Effectiveness of cardioneuroablation in different subtypes of vasovagal syncope.

BACKGROUND: Cardioneuroablation (CNA) has shown encouraging results in patients with vasovagal syncope (VVS). However, data on different subtypes was scarce. METHODS: This observational study retrospectively enrolled 141 patients [mean age: 40 ± 18 years, 51 males (36.2%)] with the diagnosis of VVS. The characteristics among different types of VVS and the outcomes after CNA were analyzed. RESULTS: After a mean follow-up of 4.3 ± 1.5 years, 41 patients (29.1%) experienced syncope/pre-syncope events after CNA. Syncope/pre-syncope recurrence significantly differed in each subtype (P = 0.04). The cardioinhibitory type of VVS had the lowest recurrence rate after the procedure (n = 6, 16.7%), followed by mixed (n = 26, 30.6%) and vasodepressive (n = 9, 45.0%). Additionally, a significant difference was observed in the analyses of the Kaplan-Meier survival curve (P = 0.02). Syncope/pre-syncope burden was significantly reduced after CNA in the vasodepressive type (P < 0.01). Vasodepressive types with recurrent syncope/pre-syncope after CNA have a lower baseline deceleration capacity (DC) level than those without (7.4 ± 1.0 ms vs. 9.0 ± 1.6 ms, P = 0.01). Patients with DC < 8.4 ms had an 8.1 (HR = 8.1, 95% CI: 2.2-30.0, P = 0.02) times risk of syncope/pre-syncope recurrence after CNA compared to patients with DC ≥ 8.4 ms, and this association still existed after adjusting for age and sex (HR = 8.1, 95% CI: 2.2-30.1, P = 0.02). CONCLUSIONS: Different subtypes exhibit different event-free rates. The vasodepressive type exhibited the lowest event-free rate, but those patients with DC ≥ 8.4 ms might benefit from CNA.

Carbon Dot-Loaded Apoptotic Vesicles Improve the Liver Kupffer Cell-Mediated Antibacterial Effect to Synergistically Alleviate Sepsis.

Sepsis is a lethal systemic inflammatory disease against infection that lacks effective therapeutic approaches. Liver resident macrophage Kupffer cell (KC)-initiated bacterial clearance is crucial for the host to defend against infection. However, it remains unclear whether this process also governs the antibacterial therapy of sepsis that would be used to improve therapeutic outcomes. Here, we found that copper-doped carbon dots (Cu-CDs) exhibited superior antibacterial capabilities in vitro but displayed limited therapeutic effects in septic mice due to their limited ability to target the liver and restore KC antimicrobial capacity. Thus, we developed a composite nanodrug of copper-doped carbon dot-loaded apoVs (CC-apoVs) that combined the antibacterial ability of Cu-CDs and liver KC targeting features of apoV. Moreover, intravenous injection of CC-apoVs markedly alleviated the systemic infection and decreased the mortality of septic mice compared to Cu-CD and apoV infusion alone. Mechanistically, CC-apoV injection rescued impaired liver KCs during sepsis and enhanced their ability to capture and kill bloodborne bacteria. In addition, apoV-promoted macrophage killing of bacteria could be blocked by the inhibition of small GTPase Rab5. This study reveals a liver KC-targeted therapeutic strategy for sepsis and provides a nanodrug CC-apoV to improve the host antibacterial defense and amplify the therapeutic effect of the nanodrug.

Characteristics of deceleration capacity and deceleration runs in vasovagal syncope.

PURPOSE: Increased vagal activity plays a prominent role in vasovagal syncope (VVS). The aim of this study was to characterize vagal function in VVS by evaluating the heart rate (HR) deceleration capacity (DC) and the HR deceleration runs (DRs) in patients with VVS between attacks. METHODS: A total of 188 consecutive VVS patients were enrolled in the study, of whom 129 had positive head-up tilt test (HUTT); 132 healthy participants were enrolled as controls. DC, DRs (DR2, i.e., episodes of 2 consecutive beat-to-beat HR decelerations), and the sum of DR8-10 (very long DR [VLDR]) were calculated using 24-h electrograms. Clinical characteristics, DC, and DRs were compared among syncope groups and controls. RESULTS: Patients with VVS had higher DC (10.63 ± 2.1 vs. 6.58 ± 1.7 ms; P < 0.001) and lower minimum HR and DR6-10 than controls. No significant differences in DC or DR6-10 were found between the patients with positive and those with negative HUTT results. In multivariate logistic regression analysis, minimum HR ≥ 40 bpm (odds ratio [OR] 0.408, 95% confidence interval [CI] 0.167-0.989; P = 0.048), daytime DC ≥ 7.37 ms (OR 3.040, 95% CI 1.220-7.576; P = 0.013), and VLDR ≥ 0.046% (OR 0.306, 95% CI 0.138-0.679; P = 0.004) were demonstrated to be risk factors significantly associated with VVS. CONCLUSION: Compared to healthy controls, patients with VVS demonstrated distinct HR deceleration profiles between attacks, including overall higher DC and lower DR6-10.

Corrigendum: Adiponectin modified BMSCs alleviate heart fibrosis via inhibition TGF-beta1/smad in diabetic rats.

[This corrects the article DOI: 10.3389/fcell.2021.644160.].

Selection of patients with symptomatic vagal-induced sinus node dysfunction: Who will be the best candidate for cardioneuroablation?

Sinus node dysfunction is a multifaceted disorder with variable manifestations, the prevalence of which increases with age. In a specific group of patients, excessive vagal activity may be the sole cause for this condition. These patients are characterized as having recurrent daytime symptoms attributed to bradyarrhythmia, no evidence of organic sinus node lesions, cardiac vagal overactivation, and are non-elderly. For sinus node dysfunction patients, a permanent pacemaker implantation appears to be the ultimate solution, although it is not an etiological treatment. Cardioneuroablation is a promising emerging therapy that can fundamentally eliminate symptoms in a highly selective sub-set of sinus node dysfunction patients by cardiac vagal nerve denervation. Denervation with ablation for vagal-induced sinus node dysfunction can effectively improve sinus bradycardia and reduce syncope. To date, guidelines for selection of suitable candidates for cardioneuroablation remain lacking. The primary objective of this study was to distinguish the nature of abnormal sinus node function and to find methods for quantifying vagal tone. Clear selection criteria could help physicians in identification of patients with autonomic imbalance, thereby maximizing patient benefits and the success rate of cardioneuroablations.

Structural optimization and in vivo evaluation of a colorectal stent with anti-migration and anti-tumor properties.

Clinically, colorectal stents can only palliatively relieve obstruction caused by colorectal cancer (CRC), with a high incidence of stent migration and tumor-related re-obstruction. To overcome these shortcomings, we developed a colorectal stent composed of a structure-optimized nitinol braided stent and a tubular film including an inner layer of poly (ethylene-co-vinyl acetate) (EVA) and a segmental outer layer of EVA with paclitaxel (PTX). The braiding pattern, segment number, and end shape of the stent were optimized based on the mechanical properties, ex vivo and in vivo anti-migration performance, and tissue response of the stent. The optimized nitinol stent had a structure of one middle segment in a hook-pattern and two end segments in a cross-pattern with two studs on each end in a staggered arrangement. Structure-optimized colorectal stents were prepared and evaluated in vivo. PTX released from the stent was mostly distributed in the rabbit rectum in contact with it. The biosafety of the colorectal stent was evaluated using blood tests, biochemical analysis, anatomical observation, and pathological analysis. The anti-tumor effect of the stent was also evaluated by endoscopy, anatomical observation, and pathological and immunohistochemical analyses in rabbits with orthotopic CRC. The results demonstrate that the optimized colorectal stents have effective anti-migration ability and anti-tumor effects with good biosafety. STATEMENT OF SIGNIFICANCE: In order to overcome the most common disadvantages of migration and re-obstruction of colorectal stents clinically, a colorectal stent composed of a structure-optimized nitinol stent and a tubular film including an inner layer of EVA and a segmental outer layer of EVA with PTX was put forward in this study. The optimized nitinol stent had a structure of one middle segment in hook-pattern and two end segments in cross-pattern with two studs on each end in staggered arrangement. The resulting colorectal stent has been proved with good anti-migration ability, anti-tumor effects, and biosafety in vivo, which provides a safe and effective potential treatment modality for patients with colorectal cancer.

The optimization of ligature/bone defect-induced periodontitis model in rats.

The destruction of alveolar bone is a crucial manifestation of severe chronic periodontitis, which stem cell-based bioengineered therapies are expected to cure. Therefore, a cost-effective, reproducible, quantifiability and easier to administrate animal model that mimics human periodontitis is of great importance for further endeavor. In this study, we created periodontitis rat models in silk ligation group, bone defect group and bone defect/silk ligation group, respectively. Obvious periodontal inflammation but slight alveolar bone resorption was observed in the ligation group, while surgical trauma was not robust enough to continually worsen the constructed bone defect area in the bone defect group. In the bone defect/ligature group, significant and stable periodontal inflammation was the most enduring with similar evolving pathological patterns of human periodontitis. It also exhibited enhanced clinical similarity and confirmed its superiority in quantitativeness. The present rat model is the first study to reproduce a pathological process similar to human periodontitis with reliable stability and repeatability, manifesting a priority to previous methods. Day 9-12 is the best time for reproducing severe periodontitis syndromes with vertical bone resorption in this model.

On the correlation between serum Cystatin C and Parkinson's disease in the Chinese population: a promising biomarker?

As there is no clear biomarker to diagnose Parkinson's disease, this meta-analysis aims to comprehensively evaluates the correlation between serum Cystatin C levels and Parkinson's disease in the Chinese population by the meta-analysis method. PubMed, Web of Science, Embase, Cochrane Library, China national knowledge infrastructure, and China WanFang databases were systematically searched on the correlation between serum Cystatin C and Parkinson's disease. The results showed that Cystatin C level in Parkinson's disease patients compared with the control group, the standardized mean difference = 1.78 (95% CI: 1.33~2.24, P < 0.05). The level of Cystatin C in the late Parkinson's disease stage compared with that in the mid-term of Parkinson's disease, the standardized mean difference was = 0.78 (95% CI: 0.08~1.49, P < 0.05). The Cystatin C level in the mid-term of Parkinson's disease compared with that in the early Parkinson's disease stage, the standardized mean difference was 1.24 (95% CI: 0.35~2.12, P < 0.05). The level of Cystatin C in Parkinson's disease with mild cognitive impairment compared with Parkinson's disease without mild cognitive impairment, the standardized mean difference was 1.29 (95% CI: 0.47~2.10, P < 0.05). The differences were all statistically significant. In conclusion, a high level of serum Cystatin C may be involved in the occurrence and development of Parkinson's disease, whose level is higher in Parkinson's disease patients with mild cognitive impairment than that in Parkinson's disease without mild cognitive impairment. Therefore, Cystatin C in serum is a promising biomarker for diagnosing Parkinson's disease.

CD157 in bone marrow mesenchymal stem cells mediates mitochondrial production and transfer to improve neuronal apoptosis and functional recovery after spinal cord injury.

BACKGROUND: Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. METHODS: We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. RESULTS: CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. CONCLUSION: The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

Adiponectin Modified BMSCs Alleviate Heart Fibrosis via Inhibition TGF-beta1/Smad in Diabetic Rats.

Background: Accumulating evidence suggested that bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential for diabetes and heart diseases. However, the effects of BMSC on reducing myocardial fibrosis need to be optimized. This study aimed to investigate the mechanism of adiponectin (APN) modified BMSCs on myocardial fibrosis in diabetic model in vivo and in vitro. Methods: The high-fat diet combined with streptozotocin (STZ) injection were used to induced diabetic rat model. H9c2 cells were cultured under a high glucose medium as in vitro model. The BMSCs were modified by APN plasmid or APN small interfering RNA (siRNA), then transplanted to the diabetic rats by a single tail-vein injection, or co-cultured with H9c2 cells. Results: We demonstrated that diabetic rats showed typical diabetic symptoms, such as decreased cardiac function, accumulation of pathological lesions and collagen expression. However, these impairments were significantly prevented by the APN modified BMSCs treatment while no effects on APN siRNA modified BMSCs treated diabetic rats. Moreover, we confirmed that APN modified BMSCs could attenuate the expression of TGF-beta1/smad to suppress the myocardial fibrosis in the diabetic rats and high glucose induced H9c2 cells. Conclusion: The present results for the first time showed that APN modified BMSCs exerted protection on cardiac fibrosis via inhibiting TGF-beta1/smad signal pathway in diabetic rats. Our findings suggested that APN modified BMSCs might be a novel and optimal therapy for the diabetic cardiomyopathy in future.

Simultaneous ultraviolet B-induced photo-oxidation of tryptophan/tyrosine and racemization of neighboring aspartyl residues in peptides.

Although proteins consist exclusively of l-amino acids, it is well known that d-isomers of aspartyl (Asp) residues occur at specific sites in lens crystallins of elderly people with cataracts. The presence of d-isomers is thought to result from the racemization of Asp residues in the crystallins during aging. It has been reported that this racemization progresses owing to UV-B exposure; however, the underlying mechanism remains unknown because Asp is not a photosensitive residue because there is no aromatic group in its chemical structure. In this study, we synthesized peptides in which the residue neighboring the Asp was the photosensitive residue tryptophan (Trp) or tyrosine (Tyr). After exposing these peptides to UV-B, we used RP-HPLC to confirm that racemization of Asp residues occurred in peptides in which a Trp or Tyr residue was inserted near the Asp; simultaneously, several varieties of photoproducts derived from Trp and Tyr were detected by mass spectroscopy. Promotion of the racemization of Asp residues in peptides with a neighboring Trp was much more significant than in those with Tyr. In particular, when Trp was next to an Asp residue on the C-terminal side of the peptide, the racemization reaction was accelerated.