Paravalvular aortic regurgitation (PAR) negatively affects the prognosis after transcatheter aortic valve replacement (TAVR) with dramatically increased morbidity and mortality in patients with more ...than mild PAR. Because transcatheter heart valves are implanted in a sutureless fashion using oversizing to anchor the prosthesis stent frame at the level of the virtual aortic annulus, stent frame underexpansion due to heavily calcified cusps, suboptimal placement of the prosthesis, and/or annulus-prosthesis-size mismatch due to malsizing can contribute to paravalvular leakage. In contrast to open heart surgery, TAVR does not offer the opportunity to measure the aortic annulus under direct vision during the procedure. Therefore, the dilemma before each TAVR procedure is the appropriate sizing of the dimensions of the aortic annulus and to choose not only the size but also the transcatheter heart valve type (self-expanding vs. balloon-expandable) that fits the given anatomy best. Because precise echocardiographic quantification of PAR in patients with TAVR remains challenging especially in the acute implantation situation, a multimodal approach for the evaluation of PAR with the use of hemodynamic measurements and imaging modalities is imperative to precisely quantify the severity of aortic regurgitation immediately after valve implantation and to identify patients who will benefit from corrective measures such as post-dilation or valve-in-valve implantation. Every measure has to be taken to prevent or reduce PAR to provide a satisfying long-term clinical outcome.
The gate control theory of pain proposes that inhibitory neurons of the spinal dorsal horn exert critical control over the relay of nociceptive signals to higher brain areas. Here we investigated how ...the glycinergic subpopulation of these neurons contributes to modality-specific pain and itch processing. We generated a GlyT2::Cre transgenic mouse line suitable for virus-mediated retrograde tracing studies and for spatially precise ablation, silencing, and activation of glycinergic neurons. We found that these neurons receive sensory input mainly from myelinated primary sensory neurons and that their local toxin-mediated ablation or silencing induces localized mechanical, heat, and cold hyperalgesia; spontaneous flinching behavior; and excessive licking and biting directed toward the corresponding skin territory. Conversely, local pharmacogenetic activation of the same neurons alleviated neuropathic hyperalgesia and chloroquine- and histamine-induced itch. These results establish glycinergic neurons of the spinal dorsal horn as key elements of an inhibitory pain and itch control circuit.
•Glycinergic dorsal horn neurons exert segmental control over pain and itch•Their local inhibition causes hyperalgesia and signs of spontaneous discomfort•Local activation reduces acute pain, neuropathic hyperalgesia, and chemical itch
Foster et al. establish dorsal horn glycinergic neurons as critical elements of a spinal gate for pain and itch. Silencing and ablation of these neurons induces local hyperalgesia and spontaneous discomfort, whereas their activation alleviates pain and itch.
Objectives The aim of this study was to determine the influence of baseline renal function and periprocedural acute kidney injury (AKI) on prognosis after transcatheter aortic valve implantation ...(TAVI). Background Evidence is growing that renal function is a major predictor of mortality in patients after TAVI. Methods TAVI was performed with the 18-F CoreValve prosthesis via transfemoral access. All-cause mortality was determined 30 days and 1 year after TAVI in 77 patients with a mean Society of Thoracic Surgeons mortality score of 9.3 ± 6.1% and a mean logistic European System for Cardiac Operative Risk Evaluation of 31.2 ± 17.6%. Results Overall procedural success rate was 98% with 1 periprocedural death. The 30-day mortality was 10%, and 1-year mortality was 26%. The mortality risk increased stepwise across quartiles of baseline serum creatinine. An AKI occurred in 20 of 77 patients: 12 patients (60%) with AKI died during follow-up. The incidence of AKI was related to peripheral arterial disease (65% vs. 39%; p = 0.04), the occurrence of a systemic inflammatory response syndrome (60% vs. 21%, p = 0.002), and post-procedural peri-prosthetic regurgitation ≥2+ (35% vs. 9%, p = 0.02). Impaired renal function at baseline reflected by serum creatinine ≥1.58 mg/dl (hazard ratio: 3.9, 95% confidence interval: 1.6 to 9.5; p = 0.002) and the occurrence of AKI (hazard ratio: 5.9, 95% confidence interval: 2.4 to 14.5, p < 0.001) that was not related to the amount of contrast dye were strong predictors of 1-year mortality after TAVI. Conclusions Impaired renal function at baseline and the occurrence of periprocedural AKI, independent whether renal function returns to baseline or not, are strong predictors of 30-day and 1-year mortality after TAVI.
Individual cortical neurons can selectively respond to specific environmental features, such as visual motion or faces. How this relates to the selectivity of the presynaptic network across cortical ...layers remains unclear. We used single-cell–initiated, monosynaptically restricted retrograde transsynaptic tracing with rabies viruses expressing GCaMP6s to image, in vivo, the visual motion–evoked activity of individual layer 2/3 pyramidal neurons and their presynaptic networks across layers in mouse primary visual cortex. Neurons within each layer exhibited similar motion direction preferences, forming layer-specific functional modules. In one-third of the networks, the layer modules were locked to the direction preference of the postsynaptic neuron, whereas for other networks the direction preference varied by layer. Thus, there exist feature-locked and feature-variant cortical networks.
Identifying the connectome of adult-generated neurons is essential for understanding how the preexisting circuitry is refined by neurogenesis. Changes in the pattern of connectivity are likely to ...control the differentiation process of newly generated neurons and exert an important influence on their unique capacity to contribute to information processing. Using a monosynaptic rabies virus-based tracing technique, we studied the evolving presynaptic connectivity of adult-generated neurons in the dentate gyrus (DG) of the hippocampus and olfactory bulb (OB) during the first weeks of their life. In both neurogenic zones, adult-generated neurons first receive local connections from multiple types of GABAergic interneurons before long-range projections become established, such as those originating from cortical areas. Interestingly, despite fundamental similarities in the overall pattern of evolution of presynaptic connectivity, there were notable differences with regard to the development of cortical projections: although DG granule neuron input originating from the entorhinal cortex could be traced starting only from 3 to 5 wk on, newly generated neurons in the OB received input from the anterior olfactory nucleus and piriform cortex already by the second week. This early glutamatergic input onto newly generated interneurons in the OB was matched in time by the equally early innervations of DG granule neurons by glutamatergic mossy cells. The development of connectivity revealed by our study may suggest common principles for incorporating newly generated neurons into a preexisting circuit.
Accumulating evidence suggests that changes in the metabolic signature of astrocytes underlie their response to neuroinflammation, but how proinflammatory stimuli induce these changes is poorly ...understood. By monitoring astrocytes following acute cortical injury, we identified a differential and region-specific remodeling of their mitochondrial network: while astrocytes within the penumbra of the lesion undergo mitochondrial elongation, those located in the core—the area invaded by proinflammatory cells—experience transient mitochondrial fragmentation. In brain slices, proinflammatory stimuli reproduced localized changes in mitochondrial dynamics, favoring fission over fusion. This effect was triggered by Drp1 phosphorylation and ultimately resulted in reduced respiratory capacity. Furthermore, maintenance of the mitochondrial architecture critically depended on the induction of autophagy. Deletion of Atg7, required for autophagosome formation, prevented the reestablishment of tubular mitochondria, leading to marked reactive oxygen species accumulation and cell death. Thus, our data reveal autophagy to be essential for regenerating astrocyte mitochondrial networks during inflammation.
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•Inflammatory insults induce regionalized mitochondrial fragmentation in astrocytes•Drp1 activation mediates transient mitochondrial fission during inflammation•Inflammatory stimuli impair mitochondrial bioenergetics and increase ROS production•Autophagy is required for maintaining tubular mitochondria and astrocyte survival
Inferring the direction of image motion is a fundamental component of visual computation and essential for visually guided behavior. In the retina, the direction of image motion is computed in four ...cardinal directions, but it is not known at which circuit location along the flow of visual information the cardinal direction selectivity first appears. We recorded the concerted activity of the neuronal circuit elements of single direction-selective (DS) retinal ganglion cells at subcellular resolution by combining GCaMP3-functionalized transsynaptic viral tracing and two-photon imaging. While the visually evoked activity of the dendritic segments of the DS cells were direction selective, direction-selective activity was absent in the axon terminals of bipolar cells. Furthermore, the glutamate input to DS cells, recorded using a genetically encoded glutamate sensor, also lacked direction selectivity. Therefore, the first stage in which extraction of a cardinal motion direction occurs is the dendrites of DS cells.
•Dendritic segments of ON direction-selective cells are direction selective•Type-5 bipolar cells are connected to ON direction-selective cells•Activity of bipolar cell axon terminals is not selective for motion direction•Concerted activity within the circuit of a single ON direction-selective cell
Yonehara et al. record the concerted activity of the circuit elements of single direction-selective retinal ganglion cells at subcellular resolution. The first stage in which extraction of a cardinal motion direction occurs is the dendrites of the ganglion cell.
Consuming a calorically dense diet stimulates microglial reactivity in the mediobasal hypothalamus (MBH) in association with decreased number of appetite-curbing pro-opiomelanocortin (POMC) neurons; ...whether the reduction in POMC neuronal function is secondary to the microglial activation is unclear. Here we show that in hypercaloric diet-induced obese mice, persistently activated microglia in the MBH hypersecrete TNFα that in turn stimulate mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in their neurites, and increasing POMC neuronal firing rates and excitability. Specific disruption of the gene expressions of TNFα downstream signals TNFSF11A or NDUFAB1 in the MBH of diet-induced obese mice reverses mitochondrial elongation and reduces obesity. These data imply that in a hypercaloric environment, persistent elevation of microglial reactivity and consequent TNFα secretion induces mitochondrial stress in POMC neurons that contributes to the development of obesity.
Introduction
Mechanical circulatory support (MCS) devices are increasingly used as a treatment option in resuscitation or in patients with cardiogenic shock (CS). Prophylactic implantation in ...high‐risk percutaneous coronary interventions (HRPCI) is another upcoming indication. The i‐cor ECG‐synchronized cardiac assist device combines the hemodynamic support of a veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) with the ability to generate a pulsatile flow and thus decreasing adverse effects of VA‐ECMO on myocardial function. Aim of this study was to obtain data concerning feasibility, safety and outcomes in both indications.
Methods
A total of 47 patients (34 HRPCI, 13 CS) were included in nine German centers and participated in this study. Demographic and clinical parameters, procedural as well as follow‐up data were prospectively recorded and analyzed.
Results
Device implantation and initiation of ECG‐synchronized cardiac assist was technical successful in all cases and no failures of the consoles or disposable parts were observed. Furthermore, intended percutaneous coronary interventions and successful weaning from cardiac assist was achieved in 97.1% of HRPCI patients. We observed a 30d‐survival of 94.1% in the HRPCI group and 69.2% in the CS group. Main complications in both groups were bleeding events (14.7% HRPCI, 23.1% CS) and critical limb ischemia (2.9% HRPCI, 38.5% CS).
Conclusion
The i‐cor ECG‐synchronized cardiac assist device appears safe and feasible showing clinical outcomes comparable to existing data in the setting of high‐risk percutaneous coronary interventions and acute cardiogenic shock. Further prospective trials are warranted to identify optimal patient and interventional characteristics that will benefit most of this novel kind of mechanical circulatory support.
ECG‐synchronized cardiac assist combines the potent hemodynamic support with the ability of decreasing well described adverse effects on myocardial function of veno‐arterial extracorporeal membrane oxygenation. Forty seven patients 34 high‐risk percutaneous coronary interventions (HRPCI), 13 cardiogenic shock (CS) were included to obtain data concerning feasibility, safety and outcomes in both indications. The i‐cor ECG‐synchronized cardiac assist device appears safe and feasible. It is associated with short‐term clinical outcomes comparable to existing literature in the setting of HRPCI and acute CS.
The rescue of recombinant rabies virus (RV) from cloned cDNA is an inefficient process because it relies on the
de novo formation within cells of functional ribonucleoprotein (RNP) complexes from ...plasmid-expressed viral-like antigenome RNAs and three helper proteins. In the standard RV reverse genetics systems, bacteriophage T7 RNA polymerase drives the transcription of virus antigenome-like RNAs containing three nonviral G residues at the 5′-end and a correct 3′-end generated by the autocatalytic activity of an 85 nucleotides long hepatitis delta virus antigenomic “core” ribozyme (HDVagrz). Here, we show that employing optimized ribozyme sequences significantly improves RV rescue. Substitution of the “core” HDVagrz by a ribozyme with an enhanced cleavage activity resulted in an approximately 10-fold higher number of rescue events and faster initiation of an infectious cycle. The alternative use of a hammerhead ribozyme for the generation of an exact 5′-end similarly enhanced rescue efficiency. Notably, RV cDNA clones containing the combination of optimized 3′- and 5′-ribozymes were rescued at an at least 100-fold increase. In addition to virus rescue, reporter gene expression from transfected minigenome cDNAs was significantly enhanced by the novel ribozymes. The improved RV reverse genetics system greatly facilitates recovery of strongly attenuated viruses and vectors for biomedical applications.
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