Atrial arrhythmia is an important cause of late death in patients after the Fontan-Style operation. However, the detailed electrophysiological characteristics of the post-Fontan atrium and its ...underlying mechanisms are largely unknown. In this study, we investigated electrophysiological characteristics and the ionic remodeling in the right atrium (RA) of a canine model after the Fontan operation. We performed the operation of RA to pulmonary artery connection to mimic the Fontan operation. We undertook hemodynamic measurements, cardiac electrophysiological studies, and ion current measurements. The expression of ionic channels was analyzed by PCR and western-blotting. Our Fontan model induced RA hypertension, enlarged the size of RA, and increased atrial fibrosis, representing the classic characteristic of Fontan patients. In the Fontan group, the atrial effective refractory period and the active potential duration were reduced, and the atrial tachycardia has been more often to be induced. The electrical conduction mapping showed that the Fontan group reduced the conduction velocity. The Fontan operation significantly down-regulated the expression of
KCND
3/Kv4.3,
CACNA1C
/Cav1.2 and
SCN5A
, but up-regulated the expression of
KCNJ2
/Kir2.1. Correspondingly, The Fontan operation reduced transient-outward (
I
to
) and L-type Ca2 (
I
Ca,L
) and
I
Na
currents, while increasing the inward-rectifier current (
I
K1
). Thus, the net shortening of the action potential in the post-Fontan atrium is associated with the altered expression of ionic channels which disturbed the balance between inward and outward currents. Taken together, the Fontan operation induces the ionic remodeling, and thus altered electrophysiological characteristics of the right atrium, improving our understanding on the pathophysiology of atrial arrhythmias in Fontan patients.
To evaluate sintilimab compared with other PD-L1 inhibitors in combination with platinum-based doublet chemotherapy as the first-line treatment of non-squamous non-small-cell lung cancer.
A ...frequentist meta-analysis was used to compare outcomes, including progression-free survival, overall survival, objective response rate, time to response and safety profile.
The sintilimab combination arm had progression-free survival comparable to that of the pembrolizumab combination arm (hazard ratio HR = 1.00; 95% CI: 0.71, 1.41), the atezolizumab combination arm (HR: 0.81; 95% CI: 0.59, 1.10), the tislelizumab combination arm (HR: 0.75; 95% CI: 0.48, 1.16), the camrelizumab combination arm (HR: 0.80; 95% CI: 0.54, 1.20) and the nivolumab combination arm (HR: 0.72; 95% CI: 0.51, 1.02). Any grade or grade ≥3 adverse event was comparable between PD-L1 inhibitors.
Sintilimab showed a comparable efficacy and safety profile when compared with other PD-L1 inhibitors combined with platinum-based doublet chemotherapy as the first-line treatment of locally advanced or metastatic non-squamous non-small-cell lung cancer.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Dysregulation of mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis ...of PD. However, the underlying mechanism is incompletely elucidated. Here, we show that PD mimetics (6-hydroxydopamine, N-methyl-4-phenylpyridine or rotenone) suppressed phosphorylation of mTOR, S6K1 and 4E-BP1, reduced cell viability, and activated caspase-3 and PARP in PC12 cells and primary neurons. Overexpression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 in PC12 cells partially prevented cell death in response to the PD toxins, revealing that mTOR-mediated S6K1 and 4E-BP1 pathways due to the PD toxins were inhibited, leading to neuronal cell death. Furthermore, we found that the inhibition of mTOR signaling contributing to neuronal cell death was attributed to suppression of Akt and activation of AMPK. This is supported by the findings that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPKα with compound C partially attenuated inhibition of phosphorylation of mTOR, S6K1 and 4E-BP1, activation of caspase-3, and neuronal cell death triggered by the PD toxins. The results indicate that PD stresses activate AMPK and inactivate Akt, causing neuronal cell death via inhibiting mTOR-mediated S6K1 and 4E-BP1 pathways. Our findings suggest that proper co-manipulation of AMPK/Akt/mTOR signaling may be a potential strategy for prevention and treatment of PD.
•PD toxins inhibit mTOR-mediated S6K1 and 4E-BP1 pathways.•Inhibition of mTOR-mediated S6K1 and 4E-BP1 pathways leads to neuronal cell death.•PD toxins induce activation of AMPK and inactivation of Akt in neuronal cells.•Activated AMPK and inactivated Akt elicit suppression of mTOR signaling pathway.•Co-manipulation of AMPK/Akt/mTOR may be a potential strategy for prevention of PD.
•Ferroptosis was involved in the progression of myocardial infarction and aggravated the cardiac injury.•Salvianolic acid B inhibits ferroptosis by alleviating iron overload and oxidative ...stress.•Salvianolic acid B upregulates the expression of Nrf2pathway.•Salvianolic acid B exerts cardioprotective effects in myocardial infarction via targeting ferroptosis.
Accumulating evidence has highlighted the role of ferroptosis, a novel type of programmed cell death involved in the pathological process of myocardial infarction (MI). However, the underlying mechanism of ferroptosis in mediating MI is complicated that needs to be further investigated. Salvianolic acid B (Sal B) extracted from the traditional Chinese medicine (TCM) herb Salvia miltiorrhiza possesses pharmacological function against MI, which provides us with a new direction to explore the effect of Sal B on ferroptosis after myocardial ischemic injury. In the present study, iron accumulation and expression levels of ferroptosis-related proteins in MI rats altered in a time-dependent manner. Importantly, treatment of ferroptosis inhibitors ferrostatin-1 (Fer-1) or deferoxamine (DFO) reversed typical changes of ferroptosis, including iron overload, lipid peroxide accumulation, mitochondrial damage, and specific expression levels of ferroptosis-related proteins, thereby alleviating myocardial injury in rats. Similar results were observed in Sal B-treated MI rats in a dose-dependent manner. In addition, NFE2-related factor 2 (Nrf2) was strongly activated by the treatment of Sal B. In vivo knockdown of Nrf2 in MI rats enhanced ferroptosis and damaged the protective effect of Sal B on MI. Furthermore, Sal B administration was unable to significantly reverse expression levels of target genes of Nrf2 that were associated with iron homeostasis and oxidative stress (e.g., HO-1, xCT, Gpx4, Fth1, and Fpn1) in MI rats after knockdown of Nrf2. Taken together, Sal B contributed to protecting MI by inhibiting ferroptosis via activating the Nrf2 signaling pathway.
Abstract
Background
Accurate cephalometric analysis plays a vital role in the diagnosis and subsequent surgical planning in orthognathic and orthodontics treatment. However, manual digitization of ...anatomical landmarks in computed tomography (CT) is subject to limitations such as low accuracy, poor repeatability and excessive time consumption. Furthermore, the detection of landmarks has more difficulties on individuals with dentomaxillofacial deformities than normal individuals. Therefore, this study aims to develop a deep learning model to automatically detect landmarks in CT images of patients with dentomaxillofacial deformities.
Methods
Craniomaxillofacial (CMF) CT data of 80 patients with dentomaxillofacial deformities were collected for model development. 77 anatomical landmarks digitized by experienced CMF surgeons in each CT image were set as the ground truth. 3D UX-Net, the cutting-edge medical image segmentation network, was adopted as the backbone of model architecture. Moreover, a new region division pattern for CMF structures was designed as a training strategy to optimize the utilization of computational resources and image resolution. To evaluate the performance of this model, several experiments were conducted to make comparison between the model and manual digitization approach.
Results
The training set and the validation set included 58 and 22 samples respectively. The developed model can accurately detect 77 landmarks on bone, soft tissue and teeth with a mean error of 1.81 ± 0.89 mm. Removal of region division before training significantly increased the error of prediction (2.34 ± 1.01 mm). In terms of manual digitization, the inter-observer and intra-observer variations were 1.27 ± 0.70 mm and 1.01 ± 0.74 mm respectively. In all divided regions except Teeth Region (TR), our model demonstrated equivalent performance to experienced CMF surgeons in landmarks detection (
p
> 0.05).
Conclusions
The developed model demonstrated excellent performance in detecting craniomaxillofacial landmarks when considering manual digitization work of expertise as benchmark. It is also verified that the region division pattern designed in this study remarkably improved the detection accuracy.
Fructus Gardeniae, with the effects of discharging fire, eliminating vexation, reducing fever and causing diuresis, and cooling blood to remove apthogentic heat, could be used to treat Parkinson's ...disease (PD). Geniposide, as the main active ingredient of Fructus Gardeniae, has been shown to have neuroprotective effects in several rodent models. Rotenone, a commonly used neurotoxin, induced PD model progresses slowly, but simulates the pathological changes of PD's slow progression.
Herein, we mainly investigated the neuroprotective effects of geniposide on rotenone-induced mouse model of PD and the underlined mechanism.
C57BL/6 mice were treated with rotenone (30 mg/kg, p. o.) daily for 60 days. Geniposide (25 and 50 mg/kg, p. o.) were administered at alterative day 30 min before rotenone. On day 60, the challenging beam, spontaneous activity, and adhesive removal tests were performed to evaluate the motor activity. Dopamine, DOPAC and HVA levels were detected by UPLC-MS/MS methods. Dopaminergic neurodegeneration was assessed using immunohistochemistry staining. ROS production, MDA level and GSH: GSSG ratio were measured to analyze oxidative stress. Cleavage of PARP and caspase-3 were detected to assess neuronal apoptosis. The expression of Nrf2 and mTOR signaling were detected using Western blot.
Geniposide improved motor dysfunction, restored neurotransmitters levels, and attenuated dopaminergic neurodegeneration induced by rotenone in mice. Geniposide suppressed rotenone-induced neuronal oxidative damage associated with Nrf2 signaling, and neuronal apoptosis involving mTOR pathway.
Geniposide may exert a neuroprotective effect in a mouse model of PD by rotenone, and this effect might be relevant to Nrf2 associated antioxidant signaling and mTOR involved anti-apoptosis pathway.
Display omitted
•Geniposide improved motor deficits and restored neurotransmitters level in mice.•Geniposide recovered dopaminergic neurodegeneration in mice.•Geniposide rescued oxidative damage associated with Nrf2 signaling.•Geniposide attenuated neuronal apoptosis involving mTOR pathway.
Reactive oxygen species (ROS) produced in the ischemic myocardium can induce cardiomyocyte injury and death, resulting in cardiac remodeling. Ferroptosis, known as a newly type of cell death caused ...by iron-dependent oxidative stress, which is an essential death mechanism in cardiomyocytes. However, it is unclear whether oxidative stress products can further induce ferroptosis and aggravate cardiomyocyte injury. Geniposide (GEN), a major active component of
, possesses the natural antioxidant activity and cardioprotective effect. Herein, we evaluated the role of ferroptosis in myocardial oxidative injury and the protective effect of GEN on myocardial ferroptosis. We first detected iron overload, massive ROS, and lipid peroxidation in ferric ammonium citrate (FAC)-treated cardiomyocytes, which were typical characteristics of ferroptosis. The iron overload-induced oxidative stress and ferroptosis aggravated cardiomyocyte injury, which were significantly alleviated by GEN treatment. Similar phenotypic changes of ferroptosis were consistently discovered in hydrogen peroxide (H
O
)-induced cells, which were reversed by GEN treatment as well. Interestingly, the RNA-binding protein Grsf1, which directly upregulated Gpx4 at the translational level, was activated by GEN following myocardial oxidative injury. The specific knockdown of Grsf1 increased their sensitivity to ferroptosis and weakened the cardioprotective effect of GEN in H
O
-treated cardiomyocytes. Moreover, GEN treatment reduced iron overload and lipid peroxidation in myocardial infarction (MI) rats, thereby fighting against the cardiac ischemic injury. Collectively, our study revealed the pathogenesis of oxidative stress and ferroptosis associated with myocardial ischemia, and indicated the antioxidant and anti-ferroptosis effects of GEN on preventing myocardial injury by activating the Grsf1/GPx4 axis, serving as a potential therapeutic target.
Purpose
To analyze the accuracy of transferring casts in maximal intercuspal position to a virtual articulator by using transfer plates in the laboratory scanner before and after occlusal ...optimization.
Material and methods
Five sets of standard dental casts were mounted on a mechanical articulator in maximal intercuspal position. The number and position of occlusal contacts were determined with 12‐μm articulating foil. After a calibration process according to the manufacturer's instructions, the mountings were transferred to a virtual articulator using the transfer plates in a laboratory scanner. The occlusion of the digital casts was determined before and after the occlusal optimization process. Then, the sensitivity and positive predictive value were determined by comparing the occlusal contact points in the virtual articulator with those in the mechanical articulator. To evaluate trueness, the occlusal surface of the maxillary teeth in the mechanical articulator was recorded by polyvinyl siloxane occlusal record in maximal intercuspal position and retained on the mandibular arch. The trueness was calculated as the deviation between the occlusal surface of the maxillary teeth in the mechanical articulator and the virtual articulator. To evaluate precision, one set of the casts was scanned 10 times. And the deviation of the interarch position of the maxillary arches when superimposing the mandibular arches of every 2 different scans was calculated.
Results
The sensitivity before occlusal optimization (0.14 ± 0.15) was significantly lower than that after occlusal optimization (0.82 ± 0.10) (p = 0.003). However, there was no significant difference between the positive predictive value before (0.80 ± 0.45) and after (0.81 ± 0.09) occlusal optimization (p = 0.952). The trueness before (91.0 ± 10.7 µm) and after (75.4 ± 25.2 µm) occlusal optimization had no significant difference (p = 0.249). The precision before occlusal optimization (11.6 ± 3.8 µm) was significantly superior to that after occlusal optimization (75.6 ± 39.2 µm ) (p < 0.001).
Conclusions
The accuracy of transferring casts in maximal intercuspal position to a virtual articulator using transfer plates in the laboratory scanner could be improved after occlusal optimization and can meet the clinical needs for occlusal design and analysis of prostheses.
Objectives
This prospective study introduced a digitally designed sectioning guide and evaluated its feasibility for the extraction of horizontally impacted lower third molars.
Materials and methods
...This study included 38 horizontally impacted lower third molars, randomly divided into experimental and control groups. The teeth were extracted using a 3D-printed titanium surgical guide in the experimental group; free-hand extractions were performed in the control group. The surgical duration, tooth sectioning duration, cortical bone perforation, and postoperative complications, including pain, swelling, trismus, dry socket, infection, and hemorrhage, were evaluated.
Results
Although not statistically significant, guided surgery tended to reduce the number of tooth sectioning steps compared to free-hand extractions. There were no cases of cortical bone perforation in the experimental group. Although the surgical duration was greater in the experimental group (
p
< 0.05), there were no differences in postoperative pain, swelling, and trismus. There were no cases of postoperative infection and hemorrhage in either group.
Conclusions
3D-printed titanium surgical guides had superior accuracy and safety compared to free-hand surgery. Further studies with larger sample sizes are required to verify these findings.
Clinical relevance
The template improved the safety of tooth sectioning during impacted lower third molar surgery and resulted in a more predictable extraction. The narrow sectioning groove could fit comfortably with hypertrophic soft tissues in the posterior mandible.
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