Neutralization of Intracellular pH Homeostasis to Inhibit Osteoclasts Based on a Spatiotemporally Selective Delivery System.

Osteoporosis is a global disease caused by abnormal overactivation of osteoclasts. The acidic environment in sealing zone of osteoclasts with H+ pumped from cytoplasm is critical to the maturation of osteoclasts. Therefore, reducing the intracellular H+ concentration can reduce the H+ secretion of osteoclasts from the source. In our study, we developed a novel nanovesicle which encapsulates Na2HPO4 with a liposome hybridizes with preosteoclast membrane (Na2HPO4@Lipo-pOCm). These nanovesicles release Na2HPO4 into the preosteoclast by targeting preosteoclasts and membrane fusion, reducing the intracellular H+ concentration, and achieve biological cascade regulation of osteoclasts through simple pH regulation. In vitro and in vivo experiments confirmed that these nanovesicles reduce mitochondrial membrane potential by decreasing intracellular H+ concentration, thereby reducing the ROS in osteoclasts as well as the expression of the upstream transcription factor FOXM1 of Acp5. In short, this nanovesicle can significantly inhibit the osteoclasts and ameliorate osteoporosis caused by OVX.

Characteristics of MRI­based vertebral bone quality scores in elderly patients with vertebral fragility fractures.

OBJECTIVE: To explore the characteristics of vertebral bone quality (VBQ) scores in patients with vertebral fragility fractures, including VBQ score and single-level VBQ score, and evaluate their effectiveness as predictors. METHODS: The VBQ scores were measured using T1-weighted MRI images. VBQ scores were compared in patients with different times of previous fragility fractures. In addition, patients with fractures were matched for age and sex with patients without fractures, and VBQ scores were compared between the two groups. Finally, the predictive efficiency of VBQ scores for vertebral fragility fractures was analyzed by the receiver-operator curve (ROC). RESULTS: The average VBQ score and single-level VBQ score in patients with fractures were 3.48 ± 0.56 and 3.60 ± 0.60 and no difference among patients with different times of previous fractures. As for the age- and sex-matched patients, fracture patients had higher VBQ scores (VBQ score: 3.48 ± 0.56 vs. 2.88 ± 0.40, p < 0.001; single-level VBQ score: 3.60 ± 0.60 vs. 2.95 ± 0.44, p < 0.001). The AUCs using the VBQ score and single-level VBQ score to predict fragility fractures were 0.815 and 0.817, respectively. The optimal thresholds of the VBQ score and single-level VBQ score for predicting fragility fractures were 3.22 and 3.16, respectively. CONCLUSION: MRI­based VBQ scores are important predictors of vertebral fragility fracture but have no predictive value for the recurrence of fractures in patients with a history of fragility fractures. The VBQ score of 3.22 and single-level VBQ score of 3.16 are optimal thresholds that can be used when using lumbar MRI scans to identify individuals at high risk for fragility fractures.

Combinations of two imaging parameters to improve bone mineral density (BMD) assessment in patients with lumbar degenerative diseases.

PURPOSE: To explore whether combining the Hounsfield unit (HU) values and vertebral bone quality (VBQ) scores can improve the BMD assessment in patients with lumbar degenerative diseases. METHODS: The HU values were measured by CT image, and VBQ scores were calculated by lumbar MRI image. The correlations of the opportunistic imaging parameters to the lowest T-scores were analyzed. Receiver-operating characteristic curve (ROC) analysis was used to evaluate the accuracy in detecting osteoporosis. Finally, the specificity and sensitivity of different combined methods of the HU values and VBQ scores in the diagnosis of osteoporosis were compared. RESULTS: Patients with osteoporosis had the lowest HU values and the highest VBQ scores. The correlation coefficients between the VBQ scores and the T-scores were smaller than HU values (L1 HU value: 0.702; average HU value:0.700; L1 VBQ score: -0.413; VBQ score: -0.386). The areas under the curve (AUCs) of the HU values were greater than those of the VBQ scores, and the AUCs of the L1 VBQ score were similar to the VBQ score (L1 HU value: 0.850; average HU value:0.857; L1 VBQ score: 0.704; VBQ score: 0.673). When combining the two imaging parameters in series, the specificity of the detection of osteoporosis was improved (L1 HU value and L1 VBQ score: 87.3%; Average HU value and VBQ score: 85.9%). When combining the two imaging parameters in parallel, the sensitivity of the detection of osteoporosis was improved (L1 HU value or L1 VBQ score: 88.1%; Average HU value or VBQ score: 91.5%). CONCLUSIONS: Combinations of the HU values and VBQ scores could improve the diagnostic performance of osteoporosis. In addition, considering the same diagnostic performance but easier measurement, parameters at the single-segment level were recommended to assist in the diagnosis of osteoporosis.

Validation and derivation of short-term prognostic risk score in acute decompensated heart failure in China.

BACKGROUND: Few prognostic risk scores (PRSs) have been routinely used in acute decompensated heart failure (ADHF). We, therefore, externally validated three published PRSs (3A3B, AHEAD, and OPTIME-CHF) and derived a new PRS to predict the short-term prognosis in ADHF. METHODS: A total of 4550 patients from the Heb-ADHF registry in China were randomly divided into the derivation and validation cohorts (3:2). Discrimination of each PRS was assessed by the area under the receiver operating characteristic curve (AUROC). Logistic regression was exploited to select the predictors and create the new PRS. The Hosmer-Lemeshow goodness-of-fit test was used to assess the calibration of the new PRS. RESULTS: The AUROCs of the 3A3B, AHEAD, and OPTIME-CHF score in the derivation cohort were 0.55 (95% CI 0.53-0.57), 0.54 (95% CI 0.53-0.56), and 0.56 (95% CI 0.54-0.57), respectively. After logistic regression analysis, the new PRS computed as 1 × (diastolic blood pressure < 80 mmHg) + 2 × (lymphocyte > 1.11 × 109/L) + 1 × (creatinine > 80 µmol/L) + 2 × (blood urea nitrogen > 21 mg/dL) + 1 × [BNP 500 to < 1500 pg/mL (NT-proBNP 2500 to < 7500 pg/mL)] or 3 × [BNP ≥ 1500 (NT-proBNP ≥ 7500) pg/mL] + 3 × (QRS fraction of electrocardiogram < 55%) + 4 × (ACEI/ARB not used) + 1 × (rhBNP used), with a better AUROC of 0.67 (95% CI 0.64-0.70) and a good calibration (Hosmer-Lemeshow χ2 = 3.366, P = 0.186). The results in validation cohort verified these findings. CONCLUSIONS: The short-term prognostic values of 3A3B, AHEAD, and OPTIME-CHF score in ADHF patients were all poor, while the new PRS exhibited potential predictive ability. We demonstrated the QRS fraction of electrocardiogram as a novel predictor for the short-term outcomes of ADHF for the first time. Our findings might help to recognize high-risk ADHF patients.

MRI­based vertebral bone quality score is a comprehensive index reflecting the quality of bone and paravertebral muscle.

BACKGROUND: Recently, vertebral bone quality (VBQ) score has been shown to predict bone mineral density (BMD) and spine-related postoperative complications. However, in clinical work, we found that patients with higher VBQ scores also had more severe paravertebral muscle degeneration. PURPOSE: To explore the ability of the VBQ score to evaluate BMD and paravertebral muscle quality. STUDY DESIGN/SETTING: Retrospective single-center cohort. PATIENT SAMPLE: Patients in the spinal surgery department of our hospital. OUTCOME MEASURES: Bone mineral density and T-score were measured by dual-energy X-ray absorptiometry (DXA). The Picture Archiving and Communication Systems (PACS) measured the cross-sectional area (CSA) of the paravertebral muscles. Image J software was used to measure the degree of fat infiltration (DFF) of the paraspinal muscle. METHODS: Patients who underwent lumbar MRI and DXA simultaneously within two weeks were enrolled. The VBQ score was calculated using T1-weighted lumbar MRI images. Firstly, BMD-related and muscle-related parameters of patients with different VBQ scores were compared. Then, the correlation coefficients between the VBQ score and the parameters of BMD and paravertebral muscle were calculated. Finally, multivariate linear analysis was used to compare the contribution of each variable to the VBQ score. RESULTS: A total of 101 patients were eventually included in this study for analysis. When the VBQ score was greater than 3.0, the patients were mostly female, older, less likely to smoke, and had lower BMD. Interestingly, we found that patients with VBQ scores greater than 3.0 had smaller CSA of the paravertebral muscles (ES: 17.53±3.36 vs 19.13±3.97, p=.032; total: 29.59±5.27 vs 34.12±7.02, p<.001) and higher DFF (MF: 22.47±5.93 vs 19.64±5.28, p=.015; ES: 17.71±4.67 vs 15.74±4.62, p=.038; PM: 13.70±3.32 vs 11.33±3.02, p<.001; average: 17.96±3.78 vs 15.57±3.42, p=.001). The VBQ score was negatively correlated with the CSA (MF: r=-0.316, p=.001; ES: r =-0.388, p=.001; PM: r=0.388, p=.001) and positively correlated with the DFF (MF: r=0.344, p<.001; ES: r=0.439, p<.001; PM: =0.416, p<.001). In multivariate linear analysis, BMD, total CSA, and average DFF determined the value of the VBQ score, and the contribution of paravertebral muscle was higher than that of BMD (BMD: r=-0.203, p=.024; total CSA: r=-0.294, p=.003; average DFF: r=0.261, p=.011). CONCLUSIONS: This study is the first to find a positive association between the VBQ score and paravertebral muscle degeneration, and this association may be independent of BMD. VBQ can reflect the quality of bone and paravertebral muscle, which is its special advantage in clinical application.

Targeting initial tumour-osteoclast spatiotemporal interaction to prevent bone metastasis.

Bone is the most common site of metastasis, and although low proliferation and immunoediting at the early stage make existing treatment modalities less effective, the microenvironment-inducing behaviour could be a target for early intervention. Here we report on a spatiotemporal coupling interaction between tumour cells and osteoclasts, and named the tumour-associated osteoclast 'tumasteoclast'-a subtype of osteoclasts in bone metastases induced by tumour-migrasome-mediated cytoplasmic transfer. We subsequently propose an in situ decoupling-killing strategy in which tetracycline-modified nanoliposomes encapsulating sodium bicarbonate and sodium hydrogen phosphate are designed to specifically release high concentrations of hydrogen phosphate ions triggered by tumasteoclasts, which depletes calcium ions and forms calcium-phosphorus crystals. This can inhibit the formation of migrasomes for decoupling and disrupt cell membrane for killing, thereby achieving early prevention of bone metastasis. This study provides a research model for exploring tumour cell behaviour in detail and a proof-of-concept for behaviour-targeting strategy.

Platelet-derived extracellular vesicles ameliorate intervertebral disc degeneration by alleviating mitochondrial dysfunction.

Mitochondrial dysfunction causes the production of reactive oxygen species (ROS) and oxidative damage, and oxidative stress and inflammation are considered key factors causing intervertebral disc degeneration (IVDD). Thus, restoring the mitochondrial dysfunction is an attractive strategy for treating IVDD. Platelet-derived extracellular vesicles (PEVs) are nanoparticles that target inflammation. Moreover, the vesicles produced by platelets (PLTs) have considerable anti-inflammatory effects. We investigate the use of PEVs as a therapeutic strategy for IVDD in this study. We extract PEVs and evaluate their properties; test their effects on H2O2-induced oxidative damage of nucleus pulposus (NP) cells; verify the role of PEVs in repairing H2O2-induced cellular mitochondrial dysfunction; and demonstrate the therapeutic effects of PEVs in a rat IVDD model. The results confirm that PEVs can restore impaired mitochondrial function, reduce oxidative stress, and restore cell metabolism by regulating the sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α)-mitochondrial transcription factor A (TFAM) pathway; in rat models, PEVs retard the progression of IVDD. Our results demonstrate that the injection of PEVs can be a promising strategy for treating patients with IVDD.

Associations between serum electrolyte and short-term outcomes in patients with acute decompensated heart failure.

INTRODUCTION: There is a dearth of comprehensive studies on the association between serum electrolyte and adverse short-term prognosis of Chinese patients with acute decompensated heart failure (ADHF). PATIENTS AND METHODS: A total of 5166 patients with ADHF were divided into four serum electrolyte-related study populations (potassium (n = 5145), sodium (n = 5135), chloride (n = 4966), serum total calcium (STC) (n = 4143)) under corresponding exclusions. Different logistic regression models were utilized to gauge the association between these electrolytes or the number of electrolyte abnormalities and the risk of a composite of all-cause mortality or 30-day heart failure (HF) readmission. RESULTS: In multivariable adjusted analysis, patients with potassium below 3.5 mmol/L (odds ratios (ORs) 1.45; 95% confidence interval (CI):1.07-1.95), 4.01-4.50 mmol/L (OR: 1.29, CI: 1.02-1.62), 4.51-5.00 mmol/L (OR: 1.43, CI: 1.08-1.90) and above 5.00 mmol/L (OR: 1.74, CI: 1.21-2.51) had an increased risk of outcome when compared with potassium at 3.50-4.00 mmol/L. Sodium levels were inversely related to the risk of a composite outcome (<130 mmol/L: OR: 2.73 (95% CI, 1.81-4.12); 130-134 mmol/L: OR, 1.97 (CI, 1.45-2.68); 135-140 mmol/L: OR, 1.45 (CI, 1.17-1.81); p for trend < 0.001) in comparison with sodium at 141-145 mmol/L. Chloride < 95 mmol/L corresponded to a higher risk of a composite outcome with an OR of 1.65 (95% CI, 1.16-2.37) in contrast to chloride levels at 101-105 mmol/L. In addition, the adjusted ORs (95% CI) for a composite outcome comparing the STC < 2.00 and 2.00-2.24 vs. 2.25-2.58 mmol/L were 0.98 (0.69-1.43) and 1.13 (0.89-1.44), respectively. Besides that, the number of electrolyte abnormalities was positively related to the risk of a composite outcome (N = 1, OR 1.40, 95% CI: 1.13-1.73; N = 2, OR 2.51, 95% CI: 1.85-3.42; N = 3, OR 2.47, 95% CI: 1.45-4.19; p for trend < 0.001) in comparison with N = 0. CONCLUSIONS: A deviation of potassium levels from 3.50 to 4.00 mmol/L, lower sodium levels and hypochloremia were associated with poorer short-term prognosis of ADHF. Furthermore, the number of electrolyte abnormalities positively correlated with adverse short-term prognosis of patients with ADHF. Key MessagesADHF patients with baseline serum potassium at first half part of normal range (3.50-4.00 mmol/L) may herald the lowest risk of recent cardiovascular events.Serum sodium and chloride levels exhibit discrepancies in terms of risk of short-term adverse events of ADHF patients.The number of electrolyte abnormalities is a significant predictor of poor short-term prognosis in patients with ADHF. CLINICAL TRIAL REGISTRATION URL: http://www.chictr.org.cn/showproj.aspx?proj=23139. Unique identifier: ChiCTR-POC-17014020.

Suppression of osteoclast multinucleation via a posttranscriptional regulation-based spatiotemporally selective delivery system.

Redundancy of multinucleated mature osteoclasts, which results from the excessive fusion of mononucleated preosteoclasts (pOCs), leads to osteolytic diseases such as osteoporosis. Unfortunately, the currently available clinical drugs completely inhibit osteoclasts, thus interfering with normal physiological bone turnover. pOC-specific regulation may be more suitable for maintaining bone homeostasis. Here, circBBS9, a previously unidentified circular RNA, was found to exert regulatory effects via the circBBS9/miR-423-3p/Traf6 axis in pOCs. To overcome the long-standing challenge of spatiotemporal RNA delivery to cells, we constructed biomimetic nanoparticles to achieve the pOC-specific targeted delivery of circBBS9. pOC membranes (POCMs) were extracted to camouflage cationic polymer for RNA interference with circBBS9 (POCM-NPs@siRNA/shRNAcircBBS9). POCM-NPs endowed the nanocarriers with improved stability, accurate pOC targeting, fusogenic uptake, and reactive oxygen species-responsive release. In summary, our findings may provide an alternative strategy for multinucleated cell-related diseases that involves restriction of mononucleated cell multinucleation through a spatiotemporally selective delivery system.

Use of cutting balloons in coronary interventions.

OBJECTIVE: To study the efficacy and safety of cutting balloons in coronary interventions. METHODS: Twenty-two patients with 23 narrowed coronary arteries and 25 lesions enrolled the study, 17 of whom had 18 diseased coronary arteries and 18 lesions were in-stent restenosis. The average time from previous stenting was 7.60 +/- 3.53 months. The lesions were dilated with cutting balloons. RESULTS: All of the lesions were dilated successfully by 5.16 +/- 2.30 inflations of a cutting balloon. The mean total duration of balloon inflation was 233.96 +/- 94.83 seconds at pressures up to 9.40 +/- 1.96 bars. The severity of vascular stenosis was lessened substantially (89.64 +/- 8.65% vs 17.60 +/- 17.15%, P = 0.000) without severe complications. Three restenotic lesions were further dilated with conventional balloons, another one was stented again because of a dissection distal to the previous stent. Three primary lesions were stented for dissection or residual stenosis. Angina pectoris reoccurred in two patients in a mean follow-up period of 7.42 +/- 6.87 (range 0.5-20) months. CONCLUSION: Cutting balloon dilation is an effective and safe choice in interventions for coronary disease especially for in-stent restenosis.