Contrast-Enhanced CT-Based Deep Learning Radiomics Nomogram for the Survival Prediction in Gallbladder Cancer Postoperative.

RATIONALE AND OBJECTIVES: An accurate prognostic model is essential for the development of treatment strategies for gallbladder cancer (GBC). This study proposes an integrated model using clinical features, radiomics, and deep learning based on contrast-enhanced computed tomography (CT) images for survival prediction in patients with GBC after surgical resection. METHODS: A total of 167 patients with GBC who underwent surgical resection at two medical institutions were retrospectively enrolled. After obtaining the pre-treatment CT images, the tumor lesions were manually segmented, and handcrafted radiomics features were extracted. A clinical prognostic signature and radiomics signature were built using machine learning algorithms based on the optimal clinical features or handcrafted radiomics features, respectively. Subsequently, a DenseNet121 model was employed for transfer learning on the radiomics image data and as the basis for the deep learning signature. Finally, we used logistic regression on the three signatures to obtain the unified multimodal model for comprehensive interpretation and analysis. RESULTS: The integrated model performed better than the other models, exhibiting the highest area under the curve (AUC) of 0.870 in the test set, and the highest concordance index (C-index) of 0.736 in predicting patient survival rates. A Kaplan-Meier analysis demonstrated that patients in high-risk group had a lower survival probability compared to those in low-risk group (log-rank p < 0.05). CONCLUSION: The nomogram is useful for predicting the survival of patients with GBC after surgical resection, helping in the identification of high-risk patients with poor prognosis and ultimately facilitating individualized management of patients with GBC.

Machine learning-based identification of symptomatic carotid atherosclerotic plaques with dual-energy computed tomography angiography.

OBJECTIVE: This study aimed to develop and validate a machine learning model incorporating both dual-energy computed tomography (DECT) angiography quantitative parameters and clinically relevant risk factors for the identification of symptomatic carotid plaques to prevent acute cerebrovascular events. METHODS: The data of 180 patients with carotid atherosclerosis plaques were analysed from January 2017 to December 2021; 110 patients (64.03±9.58 years old, 20 women, 90 men) were allocated to the symptomatic group, and 70 patients (64.70±9.89 years old, 50 women, 20 men) were allocated to the asymptomatic group. Overall, five machine learning models using the XGBoost algorithm, based on different CT and clinical features, were developed in the training cohort. The performances of all five models were assessed in the testing cohort using receiver operating characteristic curves, accuracy, recall rate, and F1 score. RESULTS: The shapley additive explanation (SHAP) value ranking showed fat fraction (FF) as the highest among all CT and clinical features and normalised iodine density (NID) as the 10th. The model based on the top 10 features from the SHAP measurement showed optimal performance (area under the curve [AUC] .885, accuracy .833, recall rate .933, F1 score .861), compared with the other four models based on conventional CT features (AUC .588, accuracy .593, recall rate .767, F1 score .676), DECT features (AUC .685, accuracy .648, recall rate .667, F1 score .678), conventional CT and DECT features (AUC .819, accuracy .740, recall rate .867, F1 score .788), and all CT and clinical features (AUC .878, accuracy .833, recall rate .867, F1 score .852). CONCLUSION: FF and NID can serve as useful imaging markers of symptomatic carotid plaques. This tree-based machine learning model incorporating both DECT and clinical features could potentially comprise a non-invasive method for identification of symptomatic carotid plaques to guide clinical treatment strategies.

Orthodontic retreatment of an adult woman with mandibular backward positioning and temporomandibular joint disorder: A case report.

BACKGROUND: The role of occlusal factors on the occurrence of temporomandibular joint disorders (TMDs) is still unclear and it is tricky for orthodontists to treat malocclusions in patients with TMDs. We report the case of the second orthodontic treatment of an adult female with Class II division 2 malocclusion associated with TMD. With the removal of anterior occlusal interference, TMD symptoms were alleviated and cone beam computed tomography (CBCT) images showed the bilateral condyles shifted forward. CASE SUMMARY: This case report presented an orthodontic retreatment of an adult female with TMD and mandibular backward positioning based on CBCT examination and Joint Space Index (JSI) analysis. The left and right JSI values of -38.5 and -52.6 indicated that the position of bilateral condyles had posterior displacement. Ten years prior to this evaluation, she underwent orthodontic treatment resulting in the extraction of two upper premolars and one lower central incisor. The joint symptoms, including pain and sounds, were alleviated along with verified mandibular forward repositioning by extraction of another lower central incisor. CONCLUSION: Mandibular backward positioning could be associated with TMD. JSI analysis based on CBCT is a convenient way to examine condylar positions quantitatively.

Obstructive sleep apnea increases heart rhythm disorders and worsens subsequent outcomes in elderly patients with subacute myocardial infarction.

OBJECTIVE: Obstructive sleep apnea (OSA) is a potential cardiovascular risk. We aimed to investigate the association of OSA with heart rhythm disorders and prognosis in elderly patients with new-onset acute myocardial infarction (AMI). METHODS: We prospectively enrolled 252 AMI elderly patients (mean age, 68.5 ± 6.9 years) who were undergoing revascularization and completed a sleep study during their hospitalization. All subjects were categorized into non-OSA (apnea-hypopnea index (AHI) < 15, n = 130) and OSA (AHI ≥ 15, n = 122) groups based on the AHI. The changes in the autonomic nervous system, incidence of arrhythmia during nocturnal sleep, and major adverse cardiovascular and cerebrovascular events (MACCEs) were compared between the groups. RESULTS: The mean AHI value in all AMI patients was 22.8 ± 10.9. OSA patients showed higher levels of body mass index and peak high-sensitivity C-reactive protein and lower levels of minimum nocturnal oxygen saturation (MinSaO2), as well as greater proportion of multivessel coronary artery disease (all P < 0.05). The OSA group also showed significant increases in heart rate variability and heart rate turbulence onset (both P < 0.05) and higher incidence of arrhythmia (including sinus, atrial, and ventricular in origin). At a median follow-up of 6 months (mean 0.8-1.6 years), OSA (AHI ≥ 15) combined with hypoxia (MinSaO 2 ≤ 80%) was independently associated with the incidence of MACCEs (hazard ratio [HR]: 4.536; 95% confidence interval [CI]: 1.461-14.084,P = 0.009) after adjusting for traditional risk factors. CONCLUSIONS: OSA and OSA-induced hypoxia may correlate with the severity of myocardial infarction, increase the occurrence of heart rhythm disorders in elderly subacute MI patients, and worsen their short-term poor outcomes.

Efficacy Evaluation and Tracking of Bone Marrow Stromal Stem Cells in a Rat Model of Renal Ischemia-Reperfusion Injury.

OBJECTIVES: The aim of this study was to evaluate the effects of bone marrow stromal stem cells (BMSCs) on renal ischemia-reperfusion injury (RIRI) and dynamically monitor engrafted BMSCs in vivo for the early prediction of their therapeutic effects in a rat model. METHODS: A rat model of RIRI was prepared by clamping the left renal artery for 45 min. One week after renal artery clamping, 2 × 106 superparamagnetic iron oxide- (SPIO-) labeled BMSCs were injected into the renal artery. Next, MR imaging of the kidneys was performed on days 1, 7, 14, and 21 after cell transplantation. On day 21, after transplantation, serum creatinine (Scr) and urea nitrogen (BUN) levels were assessed, and HE staining and TUNEL assay were also performed. RESULTS: The body weight growth rates in the SPIO-BMSC group were significantly higher than those in the PBS group (P < 0.05), and the Scr and BUN levels were also significantly lower than those in the PBS group (P < 0.05). HE staining showed that the degree of degeneration and vacuole-like changes in the renal tubular epithelial cells in the SPIO-BMSC group was significantly better than that observed in the PBS group. The TUNEL assay showed that the number of apoptotic renal tubular epithelial cells in the SPIO-BMSC group was significantly lower than that in the PBS group. The T2 value of the renal lesion was the highest on day 1 after cell transplantation, and it gradually decreased with time in both the PBS and SPIO-BMSC groups but was always the lowest in the SPIO-BMSC group. CONCLUSION: SPIO-labeled BMSC transplantation can significantly promote the recovery of RIRI and noninvasive dynamic monitoring of engrafted cells and can also be performed simultaneously with MRI in vivo for the early prediction of therapeutic effects.

A dual-mode nanoparticle based on natural biomaterials for photoacoustic and magnetic resonance imaging of bone mesenchymal stem cells in vivo.

Stem cell imaging in vivo is critical to elucidate the homing, distribution, survival, and repair mechanisms and to evaluate the therapeutic effects of engrafted stem cells. Unfortunately, unimodal imaging of stem cells does not simultaneously satisfy all current requirements owing to their intrinsic limitations. Obviously, bimodal or multimodal imaging of stem cells is a promising strategy for circumventing this issue. This study aimed to design and synthesize a novel dual-modal polyethylene glycol-modified magnetic nanoparticle (Fe3+-PEG-MNP) based on natural biomaterials including melanin and Fe ions for photoacoustic (PA) and magnetic resonance (MR) imaging of stem cells in vivo. The Fe3+-PEG-MNPs were characterized and their PA/MR imaging capability and cytotoxicity were evaluated. Bone marrow mesenchymal stem cells (BM-MSCs) labeled with Fe3+-PEG-MNPs were subjected to PA and MR imaging in vitro and in vivo. Consequently, Fe3+-PEG-MNPs displayed many superior properties, including ultra-small particle size, higher stability, water solubility, easy labeling of cells, lower cytotoxicity, high biosafety, excellent capability of PA/MR imaging, high sensitivity and long-term monitoring in vitro and in vivo. In particular, PA and MR signals of labeled BM-MSCs were maintained for at least 35 and 28 d, respectively, in vivo. Therefore, Fe3+-PEG-MNPs are ideal dual-modal PA/MR nanoparticles for non-invasive and effective monitoring of engrafted stem cells in vivo.

[Orthodontic intrusion of the first and second mandibular molars with a vacuum-formed removable appliance: a case report].

This case report focused on a patient with supraeruption of the first and second mandibular molars as a result of loss of the first and second maxillary molars for a long time. We adopted a combination of a vacuum-formed removable appliance and elastics to intrude the first and second mandibular molars by using a continuous, light force to acquire sufficient restoration space for maxillary molars. Thus, the dental-implant treatment was successful, and a good and stable occlusal relationship was established.

A promising magnetic resonance stem cell tracer based on natural biomaterials in a biological system: manganese(II) chelated to melanin nanoparticles.

BACKGROUND: Melanin and manganese are both indispensable natural substances that play crucial roles in the human body. Melanin has been used as a multimodality imaging nanoplatform for biology science research because of its natural binding ability with metal ions (eg, 64Cu2+, Fe3+, and Gd3+). Because of its effects on T1 signal enhancement, Mn-based nanoparticles have been used in magnetic resonance (MR) quantitative cell tracking in vivo. Stem cell tracking in vivo is an essential technology used to characterize engrafted stem cells, including cellular viability, biodistribution, differentiation capacity, and long-term fate. METHODS: In the present study, manganese(II) ions chelated to melanin nanoparticles [MNP-Mn(II)] were synthesized. The characteristics, stem cell labeling efficiency, and cytotoxicity of the nanoparticles were evaluated. MR imaging of the labeled stem cells in vivo and in vitro were also further performed. In T1 relaxivity (r1), MNP-Mn(II) were significantly more abundant than Omniscan. Bone marrow-derived stem cells (BMSCs) can be labeled easily by coincubating with MNP-Mn(II), suggesting that MNP-Mn(II) had high biocompatibility. RESULTS: Cell Counting Kit-8 assays revealed that MNP-Mn(II) had almost no cytotoxicity when used to label BMSCs, even with a very high concentration (1,600 µg/mL). BMSCs labeled with MNP-Mn(II) could generate a hyperintense T1 signal both in vitro and in vivo, and the hyperintense T1 signal in vivo persisted for at least 28 days. CONCLUSION: Taken together, our results showed that MNP-Mn(II) possessed many excellent properties for potential quantitative stem cell tracking in vivo.

Glycated Apolipoprotein A-IV Induces Atherogenesis in Patients With CAD in Type 2 Diabetes.

BACKGROUND: Nonenzymatic glycation of apolipoproteins plays a role in the pathogenesis of the vascular complications of diabetes. OBJECTIVES: This study investigated whether apolipoprotein (apo) A-IV was glycated in patients with type 2 diabetes mellitus (T2DM) and whether apoA-IV glycation was related to coronary artery disease (CAD). The study also determined the biological effects of glycated apoA-IV. METHODS: The authors consecutively enrolled 204 patients with T2DM without CAD (Group I), 515 patients with T2DM with CAD (Group II), and 176 healthy subjects (control group) in this study. ApoA-IV was precipitated from ultracentrifugally isolated high-density lipoprotein, and its glycation level was determined based on Western blotting densitometry (relative intensity of apoA-IV glycation). ApoA-IV NƐ-(carboxylmethyl) lysine (CML) modification sites were identified by mass spectrometry in 37 control subjects, 63 patients in Group I, and 138 patients in Group II. Saline or glycated apoA-IV (g-apoA-IV) generated by glyoxal culture was injected into apoE-/- mice to evaluate atherogenesis, and was also used for the cell experiments. RESULTS: The relative intensity and the abundance of apoA-IV glycation were associated with the presence and severity of CAD in patients with T2DM (all p < 0.05). The experiments showed that g-apoA-IV induced proinflammatory reactions in vitro and promoted atherogenesis in apoE-/- mice through the nuclear receptor NR4A3. G-apoA-IV with mutations (K-A) at high-frequency glycation sites exhibited more weakened proinflammatory and atherogenic effects than did g-apoA-IV both in vitro and in vivo. CONCLUSIONS: ApoA-IV glycation is associated with CAD severity in patients with T2DM, and g-apoA-IV induces atherogenesis through NR4A3 in apoE-/- mice.

Association of Serum HMGB2 Levels With In-Stent Restenosis: HMGB2 Promotes Neointimal Hyperplasia in Mice With Femoral Artery Injury and Proliferation and Migration of VSMCs.

OBJECTIVE: In a previous study, we established diabetic and nondiabetic minipig models with coronary artery in-stent restenosis (ISR). Mass spectrometry showed that high-mobility group box (HMGB) 2 level was higher in ISR than in non-ISR tissue from diabetic minipigs. We here investigated whether serum HMGB2 levels were related to ISR in coronary artery disease patients. The effect of HMGB2 was evaluated in mice with femoral artery wire injury and in human aortic smooth muscle cells. APPROACH AND RESULTS: From 2513 patients undergoing coronary artery intervention and follow-up angiography at ≈1 year, 262 patients were diagnosed with ISR, and 298 patients with no ISR were randomly included as controls. Serum HMGB2 levels were significantly higher in patients with ISR than in those without ISR and were associated with ISR severity. Multivariable logistic regression analysis showed that HMGB2 level was independently associated with ISR. In experiments, HMGB2 expression was increased in vascular tissue after injury. Perivascular HMGB2 administration promoted injury-induced neointimal hyperplasia in C57Bl/6 mice compared with in the control, whereas such pathophysiological features were attenuated in Hmgb2-/- mice. Mechanistically, HMGB2 enhanced neointimal hyperplasia in mice and proliferation and migration in human aortic smooth muscle cells by inducing reactive oxygen species through increased p47phox phosphorylation. Knocking down p47phox, however, inhibited HMGB2-induced effects in human aortic smooth muscle cells. Finally, HMGB2-induced effects were significantly declined in receptor of advanced glycation end products knockdown or deficient cells, but not in Toll-like receptor 4 knockdown or deficient cells. CONCLUSIONS: Serum HMGB2 levels were associated with ISR in patients. HMGB2 promoted neointimal hyperplasia in mice with arterial wire injury through reactive oxygen species activation.

Association of serum HMGB2 level with MACE at 1 mo of myocardial infarction: Aggravation of myocardial ischemic injury in rats by HMGB2 via ROS.

High-mobility group box (HMGB) family is related to inflammatory diseases. We investigated whether serum HMGB2 levels are related to myocardial infarction (MI) severity and major adverse cardiac events (MACE) during MI. We included 432 consecutive patients with ST-segment elevation myocardial infarction and 312 controls. Serum HMGB2 levels were significantly higher in MI patients than in controls. Increased HMGB2 levels were associated with MACE and negatively with ejection fraction in MI patients. HMGB2 was an independent determinant of MACE in logistic regression analysis. HMGB2 protein (10 µg) or saline was injected intramyocardially in MI rats, with or without coadministration of the NADPH oxidase inhibitor apocynin. After 72 h, pathological, echocardiographic, and hemodynamic examinations showed that HMGB2 increased infarct size and worsened cardiac function in MI rats. Moreover, HMGB2 administration enhanced reactive oxygen species (ROS) production, cell apoptosis, inflammation, and autophagosome clearance impairment, which were attenuated by coadministration of apocynin or knock down of receptor for advanced glycation end products (RAGE). In conclusion, increased serum HMGB2 levels are associated with MI severity and MACE at 1 mo. HMGB2 promotes myocardial ischemic injury in rats and hypoxic H9C2 cell damage via ROS provoked by RAGE.NEW & NOTEWORTHY We demonstrate that serum high-mobility group box 2 is associated with major adverse cardiac events at 1 mo in myocardial infarction patients. Mechanistically, high-mobility group box 2 promotes reactive oxygen species production via receptor for advanced glycation end products signaling in ischemic myocardium, thereby aggravating cell apoptosis, inflammation, and autophagosome clearance impairment. This study reveals that high-mobility group box 2 is a novel factor enhancing ischemic injury in myocardial infarction.

Effective tracking of bone mesenchymal stem cells in vivo by magnetic resonance imaging using melanin-based gadolinium3+ nanoparticles.

Tracking transplanted stem cells is necessary to clarify cellular properties and improve transplantation success. In this study, we designed and synthesized melanin-based gadolinium3+ (Gd3+ )-chelate nanoparticles (MNP-Gd3+ ) of ∼7 nm for stem cell tracking in vivo. MNP-Gd3+ possesses many beneficial properties, such as its high stability and sensitivity, shorter T1 relaxation time, higher cell labeling efficiency, and lower cytotoxicity compared with commercial imaging agents. We found that the T1 relaxivity (r1 ) of MNP-Gd3+ was significantly higher than that of Gd-DTPA; the nanoparticles were taken up by bone mesenchymal stem cells (BMSCs) via endocytosis and were broadly distributed in the cytoplasm. Based on an in vitro MTT assay, no cytotoxicity of labeled stem cells was observed for MNP-Gd3+ concentrations of less than 800 µg/mL. Furthermore, we tracked MNP-Gd3+ -labeled BMSCs in vivo using 3.0T MRI equipment. After intramuscular injection, MNP-Gd3+ -labeled BMSCs were detected, even after four weeks, by 3T MRI. We concluded that MNP-Gd3+ nanoparticles at appropriate concentrations can be used to effectively monitor and track BMSCs in vivo. MNP-Gd3+ nanoparticles have potential as a new positive MRI contrast agent in clinical applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 131-137, 2017.

Increment of HFABP Level in Coronary Artery In-Stent Restenosis Segments in Diabetic and Nondiabetic Minipigs: HFABP Overexpression Promotes Multiple Pathway-Related Inflammation, Growth and Migration in Human Vascular Smooth Muscle Cells.

BACKGROUND: Our previous study suggested that heart-type fatty acid-binding protein (HFABP) levels were greatly elevated in the conditioned medium of explant culture of in-stent restenosis (ISR) tissue from diabetic minipigs compared with those of non-ISR tissue. We here verified this result in animal tissues and investigated the impact of HFABP overexpression in human aortic smooth muscle cells (hASMCs). METHODS AND RESULTS: In Western blot and real-time RT-PCR, HFABP protein and mRNA levels were significantly higher in ISR than in non-ISR tissues from minipigs, and higher in the ISR tissue from diabetic minipigs than that from nondiabetic minipigs. The mRNA microarray and cellular effects of hASMC retroviral overexpression of HFABP and vector was analyzed. Compared with vector, HFABP transduction activates multiple signaling pathways (e.g. adipokine, TGF-ß, Toll-like receptor, Wnt, Hedgehog, ErbB and Notch) and promotes inflammation, growth and migration in hASMCs whereas the knockdown of HFABP by small hairpin RNA attenuates these effects. CONCLUSION: HFABP expression is significantly higher in ISR tissue than in non-ISR tissue from diabetic and nondiabetic minipigs. Overexpression of HFABP induces multiple pathway-related promotion of inflammation, growth and migration in vascular SMCs, suggesting a potential role in coronary artery ISR.

Effects of Magnetically Guided, SPIO-Labeled, and Neurotrophin-3 Gene-Modified Bone Mesenchymal Stem Cells in a Rat Model of Spinal Cord Injury.

Despite advances in our understanding of spinal cord injury (SCI) mechanisms, there are still no effective treatment approaches to restore functionality. Although many studies have demonstrated that transplanting NT3 gene-transfected bone marrow-derived mesenchymal stem cells (BMSCs) is an effective approach to treat SCI, the approach is often low efficient in the delivery of engrafted BMSCs to the site of injury. In this study, we investigated the therapeutic effects of magnetic targeting of NT3 gene-transfected BMSCs via lumbar puncture in a rat model of SCI. With the aid of a magnetic targeting cells delivery system, we can not only deliver the engrafted BMSCs to the site of injury more efficiently, but also perform cells imaging in vivo using MR. In addition, we also found that this composite strategy could significantly improve functional recovery and nerve regeneration compared to transplanting NT3 gene-transfected BMSCs without magnetic targeting system. Our results suggest that this composite strategy could be promising for clinical applications.

C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis.

AIMS: We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1. METHODS AND RESULTS: We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 µg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice. CONCLUSION: C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice.

Valsartan decreases platelet activity and arterial thrombotic events in elderly patients with hypertension.

BACKGROUND: Angiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension. METHODS: Two-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA). RESULTS: PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L). CONCLUSIONS: AT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Transplantation of neurotrophin-3-expressing bone mesenchymal stem cells improves recovery in a rat model of spinal cord injury.

BACKGROUND: This study aimed to investigate the therapeutic effects of transplanting neutrophin-3 (NT-3)-expressing bone marrow-derived mesenchymal stem cells (BMSCs) in a rat model of spinal cord injury (SCI). METHODS: Forty-eight adult female Sprague-Dawley rats were randomly assigned to three groups: the control, BMSC, and NT-3-BMSC groups. BMSCs were infected with NT-3-DsRed or DsRed lentivirus and injected into the cerebrospinal fluid (CSF) via lumbar puncture (LP) 7 days after SCI in the NT-3-BMSC and BMSC groups, respectively. The hind-limb motor function of all rats was recorded using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale on days 1, 3, 7, 14, 21, 28, and 35 after transplantation. Haematoxylin-eosin (HE) staining, immunofluorescence labelling, and western blotting were performed at the final time point. RESULTS: Expressions of NT-3, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) proteins increased significantly in the NT-3-BMSC group, and hind-limb locomotor functions improved significantly in the NT-3-BMSC group compared with the other two groups. The cystic cavity area was smallest in the NT-3-BMSC group. In the NT-3-BMSC group, neurofilament 200 (NF200) and glial fibrillary acidic protein (GFAP) expression levels around the lesions were significantly increased and decreased, respectively. CONCLUSIONS: Our findings demonstrate that transplantation of NT-3 gene-modified BMSCs via LP can strengthen the therapeutic benefits of BMSC transplantation. We observed that these modified cells increased locomotor function recovery, promoted nerve regeneration, and improved the injured spinal cord microenvironment, suggesting that it could be a promising treatment for SCI.

Two-dimensional fluorescence in-gel electrophoresis of coronary restenosis tissues in minipigs: increased adipocyte fatty acid binding protein induces reactive oxygen species-mediated growth and migration in smooth muscle cells.

OBJECTIVE: We aimed to uncover the protein changes of coronary artery in-stent restenosis (ISR) tissue in minipigs with and without streptozotocin-induced diabetes mellitus by quantitative 2-dimensional fluorescence in-gel electrophoresis (2D-DIGE), and to investigate the influences of crucial proteins identified, particularly adipocyte fatty acid binding protein (AFABP), in human arterial smooth muscle cells. METHODS AND RESULTS: Sirolimus-eluting stents were implanted in the coronary arteries of 15 diabetic and 26 nondiabetic minipigs, and angiography was repeated after 6 months. The intima tissue of significant ISR and non-ISR segments in both diabetic and nondiabetic minipigs was analyzed by 2D-DIGE and MALDI-TOF/TOF mass spectrometry. AFABP level was significantly increased in ISR tissue than in non-ISR tissue in both diabetic and nondiabetic minipigs, with level being higher in diabetic ISR than in nondiabetic ISR tissue. In human arterial smooth muscle cells, overexpression of AFABP significantly altered phenotype and promoted growth and migration, with effects more prominent in high-glucose than in low-glucose medium, whereas AFABP knockdown inhibited these effects. AFABP overexpression increased reactive oxygen species production by upregulating the expression of NADPH oxidase subunits Nox1, Nox4, and P22 through multiple pathways, with elevation of downstream gene cyclin D1, matrix metalloproteinase-2, and monocyte chemoattractant protein-1. However, AFABP-induced effects were inhibited by diphenyleneiodonium, pathway inhibitors, and small interfering RNA. In addition, the supernatant from AFABP-expressing human arterial smooth muscle cells and recombinant AFABP also promoted cellular growth and migration. CONCLUSIONS: This study has demonstrated that AFABP is significantly increased in coronary artery ISR segments of both diabetic and nondiabetic minipigs. Increased AFABP expression and secretory AFABP of human arterial smooth muscle cells promote growth and migration via reactive oxygen species-mediated activation.

Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats.

OBJECTIVE: Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE). This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney. METHODS: Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks). Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods. Renal AGEs, RAGE, endogenous secretory RAGE (esRAGE), and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Mesangial expansion and microalbuminuria were aggravated in diabetic rats, and improved with atorvastatin treatment. Serum sRAGE levels were lower in diabetic than in normal rats. After atorvastatin treatment, serum and renal sRAGE levels were up-regulated, while renal RAGE expression was decreased in diabetic rats, associated with a reduction in accumulation of AGEs, though renal esRAGE mRNA expression was not significantly increased. CONCLUSIONS: Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation, down-regulating RAGE expression and up-regulating sRAGE in the kidney.

Increased serum levels of S100B are related to the severity of cardiac dysfunction, renal insufficiency and major cardiac events in patients with chronic heart failure.

OBJECTIVE: To investigate the correlations between S100B and the severity of cardiac dysfunction, renal insufficiency (RI) and prognosis in chronic heart failure (CHF). METHOD: Serum levels of S100B, TNF-α, high sensitivity CRP and NT-proBNP were determined in CHF patients with (n=96) and without RI (n=146). Patients with RI only (n=62) and control subjects (n=64) served for comparison. Patients were followed up for one year. RESULTS: S100B levels were higher in CHF patients with a further elevation in those with RI (P<0.01). Serum S100B levels correlated with left ventricular ejection fraction, left ventricular end-diastolic volume and NT-proBNP in CHF patients, and eGFR in patients with RI (all P<0.05). Increased S100B levels were associated with major cardiac events (MCE), and were independently associated with the presence of CHF (all P<0.05). CONCLUSION: Increased serum S100B levels were associated with the severity of cardiac dysfunction, RI and an adverse prognosis in CHF patients. It represents an independent risk factor for CHF.