ECMO support, blood flow in the LAD increased from 28 ± 25 mL/min during acute unsupported cardiogenic shock to 67 ± 50 mL/min (P = 0.003), and LAP and LVEDP decreased to 8 + 5 mm Hg (P = 0.7) and 5 ± 3 mm Hg (P = 0.5), respectively. In this swine model of acute cardiogenic shock, VA-ECMO improved coronary blood flow and provided some degree of left ventricular unloading for the short duration of the study.

Time-resolved fluorescence spectroscopy measures clustering and mobility of a G protein-coupled receptor opsin in live cell membranes.

Determining membrane protein quaternary structure is extremely challenging, especially in live cell membranes. We measured the oligomerization of opsin, a prototypical G protein-coupled receptor with pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). Individual cell measurements revealed that opsin is predominantly organized into dimeric clusters. At low concentrations, we observed that the population of oligomers increased linearly with the square of the individual monomer populations. This finding supports a monomer-dimer equilibrium and provides an experimental measurement of the equilibrium constant.