Transcatheter heart valve explant with infective endocarditis-associated prosthesis failure and outcomes: the EXPLANT-TAVR international registry.

BACKGROUND AND AIMS: Surgical explantation of transcatheter heart valves (THVs) is rapidly increasing, but there are limited data on patients with THV-associated infective endocarditis (IE). This study aims to assess the outcomes of patients undergoing THV explant for IE. METHODS: All patients who underwent THV explant between 2011 and 2022 from 44 sites in the EXPLANT-TAVR registry were identified. Patients with IE as the reason for THV explant were compared to those with other mechanisms of bioprosthetic valve dysfunction (BVD). RESULTS: A total of 372 patients from the EXPLANT-TAVR registry were included. Among them, 184 (49.5%) patients underwent THV explant due to IE and 188 (50.5%) patients due to BVD. At the index transcatheter aortic valve replacement, patients undergoing THV explant for IE were older (74.3 ± 8.6 vs. 71 ± 10.6 years) and had a lower Society of Thoracic Surgeons risk score [2.6% (1.8-5.0) vs. 3.3% (2.1-5.6), P = .029] compared to patients with BVD. Compared to BVD, IE patients had longer intensive care unit and hospital stays (P < .05) and higher stroke rates at 30 days (8.6% vs. 2.9%, P = .032) and 1 year (16.2% vs. 5.2%, P = .010). Adjusted in-hospital, 30-day, and 1-year mortality was 12.1%, 16.1%, and 33.8%, respectively, for the entire cohort, with no significant differences between groups. Although mortality was numerically higher in IE patients 3 years postsurgery (29.6% for BVD vs. 43.9% for IE), Kaplan-Meier analysis showed no significant differences between groups (P = .16). CONCLUSIONS: In the EXPLANT-TAVR registry, patients undergoing THV explant for IE had higher 30-day and 1-year stroke rates and longer intensive care unit and hospital stays. Moreover, patients undergoing THV explant for IE had a higher 3-year mortality rate, which did not reach statistical significance given the relatively small sample size of this unique cohort and the reduced number of events.

Surgical Management and Mechanical Circulatory Support in High-Risk Pulmonary Embolisms: Historical Context, Current Status, and Future Directions: A Scientific Statement From the American Heart Association.

Acute pulmonary embolism is the third leading cause of cardiovascular death, with most pulmonary embolism-related mortality associated with acute right ventricular failure. Although there has recently been increased clinical attention to acute pulmonary embolism with the adoption of multidisciplinary pulmonary embolism response teams, mortality of patients with pulmonary embolism who present with hemodynamic compromise remains high when current guideline-directed therapy is followed. Because historical data and practice patterns affect current consensus treatment recommendations, surgical embolectomy has largely been relegated to patients who have contraindications to other treatments or when other treatment modalities fail. Despite a selection bias toward patients with greater illness, a growing body of literature describes the safety and efficacy of the surgical management of acute pulmonary embolism, especially in the hemodynamically compromised population. The purpose of this document is to describe modern techniques, strategies, and outcomes of surgical embolectomy and venoarterial extracorporeal membrane oxygenation and to suggest strategies to better understand the role of surgery in the management of pulmonary embolisms.

Minimalist transcatheter aortic valve replacement misses paravalvular regurgitation: Incidence and echocardiographic distribution of missed paravalvular regurgitation.

BACKGROUND: Paravalvular regurgitation (PVR) may be missed intraoperatively with transthoracic echocardiography (TTE) guided minimalist TAVR. We sought to determine the incidence and echocardiographic distribution of PVR missed on intra-op TTE, but detected on predischarge TTE. METHODS: From July 2015 to 2020, 475 patients with symptomatic severe native aortic stenosis underwent TTE-guided minimalist TAVR. Missed PVR was defined as predischarge PVR that was ≥1 grade higher than the corresponding intra-op PVR severity. PVR was classified as anterior or posterior on the four standard TTE views; parasternal short-axis (PSAX), parasternal long-axis (PLAX), apical 3-chamber (A3C), and 5-chamber (A5C). Location-specific risk of missed PVR was then determined. RESULTS: Mild or greater PVR was seen in 55 (11.5%) cases intra-op and 91 (19.1%) at predischarge, with no severe PVR. Among the 91 patients with ≥mild predischarge PVR, missed PVR was present in 42 (46.2%). Compared to the corresponding anterior jets, missed PVR rate was significantly higher for posterior jets in PLAX (62.5% vs. 25.0%, p = 0.005), A5C (56.9% vs. 25.0%, p = 0.009), PSAX (66.7% vs. 24.3%, 0.001), but not A3C (58.5% vs. 40.0%, p = 0.28). CONCLUSIONS: Intraoperative TTE-guided minimalist TAVR either misses nearly half of ≥mild PVR or underestimates PVR by ≥1 grade when compared to predischarge TTE. Posterior PVR jets are more likely to be missed. Transesophageal echo guidance may help minimize missing PVR. Further studies are warranted.

Does the evolution of ontogenetic niche shifts favour species coexistence? An empirical test in Trinidadian streams.

A major question in ecology is how often competing species evolve to reduce competitive interactions and facilitate coexistence. One untested route for a reduction in competitive interactions is through ontogenetic changes in the trophic niche of one or more of the interacting species. In such cases, theory predicts that two species can coexist if the weaker competitor changes its resource niche to a greater degree with increased body size than the superior competitor. We tested this prediction using stable isotopes that yield information about the trophic position (δ15 N) and carbon source (δ13 C) of two coexisting fish species: Trinidadian guppies Poecilia reticulata and killifish Rivulus hartii. We examined fish from locations representing three natural community types: (1) where killifish and guppies live with predators, (2) where killifish and guppies live without predators and (3) where killifish are the only fish species. We also examined killifish from communities in which we had introduced guppies, providing a temporal sequence of the community changes following the transition from a killifish only to a killifish-guppy community. We found that killifish, which are the weaker competitor, had a much larger ontogenetic niche shift in trophic position than guppies in the community where competition is most intense (killifish-guppy only). This result is consistent with theory for size-structured populations, which predicts that these results should lead to stable coexistence of the two species. Comparisons with other communities containing guppies, killifish and predators and ones where killifish live by themselves revealed that these results are caused primarily by a loss of ontogenetic niche changes in guppies, even though they are the stronger competitor. Comparisons of these natural communities with communities in which guppies were translocated into sites containing only killifish showed that the experimental communities were intermediate between the natural killifish-guppy community and the killifish-guppy-predator community, suggesting contemporary evolution in these ontogenetic trophic differences. These results provide comparative evidence for ontogenetic niche shifts in contributing to species coexistence and comparative and experimental evidence for evolutionary or plastic changes in ontogenetic niche shifts following the formation of new communities.

Morin and isoquercitrin protect against ischemic neuronal injury by modulating signaling pathways and stimulating mitochondrial biogenesis.

Objetive: The search for the etiology of Alzheimer's disease has revealed dysregulation of amyloid protein precursors, ß-secretase, mitophagy, apoptosis, and Tau protein genes after ischemic brain injury. Due to this and the fact that some flavonoids have demonstrated anti-amyloidogenic effects on AD targets, we aimed to investigate whether they are effective against an ischemic neuronal injury not only by its antioxidant effects and clarify their mechanism.We simulated the energy depletion that characterizes ischemic processes using iodoacetic acid on HT22 cells. In vitro ischemic assays were also performed under OXPHOS inhibition using inhibitors of the different mitochondrial complexes and intracellular ATP, NADH and NADPH levels were determined. The signaling pathways of MAP kinase (MAPK) and of the PI3K/Akt mTOR were analyzed for its close association with post-ischemic survival.Results: Morin and isoquercitrin showed a significant neuroprotective effect against IAA toxicity, favored the activity of the mitochondrial complexes and prevented the decrease in ERK phosphorylation and activation of the stress proteins JNK and p38 caused by IAA treatment, as well as prevented satisfactorily mTOR and p70 dephosphorylation. They provide a considerable resistance to ischemic brain injury by modulating signaling pathways that stimulate mitochondrial biogenesis and promoting the activity of electron transport chain.Highlights Morin and isoquercitrin showed a significant neuroprotective effect against IAA toxicity.Morin and isoquercitrin favor the activity of the mitochondrial complexes I, III and V.Morin and isoquercitrin prevent the decrease in ERK phosphorylation caused by IAA.Morin shows a better profile avoiding Akt dephosphorylation than isoquercetrin.Morin and isoquercitrin prevent dephosphorylation of mTOR and p70.

Practical approach to confirm femoral artery patency after percutaneous closure for veno-arterial extracorporeal membrane oxygenation decannulation.

BACKGROUND: We describe a technique to assess blood flow distal to the decannulation site after deployment of Perclose ProGlide (Abbott Vascular, Abbott Park, Ill) in patients on femoral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. TECHNIQUE: An antegrade distal perfusion catheter was placed in all patients, and decannulation was primarily performed at bedside (N = 11/12). With the VA-ECMO circuit switched off, a needle was inserted into the arterial tubing, passed through the femoral arterial cannula into the artery. The arterial cannula was removed over a wire and the previously placed Proglide Perclose sutures were secured. Back bleeding from the antegrade distal perfusion catheter, confirmed using a three-way connector, indicated blood flow to the superficial femoral artery. This was followed by confirmation of blood flow to the lower leg using a Doppler ultrasound. Hemostasis of the antegrade perfusion catheter was achieved through manual compression. RESULTS: We implemented this technique in 12 patients with a technical success rate of 100%. There were no ipsilateral leg ischemia, bleeding, pseudoaneurysm, or infection after decannulation. CONCLUSIONS: This technique allows prompt assessment of blood flow to the distal leg immediately following arterial decannulation.

Outcomes and feasibility of redo-TAVR after Sapien 3 Ultra TAVR in extremely-undersized versus nominally-sized annuli.

OBJECTIVES: To compare outcomes in Sapien 3 Ultra (S3U) transcatheter aortic valve replacement (TAVR) with extreme annular undersizing (EAU) versus nominal annular sizing (NAS). BACKGROUND: The Edwards S3U valve has reduced paravalvular leak (PVL) in TAVR but outcomes remain unknown in extremely undersized anatomy. Implanting a smaller S3U valve may facilitate future redo-TAVR but risk compromising hemodynamics. METHODS: From December 2019 to July 2021, 366 patients with native aortic stenosis underwent S3U TAVR. Patients with EAU (annular areas >430 mm2 for 23 mm or >546 mm2 for 26 mm) were compared to NAS (338-430 mm2 for 23 mm or 430-546 mm2 for 26 mm). In-hospital and 30-day outcomes, and redo-TAVR feasibility were determined. RESULTS: There were 79 (21.6%) EAU patients, with more bicuspid (p = 0.0014) and ≥moderate annular/left ventricular outflow tract calcification (p < 0.001). The EAU group had less annular oversizing than NAS group (23 mm: -8.2 ± 2.6% vs. 4.0 ± 7.0%, p < 0.001; 26 mm: -8.9 ± 2.2% vs. 6.7 ± 6.9%, p < 0.001), more balloon overfilling (71.3% vs. 11.6%, p < 0.001), and postdilatation (15.0% vs. 5.8%, p = 0.016). No differences were found in in-hospital or 30-day mortality and stroke (p > 0.05). Mild PVL (13.4% EAU vs. 11.5% NAS, p = 0.56) and mean gradients (23 mm: 13.0 ± 4.5 vs. 14.1 ± 5.4 mmHg, p = 0.40; 26 mm: 11.4 ± 4.1 vs. 11.5 ± 3.9 mmHg, p = 1.0) were similar at 30 days. Had the EAU group undergone NAS with the larger Sapien 3/S3U, by computed tomography analysis simulating 80:20 or 90:10 target implant depth, 33.3%-60.9% (vs. 4.3%-23.2%) would not be feasible for redo-TAVR due to high risk of coronary obstruction. CONCLUSIONS: In this first report of EAU with S3U TAVR, similar excellent short-term outcomes can be achieved compared to NAS, and may preserve future redo-TAVR option.

High flow from Impella 5.5 with partial veno-arterial extracorporeal membrane oxygenation support: Case series.

Optimal flow balance between Impella 5.5 and veno-arterial extracorporeal membrane oxygenation (ECMO) support in the setting of EC-PELLA (ECMO+Impella) is unknown. Outcomes of high Impella 5.5 flow in the setting of EC-PELLA support were reviewed (N = 7). EC-PELLA was successfully explanted in 6 patients (bridge-to-transplant, N = 1; bridge-to-recovery, N = 5). The median duration of EC-PELLA support in explanted patients was 6 days. Survival at discharge was 71.4% (5 patients). In terms of device-related events, either VA-ECMO or Impella-related complications were not experienced. The median performance level of Impella 5.5 was P5 at the time of starting EC-PELLA support and then increased with time up to the median of P8 with increment of the Impella flow, and index (L/min/m2 ). The percentage of Impella flow per total EC- PELLA flow reached 50% after 48 h of support. The vasoactive-inotropic score and serum lactate level improved after institution of EC-PELLA support as well as the pulmonary artery pressures and central venous pressure. In conclusion, a high pump flow from Impella 5.5 with partial VA-ECMO support in the setting of EC-PELLA provided great support with favorable survival and device-related complications rate.

Population dynamics and entrainment of basal ganglia pacemakers are shaped by their dendritic arbors.

The theory of phase oscillators is an essential tool for understanding population dynamics of pacemaking neurons. GABAergic pacemakers in the substantia nigra pars reticulata (SNr), a main basal ganglia (BG) output nucleus, receive inputs from the direct and indirect pathways at distal and proximal regions of their dendritic arbors, respectively. We combine theory, optogenetic stimulation and electrophysiological experiments in acute brain slices to ask how dendritic properties impact the propensity of the various inputs, arriving at different locations along the dendrite, to recruit or entrain SNr pacemakers. By combining cable theory with sinusoidally-modulated optogenetic activation of either proximal somatodendritic regions or the entire somatodendritic arbor of SNr neurons, we construct an analytical model that accurately fits the empirically measured somatic current response to inputs arising from illuminating the soma and various portions of the dendritic field. We show that the extent of the dendritic tree that is illuminated generates measurable and systematic differences in the pacemaker's phase response curve (PRC), causing a shift in its peak. Finally, we show that the divergent PRCs correctly predict differences in two major features of the collective dynamics of SNr neurons: the fidelity of population responses to sudden step-like changes in inputs; and the phase latency at which SNr neurons are entrained by rhythmic stimulation, which can occur in the BG under both physiological and pathophysiological conditions. Our novel method generates measurable and physiologically meaningful spatial effects, and provides the first empirical demonstration of how the collective responses of SNr pacemakers are determined by the transmission properties of their dendrites. SNr dendrites may serve to delay distal striatal inputs so that they impinge on the spike initiation zone simultaneously with pallidal and subthalamic inputs in order to guarantee a fair competition between the influence of the monosynaptic direct- and polysynaptic indirect pathways.

Several targets involved in Alzheimer's disease amyloidogenesis are affected by morin and isoquercitrin.

Long-term consumption of phytochemicals has been associated with a decreased risk of dementia. The modes of action of two flavonols (morin and isoquercitrin) and two flavanones (hesperidin and neohesperidin) were characterized as single-compound drugs in several Alzheimer's disease (AD)-related assays. First, these phytochemicals were assayed in an amyloid toxicity model (MC65 cells). Second, we examined the activity of the flavonoids in cell-free assays against ß- and γ-secretases and acetylcholinesterase activities, as well as agents able to modify the fibrillogenesis of the amyloid ß-peptide. Additionally, they were assayed against glutamate-induced oxytosis, as scavengers of reactive oxygen species (ROS), as inhibitors of caspase-3, -8 and -9 activation and as modulators of the chymotrypsin-like activity of the ubiquitin-proteasome system. Morin and isoquercitrin, unlike flavanones, exhibited significant activities as ß- and γ-secretase inhibitors, as well as capacity to inhibit Aß aggregation and favor its disaggregation. Flavonols and flavanones showed ROS scavenger activity (P < 0.05), attenuation of caspase-3 and -9 activation (P < 0.05) and restoration of the reduced chymotrypsin-like activity of proteasome 20S (P < 0.05) upon H2O2 exposure of APPswe cells. Flavanones failed to protect against glutamate-induced oxytosis. These findings provide new insight into the anti-amyloidogenic effects of morin and isoquercitrin.

Clostridium septicum aortitis: A kiss of the devil.

BACKGROUND: Clostridium septicum aortitis is a lethal infection. C. septicum has a strong association with an underlying malignancy, most commonly in the colon. AIM: Early identification methods and management strategies of C. Septicum infection. MATERIALS AND METHODS: We present a 64-year-old man with aortic aneurysm and C. septicum bacteremia with unknown malignancy who passed away on the fourth day of hospitalization despite emergent endovascular intervention. Computed tomography showed periaortic gas which is the hallmark of infection. DISCUSSION: This case report highlights the need of prompt surgical treatment and its different modalities along with the early use of appropriate antibiotics due to the rapid spread of infection associated with high fatality. The authors also discuss the association of C. septicum aortitis with underlying occult malignancies. CONCLUSION: Delay in identification and treatment of C. Septicum is associated with very high mortality rates.

Evaluating Changes in del Nido Cardioplegia Practices in Adult Cardiac Surgery.

There has been a rapid adoption of the use of del Nido cardioplegia (DC) among adults undergoing cardiac surgery. We leveraged a multicenter database to evaluate differences over time in the choice and impact of cardioplegia type (DC vs. blood) among patients undergoing cardiac surgery. We evaluated 26,373 patients undergoing non-emergent coronary artery bypass and/or valve surgery between 2014-2015 (early period) and 2017-2018 (late period) at 31 centers. DC was compared with blood-based cardioplegia (BC: 1:1, 2:1, 4:1, 8:1, and variable ratio). We evaluated whether treatment choice differed across prespecified patient characteristics, procedure type, and perfusion practices by time period. We evaluated increased DC use with clinical outcomes (major morbidity and mortality, prolonged intubation, and renal failure), after adjusting for baseline characteristics, procedure type, center, and year. DC use increased from 19.6% in 2014-2015 to 41.5% in 2017-2018, p < .001. Increased DC use occurred among coronary artery bypass grafting (CABG), valve, and CABG + valve procedures, all p < .001. Differences in median procedural duration increased over time (DC vs. BC): 1) bypass duration was 11.0 minutes shorter with DC in the early period and 27.0 minutes shorter in the late period, and 2) cross-clamp duration was 7.0 minutes shorter with DC in the early period and 17.0 minutes shorter in the late period, all p < .001. There were no statistical differences in adjusted odds of major morbidity and mortality (odds ratio [OR]adj: 1.01), prolonged intubation (ORadj: .99), or renal failure (ORadj: .80) by DC use (p > .05). In this large multicenter experience, DC use increased over time and was associated with reduced bypass and ischemic time absent any significant differences in adjusted outcomes.

Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion.

The widely held view that the pathophysiology of Parkinson's disease arises from an under-activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre-dependent channelrhodopsin-2 (ChR2) the PfN of Vglut2-Cre mice that were dopamine-depleted with 6-hydroxydopamine (6-OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6-OHDA-treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6-OHDA lesions failed to affect short-term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA-to-AMPA ratios at PfN synapses-that were significantly larger than NMDA-to-AMPA ratios at cortical synapses-were reduced by 6-OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D5 dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short-term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de-potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.

Net Prime Volume Is Associated with Increased Odds of Blood Transfusion.

Hemodilutional anemia has been cited as a contributing factor to red blood cell (RBC) transfusions in cardiac surgery patients. Accordingly, efforts have been made to minimize hemodilution by reducing cardiopulmonary bypass (CPB) prime volume. We sought to assess the impact of these efforts on intraoperative RBC transfusions. We evaluated 21,360 patients undergoing coronary artery bypass with or without aortic valve surgery between July 2011 through December 2016 at any of 42 centers participating in the Perfusion Measures and Outcomes registry. The primary exposure was net CPB prime volume (total prime volume minus retrograde autologous prime volume) indexed to body surface area (mL/m2), which was further divided into quartiles (Q1: <262 mL/m2, Q2: 262-377 mL/m2, Q3: 377-516 mL/m2, and Q4: >516 mL/m2). The primary outcome was intraoperative RBC transfusion. We modeled the effect of index net prime volume on transfusion, adjusting for patient (age, gender, race, diabetes, vascular disease, previous myocardial infarction, ejection fraction, creatinine, preoperative hematocrit (HCT), total albumin, status, aspirin, and antiplatelet agents), procedural (procedure types) characteristics, surgical year, and hospital. The median net prime volume was 378 mL/m2 (25th percentile: 262 mL/m2, 75th percentile: 516 mL/m2). Relative to patients in Q1, patients in Q4 were more likely to be older, female, nondiabetic, have higher ejection fraction, have more ultrafiltration volume removed, and undergo more elective and aortic valve procedures (all p < .05). Patients in Q4 relative to Q1 were exposed to lower nadir HCTs on bypass, p < .05. The net prime volume was associated with an increased risk of transfusion (8.9% in Q1 vs. 22.6% in Q4, p < .001). After adjustment, patients in Q4 (relative to Q1) had a 2.9-fold increased odds (ORadj = 2.9, 95% CI [2.4, 3.4]) of intraoperative RBC transfusion. In this large, multicenter experience, patients exposed to larger net prime volumes were associated with greater adjusted odds of receiving intraoperative transfusions. Our findings reinforce the importance of efforts to reduce the net CPB prime volume. Based on these findings and other supporting evidence, the net prime volume should be adopted as a national quality measure.

Mutant α-Synuclein Overexpression Induces Stressless Pacemaking in Vagal Motoneurons at Risk in Parkinson's Disease.

α-Synuclein overexpression (ASOX) drives the formation of toxic aggregates in neurons vulnerable in Parkinson's disease (PD), including dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). Just as these populations differ in when they exhibit α-synucleinopathies during PD pathogenesis, they could also differ in their physiological responses to ASOX. An ASOX-mediated hyperactivity of SN dopamine neurons, which was caused by oxidative dysfunction of Kv4.3 potassium channels, was recently identified in transgenic (A53T-SNCA) mice overexpressing mutated human α-synuclein. Noting that DMV neurons display extensive α-synucleinopathies earlier than SN dopamine neurons while exhibiting milder cell loss in PD, we aimed to define the electrophysiological properties of DMV neurons in A53T-SNCA mice. We found that DMV neurons maintain normal firing rates in response to ASOX. Moreover, Kv4.3 channels in DMV neurons exhibit no oxidative dysfunction in the A53T-SNCA mice, which could only be recapitulated in wild-type mice by glutathione dialysis. Two-photon imaging of redox-sensitive GFP corroborated the finding that mitochondrial oxidative stress was diminished in DMV neurons in the A53T-SNCA mice. This reduction in oxidative stress resulted from a transcriptional downregulation of voltage-activated (Cav) calcium channels in DMV neurons, which led to a reduction in activity-dependent calcium influx via Cav channels. Thus, ASOX induces a homeostatic remodeling with improved redox signaling in DMV neurons, which could explain the differential vulnerability of SN dopamine and DMV neurons in PD and could promote neuroprotective strategies that emulate endogenous homeostatic responses to ASOX (e.g., stressless pacemaking) in DMV neurons. SIGNIFICANCE STATEMENT: Overexpression of mutant α-synuclein causes Parkinson's disease, presumably by driving neurodegeneration in vulnerable neuronal target populations. However, the extent of α-synuclein pathology (e.g., Lewy bodies) is not directly related to the degree of neurodegeneration across various vulnerable neuronal populations. Here, we show that, in contrast to dopamine neurons in the substantia nigra, vagal motoneurons do not enhance their excitability and oxidative load in response to chronic mutant α-synuclein overexpression. Rather, by downregulating their voltage-activated calcium channels, vagal motoneurons acquire a stressless form of pacemaking that diminishes mitochondrial and cytosolic oxidative stress. Emulating this endogenous adaptive response to α-synuclein overexpression could lead to novel strategies to protect dopamine neurons and perhaps delay the onset of Parkinson's disease.

Is Conventional Bypass for Coronary Artery Bypass Graft Surgery a Misnomer?

Although recent trials comparing on vs. off-pump revascularization techniques describe cardiopulmonary bypass (CPB) as "conventional," inadequate description and evaluation of how CPB is managed often exist in the peer-reviewed literature. We identify and subsequently describe regional and center-level differences in the techniques and equipment used for conducting CPB in the setting of coronary artery bypass grafting (CABG) surgery. We accessed prospectively collected data among isolated CABG procedures submitted to either the Australian and New Zealand Collaborative Perfusion Registry (ANZCPR) or Perfusion Measures and outcomes (PERForm) Registry between January 1, 2014, and December 31, 2015. Variation in equipment and management practices reflecting key areas of CPB is described across 47 centers (ANZCPR: 9; PERForm: 38). We report average usage (categorical data) or median values (continuous data) at the center-level, along with the minimum and maximum across centers. Three thousand five hundred sixty-two patients were identified in the ANZCPR and 8,450 in PERForm. Substantial variation in equipment usage and CPB management practices existed (within and across registries). Open venous reservoirs were commonly used across both registries (nearly 100%), as were "all-but-cannula" biopassive surface coatings (>90%), whereas roller pumps were more commonly used in ANZCPR (ANZCPR: 85% vs. PERForm: 64%). ANZCPR participants had 640 mL absolute higher net prime volumes, attributed in part to higher total prime volume (1,462 mL vs. 1,217 mL) and lower adoption of retrograde autologous priming (20% vs. 81%). ANZCPR participants had higher nadir hematocrit on CPB (27 vs. 25). Minimal absolute differences existed in exposure to high arterial outflow temperatures (36.6°C vs. 37.0°C). We report substantial center and registry differences in both the type of equipment used and CPB management strategies. These findings suggest that the term "conventional bypass" may not adequately reflect real-world experiences. Instead of using this term, authors should provide key details of the CPB practices used in their patients.

The Relationship between Intra-Operative Transfusions and Nadir Hematocrit on Post-Operative Outcomes after Cardiac Surgery.

Uncertainty exists regarding the optimal strategy for the management of anemia in the setting of cardiac surgery. We sought to improve our understanding of the role of intra-operative hematocrit (HCT) and transfusions on peri-operative outcomes following cardiac surgery. A total of 18,886 patients undergoing on-pump cardiac surgery were identified from a multi-institutional registry including surgical and perfusion data. Patients were divided into four groups based on their intra-operative nadir HCT (<21 or ≥21) and whether or not they received intra-operative red blood cell (+RBC or -RBC) transfusions. Outcomes were adjusted for the Society of Thoracic Surgeons predicted risk of mortality (PROM), pre-operative HCT, and medical center. Regardless of nadir HCT cohort, those who received a transfusion had higher PROM relative to patients who did not receive a transfusion. The mean PROM was significantly higher among those HCT ≥21 + RBC (5.3%) vs. HCT ≥ 21 - RBC (1.9%), p < .001. Similarly, the PROM was significantly higher among HCT <21 + RBC (5.1%) vs. those HCT <21 - RBC (3.1%), p < .001. Adjusted outcomes demonstrated an increased impact of RBC transfusions on adverse outcomes irrespective of nadir HCT including stroke (p < .001), renal failure (p < .001), prolonged ventilation (p < .001), and mortality (p < .001). This study demonstrates that transfusions have a more profound effect on post-operative cardiac surgery outcomes than anemia.

Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery.

INTRODUCTION: Neurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression. METHODS: The neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based on the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis. RESULTS: The best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays. DISCUSSION: The combined properties of neuroprotection, neurogenesis, and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone.

Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus.

Calcium influx elevates mitochondrial oxidant stress (mOS) in dorsal motor nucleus of the vagus (DMV) neurons that are prone to Lewy body pathologies in presymptomatic Parkinson's disease (PD) patients. In experimental PD models, treatment with isradipine, the dihydropyridine with the highest affinity to Cav1.3 channels, prevents subthreshold calcium influx via Cav1.3 channels into midbrain dopamine neurons and protects them from mOS. In DMV neurons, isradipine is also effective in reducing mOS despite overwhelming evidence that subthreshold calcium influx is negligible compared with spike-triggered influx. To solve this conundrum we combined slice electrophysiology, two-photon laser scanning microscopy, mRNA profiling, and computational modeling. We find that the unusually depolarized subthreshold voltage trajectory of DMV neurons is positioned between the relatively hyperpolarized activation curve of Cav1.3 channels and that of other high-voltage activated (HVA) calcium channels, thus creating a functional segregation between Cav1.3 and HVA calcium channels. The HVA channels flux the bulk of calcium during spikes but can only influence pacemaking through their coupling to calcium-activated potassium currents. In contrast, Cav1.3 currents, which we show to be more than an order-of-magnitude smaller than the HVA calcium currents, are able to introduce sufficient inward current to speed up firing. However, Kv4 channels that are constitutively open in the subthreshold range guarantee slow pacemaking, despite the depolarizing action of Cav1.3 and other pacemaking currents. We propose that the efficacy of isradipine in preventing mOS in DMV neurons arises from its mixed effect on Cav1.3 channels and on HVA Cav1.2 channels.

Optogenetic Interrogation of Electrophysiological Dendritic Properties and Their Effect on Pacemaking Neurons from Acute Rodent Brain Slices.

Understanding dendritic excitability is essential for a complete and precise characterization of neurons' input-output relationships. Theoretical and experimental work demonstrates that the electrotonic and nonlinear properties of dendrites can alter the amplitude (e.g., through amplification) and latency of synaptic inputs as viewed in the axosomatic region where spike timing is determined. The gold-standard technique to study dendritic excitability is using dual-patch recordings with a high-resistance electrode used to patch a piece of distal dendrite in addition to a somatic patch electrode. However, this approach is often impractical when distal dendrites are too fine to patch. Therefore, we developed a technique that utilizes the expression of Channelrhodopsin-2 (ChR2) to study dendritic excitability in acute brain slices through the combination of a somatic patch electrode and optogenetic activation. The protocol describes how to prepare acute slices from mice that express ChR2 in specific cell types, and how to use two modes of light stimulation: proximal (which activates the soma and proximal dendrites in a ~100 µm diameter surrounding the soma) with the use of a high-magnification objective and full-field stimulation through a low-magnification objective (which activates the entire somato-dendritic field of the neuron). We use this technique in conjunction with various stimulation protocols to estimate model-based spectral components of dendritic filtering and the impact of dendrites on phase response curves, peri-stimulus time histograms, and entrainment of pacemaking neurons. This technique provides a novel use of optogenetics to study intrinsic dendritic excitability through the use of standard patch-clamp slice physiology. Key features • A method for studying the effects of electrotonic and nonlinear dendritic properties on the sub- and suprathreshold responses of pacemaking neurons. • Combines somatic patch clamp or perforated patch recordings with optogenetic activation in acute brain slices to investigate dendritic linear transformation without patching the dendrite. • Oscillatory illumination at various frequencies estimates spectral properties of the dendrite using subthreshold voltage-clamp recordings and studies entrainment of pacemakers in current clamp recordings. • This protocol uses Poisson white noise illumination to estimate dendritic phase response curves and peri-stimulus time histograms.