Publications by authors named "Yanjun Zeng"

182 Publications

Lipid metabolism changes in patients with severe COVID-19.

Clin Chim Acta 2021 Feb 24;517:66-73. Epub 2021 Feb 24.

Department of Respiratory and Critical Care Medicine, Central South University, Changsha 410008, China. Electronic address:

Background: We investigated the dynamic changes in lipid profiles and their correlations with disease severity and clinical outcome in patients with severe COVID-19.

Methods: We retrospectively reviewed 519 severe COVID-19 patients with confirmed outcomes (discharged or deceased), admitted to the West Court of Union Hospital in Wuhan, China, between 29 January and 8 April 2020.

Results: Altogether, 424 severe COVID-19 patients, including 34 non-survivors and 390 survivors, were included in the final analyses. During hospitalization, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) showed an increasing trend in survivors, but showed a downward trend in non-survivors. The serum concentrations of HDL-C and apoA-I were inversely correlated with C-reactive protein (CRP), length of hospital stay of survivors, and disease severity scores. For in-hospital deaths, the areas under the receiver operating characteristic curves (AUCs) of the ratios of CRP/HDL-C and CRP/apoA-I at admission were 0.84 and 0.83, respectively. Moreover, patients with high ratios of CRP/HDL-C (>77.39) or CRP/apoA-I (>72.37) had higher mortality rates during hospitalization (log-rank p < 0.001). Logistic regression analysis demonstrated that hypertension, lactate dehydrogenase, SOFA score, and High CRP/HDL-C ratio were independent predictors of in-hospital mortality.

Conclusions: During severe COVID-19, HDL-C and apoA-I concentrations are dramatically decreased in non-survivors. Moreover, High CRP/HDL-C ratio is significantly associated with an increase in mortality and a poor prognosis.
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http://dx.doi.org/10.1016/j.cca.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903909PMC
February 2021

Thyroid dysfunction may be associated with poor outcomes in patients with COVID-19.

Mol Cell Endocrinol 2021 02 2;521:111097. Epub 2020 Dec 2.

Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. Electronic address:

Background: Coronavirus disease (COVID-19) has resulted in considerable morbidity and mortality worldwide. Thyroid hormones play a key role in modulating metabolism and the immune system. However, the prevalence of thyroid dysfunction (TD) and its association with the prognosis of COVID-19 have not yet been elucidated. In this study, we seek to address this gap and understand the link between TD and COVID-19.

Methods: Herein, we enrolled patients who were hospitalized with COVID-19 and had normal or abnormal thyroid function test results at the West Court of Union Hospital in Wuhan, China, between 29 January and February 26, 2020. We carried out follow up examinations until April 26, 2020. Data on clinical features, treatment strategies, and prognosis were collected and analyzed. TD was defined as an abnormal thyroid function test result, including overt thyrotoxicosis, overt hypothyroidism, subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid sick syndrome.

Results: A total of 25 and 46 COVID-19 patients with and without TD, respectively, were included in the study. COVID-19 patients with TD had significantly higher neutrophil counts and higher levels of C-reactive protein, procalcitonin, lactate dehydrogenase, serum creatine kinase, aspartate transaminase, and high-sensitive troponin I and a longer activated partial thromboplastin time but lower lymphocyte, platelet, and eosinophil counts. A longitudinal analysis of serum biomarkers showed that patients with TD presented persistently high levels of biomarkers for inflammatory response and cardiac injury. COVID-19 patients with TD were more likely to develop a critical subtype of the disease. Patients with TD had a significantly higher fatality rate than did those without TD during hospitalization (20% vs 0%, P = 0.002). Patients with TD were more likely to stay in the hospital for more than 28 days than were those without TD (80% vs 56.52%, P = 0.048).

Conclusions: Our preliminary findings suggest that TD is associated with poor outcomes in patients with COVID-19.
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http://dx.doi.org/10.1016/j.mce.2020.111097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709789PMC
February 2021

Canagliflozin alleviates LPS-induced acute lung injury by modulating alveolar macrophage polarization.

Int Immunopharmacol 2020 Nov 11;88:106969. Epub 2020 Sep 11.

Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, 410008, China. Electronic address:

Background: Canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor, is a novel therapeutic agent that exhibits multiple actions in type 2 diabetes. CANA can regulate intracellular glucose metabolism and exert anti-inflammatory effects in immune cells. Alveolar macrophage polarization balance is often associated with lower inflammation in acute lung injury (ALI). However, little is known about the anti-inflammatory effect of CANA on ALI.

Methods: This study aimed to determine the effect of CANA on ALI as well as its potential ability to modulate alveolar macrophage polarization in ALI mouse models and bone marrow-derived macrophages (BMDMs).

Results: The histopathological changes indicated that CANA alleviated lung injury in lipopolysaccharide-induced ALI mice models and exerted anti-inflammatory effects in the presence of lower levels of tumor necrosis factor-ɑ, interleukin-6, and interleukin-1β in bronchoalveolar lavage fluid (BALF) and serum. Moreover, flow cytometry analysis of mouse BALF cells and BMDMs demonstrated that CANA can modulate and reconstitute M1 and M2 macrophage balance, inhibiting macrophages with the M1 phenotype while promoting macrophages to shift to the M2 phenotype. Immunohistochemistry and reverse transcription polymerase chain reaction were also performed.

Conclusions: These findings indicate that CANA alleviates lung injury and exerts anti-inflammatory effects by modulating alveolar macrophage polarization balance, suggesting that CANA might act as a novel anti-inflammatory drug for treating ALI.
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http://dx.doi.org/10.1016/j.intimp.2020.106969DOI Listing
November 2020

Para-aortic lymph node tracing and dissection in advanced gastric cancer: Effectiveness of carbon nanoparticles injection through the no. 12b lymph node.

J Cancer Res Ther 2020 ;16(2):238-242

Biomedical Engineering Center, Beijing University of Technology, Beijing, China.

Background And Objectives: The relative effectiveness of tracers in guiding para-aortic lymph node dissection (PAND) in advanced gastric cancer is undefined. In this single-center, prospective study, we aimed to discuss the effectiveness of such tracers.

Materials And Methods: Between January 2015 and January 2016, 90 consecutive patients with stage T4a gastric cancer were evenly assigned to receive 0.2 mL of carbon nanoparticles (a), methylene blue (b), or no tracer (c) injection through no. 12b lymph nodes before PAND.

Results: There was no difference in the baseline characteristics between the three groups. Group A vs. B or C had a higher number of dissected lymph nodes (34.1 ± 9.8, 25.5 ± 5.5, and 22.6 ± 3.7; P < 0.001; B vs. C: P =0.321) and no. 16a2/b1 para-aortic lymph nodes (PANs; 11.8 ± 4.8, 7.0 ± 1.2, and 5.5 ± 1.2; P < 0.001; B vs. C: P =0.178) and similar rates of lymph node metastasis (20.9 ± 17.5%, 19.1 ± 15.1%, and 23.6 ± 19.7%; P = 0.511), positive dissected PAN (23.3% [7/30], 16.7% [5/30], and 16.7% [5/30]), surgery duration (252.9 + 35.4, 244.4 ± 29.0, and 250.3 + 29.9 min; P = 0.421), and blood loss (266.7 ± 115.5, 270.0 ± 82.6, and 260.0 ± 116.3 mL, P = 0.933). There was no common bile duct damage by tracer injection, and one case of duodenal stump fistula, one abdominal infection, and two anastomotic leakages in Groups A-C, respectively, were treated successfully.

Conclusions: In advanced gastric cancer treatment, carbon nanoparticle injection into no. 12b nodes appears to better trace no. 16a2/b1 PAN.
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http://dx.doi.org/10.4103/jcrt.JCRT_506_19DOI Listing
September 2020

Association of diabetes mellitus with disease severity and prognosis in COVID-19: A retrospective cohort study.

Diabetes Res Clin Pract 2020 Jul 22;165:108227. Epub 2020 May 22.

Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address:

Aims: The 2019 novel coronavirus disease (COVID-19) emerged in Wuhan, China, and was characterized as a pandemic by the World Health Organization. Diabetes is an established risk associated with poor clinical outcomes, but the association of diabetes with COVID-19 has not been reported yet.

Methods: In this cohort study, we retrospectively reviewed 258 consecutive hospitalized COVID-19 patients with or without diabetes at the West Court of Union Hospital in Wuhan, China, recruited from January 29 to February 12, 2020. The clinical features, treatment strategies and prognosis data were collected and analyzed. Prognosis was followed up until March 12, 2020.

Results: Of the 258 hospitalized patients (63 with diabetes) with COVID-19, the median age was 64 years (range 23-91), and 138 (53.5%) were male. Common symptoms included fever (82.2%), dry cough (67.1%), polypnea (48.1%), and fatigue (38%). Patients with diabetes had significantly higher leucocyte and neutrophil counts, and higher levels of fasting blood glucose, serum creatinine, urea nitrogen and creatine kinase isoenzyme MB at admission compared with those without diabetes. COVID-19 patients with diabetes were more likely to develop severe or critical disease conditions with more complications, and had higher incidence rates of antibiotic therapy, non-invasive and invasive mechanical ventilation, and death (11.1% vs. 4.1%). Cox proportional hazard model showed that diabetes (adjusted hazard ratio [aHR] = 3.64; 95% confidence interval [CI]: 1.09, 12.21) and fasting blood glucose (aHR = 1.19; 95% CI: 1.08, 1.31) were associated with the fatality due to COVID-19, adjusting for potential confounders.

Conclusions: Diabetes mellitus is associated with increased disease severity and a higher risk of mortality in patients with COVID-19.
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http://dx.doi.org/10.1016/j.diabres.2020.108227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242190PMC
July 2020

Simulated coronary arterial hemodynamics of myocardial bridging.

Rev Cardiovasc Med 2019 Dec;20(4):273-280

Biomechanics & Medical Information Institute, Beijing University of Technology, No. 100 PingLeYuan, Beijing, 100022, P. R. China.

The objective of this study was to explore the effects of myocardial bridge compression on blood flow, normal stress, circumferential stress and shear stress in mural coronary artery. An original mural coronary artery simulative device has been greatly improved and its measured hemodynamic parameters have been expanded from a single stress (normal stress) to multiple stresses to more fully and accurately simulate the true hemodynamic environment under normal stress, circumferential stress and shear stress. This device was used to more fully explore the relationship between hemodynamics and mural coronary atherosclerosis under the combined effects of multiple stresses. Results obtained from the mural coronary artery simulator showed stress abnormality to be mainly located in the proximal mural coronary artery where myocardial bridge compression was intensified and average and fluctuation values (maximum minus minimum) of proximal stress were significantly increased by 27.8% and 139%, respectively. It is concluded that myocardial bridge compression causes abnormalities in the proximal hemodynamics of the mural coronary artery. This is of great significance for understanding the hemodynamic mechanism of coronary atherosclerosis and has potential clinical value for the pathological effect and treatment of myocardial bridge.
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http://dx.doi.org/10.31083/j.rcm.2019.04.554DOI Listing
December 2019

PKR suppress NLRP3-pyroptosis pathway in lipopolysaccharide-induced acute lung injury model of mice.

Biochem Biophys Res Commun 2019 10 29;519(1):8-14. Epub 2019 Aug 29.

Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China. Electronic address:

To explore the effect of double-stranded RNA-dependent kinase (PKR) in acute lung injury (ALI) and resultant acute respiratory distress syndrome (ARDS). A mouse model of lipopolysaccharide (LPS)-induced ALI was used to evaluate the levels of phosphorylated (p)-PKR and NLRP3 in lung tissue, and the protective effects of a PKR inhibitor on lung injury. And in vitro, macrophages were incubated with LPS, with or without PKR inhibitor pre-treatment. It was observed that the levels of p-PKR protein and NLRP3 protein were significantly increased compared with those in control tissues after LPS administration. Meanwhile, treatment with PKR inhibitor decreased inflammation, injury score, wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein levels, neutrophil count in BALF, myeloperoxidase activity and expression of high-mobility group box1(HMGB1) and interleukin(IL)-1β in the lungs of LPS-challenged mice. In vitro, we demonstrated that the levels of p-PKR and NLRP3, and cell mortality rate were increased in macrophages which were incubated with LPS compared with those without LPS administration, and PKR inhibitor significantly suppressed the level of NLRP3, caspase-1, HMGB1 and IL-1β. These results indicate that PKR plays a key role in ALI through NLRP3-pyrotosis pathway and pharmacological inhibition of PKR may have potential therapeutic effects in the treatment of patients with ALI and ARDS.
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http://dx.doi.org/10.1016/j.bbrc.2019.08.054DOI Listing
October 2019

NETs promote ALI/ARDS inflammation by regulating alveolar macrophage polarization.

Exp Cell Res 2019 09 28;382(2):111486. Epub 2019 Jun 28.

Respiratory Department, Xiangya Hospital, Central South University, China. Electronic address:

Neutrophils activated during acute lung injury (ALI) form neutrophil extracellular traps (NETs) to capture pathogens. However, excessive NETs can cause severe inflammatory reactions. Macrophages are classified as M1 macrophages with proinflammatory effects or M2 macrophages with anti-inflammatory effects. During ALI, alveolar macrophages (AMs) polarize to the M1 phenotype. This study tested the hypothesis that NETs may aggravate ALI or acute respiratory distress syndrome (ARDS) inflammation by promoting alveolar macrophage polarization to the M1 type. Our research was carried out in three aspects: clinical research, animal experiments and in vitro experiments. We determined that NET levels in ARDS patients were positively correlated with M1-like macrophage polarization. NET formation was detected in murine ALI tissue and associated with increased M1 markers and decreased M2 markers in BALF and lung tissue. Treatment with NET inhibitors significantly inhibitor NETs generation, downregulated M1 markers and upregulated M2 markers. Regardless of LPS pre-stimulation, significant secretion of proinflammatory cytokines and upregulated M1 markers were detected from bone marrow-derived macrophages (M0 and M2) cocultured with high concentrations of NETs; conversely, M2 markers were downregulated. In conclusion, NETs promote ARDS inflammation during the acute phase by promoting macrophage polarization to the M1 phenotype. We propose that NETs play an important role in the interaction between neutrophils and macrophages during the early acute phase of ALI.
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http://dx.doi.org/10.1016/j.yexcr.2019.06.031DOI Listing
September 2019

Robust and energy-efficient expression recognition based on improved deep ResNets.

Biomed Tech (Berl) 2019 Sep;64(5):519-528

Biomedical Engineering Center, Beijing University of Technology, Beijing 100124, China.

To improve the robustness and to reduce the energy consumption of facial expression recognition, this study proposed a facial expression recognition method based on improved deep residual networks (ResNets). Residual learning has solved the degradation problem of deep Convolutional Neural Networks (CNNs); therefore, in theory, a ResNet can consist of infinite number of neural layers. On the one hand, ResNets benefit from better performance on artificial intelligence (AI) tasks, thanks to its deeper network structure; meanwhile, on the other hand, it faces a severe problem of energy consumption, especially on mobile devices. Hence, this study employs a novel activation function, the Noisy Softplus (NSP), to replace rectified linear units (ReLU) to get improved ResNets. NSP is a biologically plausible activation function, which was first proposed in training Spiking Neural Networks (SNNs); thus, NSP-trained models can be directly implemented on ultra-low-power neuromorphic hardware. We built an 18-layered ResNet using NSP to perform facial expression recognition across datasets Cohn-Kanade (CK+), Karolinska Directed Emotional Faces (KDEF) and GENKI-4K. The results achieved better anti-noise ability than ResNet using the activation function ReLU and showed low energy consumption running on neuromorphic hardware. This study not only contributes a solution for robust facial expression recognition, but also consolidates the low energy cost of their implementation on neuromorphic devices, which could pave the way for high-performance, noise-robust and energy-efficient vision applications on mobile hardware.
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http://dx.doi.org/10.1515/bmt-2018-0027DOI Listing
September 2019

The function and clinical relevance of lncRNA UBE2CP3-001 in human gliomas.

Arch Med Sci 2018 Oct 23;14(6):1308-1320. Epub 2018 Oct 23.

Biomechanics and Medical Information Institute, Beijing University of Technology, Beijing, China.

Introduction: Gliomas are the most frequent primary tumors in the human brain. Recent studies have identified a class of long noncoding RNAs, named lncRNAs, which were reported to participate in regulating the development of various diseases, including gliomas. In our previous studies, we found that lncRNA UBE2CP3-001 was overexpressed in gliomas but not in normal tissue. However, the molecular functions of UBE2CP3-001 in glioma are largely unknown.

Material And Methods: The presence of UBE2CP3-001 in U87 cells, glioma tissues and normal brain tissues was detected by real-time RT-PCR. The ability of U87 cells to migrate was analyzed using a cellular wound healing assay after downregulation of UBE2CP3-001. The survival rate of U87 cells after UBE2CP3-001 knockdown was also analyzed using the CCK8 assay. tumor weights from xenograft tumors transfected with UBE2CP3-001 shRNA were further analyzed using animal experiments. The expression levels of MMP-9 and TRAF3IP2 were determined by Western blot.

Results: Our data showed that UBE2CP3-001 was overexpressed in most glioma tissues ( < 0.01). Downregulation of UBE2CP3-001 could inhibit cell migration ( < 0.01) and invasiveness ( < 0.01) of U87 cells. Downregulation of UBE2CP3-001 in U87 cells also suppressed the cell proliferation ( < 0.01) and promoted apoptosis ( < 0.01). Furthermore, studies confirmed that knockdown of UBE2CP3-001 could retard the growth of U87 xenograft tumors ( < 0.01). Western blot analysis showed that knockdown of UBE2CP3-001 could effectively inhibit the expression of MMP-9 ( < 0.01) and TRAF3IP2 ( < 0.01) in U87 glioma cells.

Conclusions: These data suggest an important role of UBE2CP3-001 in glioma and indicate its potential application in anti-glioma therapy.
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http://dx.doi.org/10.5114/aoms.2018.79004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209712PMC
October 2018

Differential effects of size-specific particulate matter on emergency department visits for respiratory and cardiovascular diseases in Guangzhou, China.

Environ Pollut 2018 Dec 27;243(Pt A):336-345. Epub 2018 Aug 27.

Guangzhou Institute of Respiratory Health, Guangdong Province, China. Electronic address:

Background: Studies differentiating the cardiorespiratory morbidity effects of PM, PM, and PM (i.e. coarse PM or PMc) are still limited and inconsistent.

Objective: To estimate the acute, cumulative, and harvesting effects of exposure to the three size-specific PM on cardiorespiratory morbidity, and their concentration-response relations.

Methods: A total of 6,727,439 emergency department (ED) visits were collected from 16 public teaching hospitals in Guangzhou, from January 1st 2012 to December 31st 2015, among which over 2.1 million were asthma, COPD, pneumonia, respiratory tract infection (RTI), hypertension, stroke, and coronary heart disease (CHD). Distributed lag non-linear models (DLNM) was used to estimate the associations between the three size-specific PM and ED visits for the cardiovascular diseases. Long-term trends, seasonality, influenza epidemics, meteorological factors, and other gas pollutants, including SO2, NO, and O, were adjusted. We stratified the analyses by gender and age.

Results: Elevated PM and PM were significantly associated with increased ED visits for pneumonia, RTI, and CHD at both lag and lag. A 10 μg/m increment of PMc (at lag) was estimated to increase ED visits for pneumonia by 6.32% (95% CI, 4.19, 8.49) and for RTI by 4.72% (95% CI, 3.81, 5.63), respectively. PMc showed stronger cumulative effects on asthma in children than elderly. We observed significant harvesting effects (i.e. morbidity displacements) of the three size-specific PM on respiratory but very little on cardiovascular ED visits. The concentration-response curves suggested non-linear relations between exposures to the three different sizes of PM and respiratory morbidity.

Conclusions: Overall, the three size-specific PM demonstrated distinct acute and cumulative effects on the cardiorespiratory diseases. PM and PMc would have significant effects on pneumonia and RTI. Strategies should be considered to further reduce levels of ambient PM and PMc.
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http://dx.doi.org/10.1016/j.envpol.2018.08.068DOI Listing
December 2018

Four case reports on pelvic tumors with deep venous thromboses as main symptoms and literature review.

J Cancer Res Ther 2018 ;14(Supplement):S254-S256

Department of Biomechanics and Medical Information, Beijing University of Technology, Beijing, 100124, China.

To probe into the reasons for misdiagnoses of pelvic tumor as deep venous thromboses as well as the diagnostic methods and effective treatments on pelvic tumor. Four case reports on misdiagnosing pelvic tumor as deep venous thromboses and further analysis on the causes of misdiagnosis, diagnosis, and treatment with the literature study. The four cases were misdiagnosed as pelvic tumor, which actually were fibroneuroma, myxo.fluidity liposarcoma, moderately differentiated squamous cell carcinoma, and synovial sarcoma, respectively. The tumor in first case was completely removed, and the tumor in other three cases, which were malignant tumors, were resected when the tumors shrank with clear boundary and less blood supply after applied with 3. cycles of intra.arterial chemotherapy via an implanted pumpies. Pelvic tumor usually show up or is misdiagnosed as deep venous thromboses for its untypical clinical manifestation, so it should be on the alert for pelvic tumor when deep venous thromboses occurs. Tumor resection is preferred for benign tumor, and intra.arterial intervention chemotherapy should be applied first for malignant tumor followed by surgery.
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http://dx.doi.org/10.4103/0973-1482.139521DOI Listing
August 2018

Investigating the relationship between 25-hydroxyvitamin D and thyroid function in second-trimester pregnant women.

Gynecol Endocrinol 2018 Apr 26;34(4):345-348. Epub 2017 Oct 26.

c Biomechanics and Medical Information Institute , University of Technology , Beijing , China.

This study aims to explore the correlation between serum 25-hydroxyvitamin D and thyroid hormones during the second trimester. In total, 277 pregnant women at 13-28 weeks of gestation were enrolled. According to the level of thyrotropic-stimulating hormone, they were divided into a reduced TSH group, a normal TSH group and an elevated TSH group. In this study, we found that the prevalence of vitamin D deficiency was as high as 94.58%. The 25-hydroxyvitamin D level in the reduced TSH group was lower than that in the normal thyroid function group (p = .0005), and the 25-hydroxyvitamin D level in the elevated TSH group was higher than that in normal TSH group (p=.0339). A positive correlation was observed between 25-hydroxyvitamin D and thyrotropic-stimulating hormone (r = 0.3034, p = .0000). Furthermore, 25-hydroxyvitamin D was negatively correlated with the free thyroxine level (r = -0.1286, p = .0323) as well as the free triiodothyronine level (r = 0.1247, p = .0380). These data suggest that the relationships between 25-hydroxyvitamin D and thyroid parameters were characterized during the second trimester. Pregnant women in the second-trimester who are diagnosed with transient hyperthyroidism should be evaluated for the possibility of vitamin D deficiency.
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http://dx.doi.org/10.1080/09513590.2017.1393659DOI Listing
April 2018

ITIH4: Effective Serum Marker, Early Warning and Diagnosis, Hepatocellular Carcinoma.

Pathol Oncol Res 2018 Jul 21;24(3):663-670. Epub 2017 Aug 21.

Beijing University of Technology, 100 Pingleyuan, Chaoyang District, China.

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor evolved from cirrhosis. It is quite significant to seek accurate, easy markers for early warning and diagnosis of HCC. Through prospective cohort follow-up study and mass spectrometry, we discovered and verified a serum marker valuable for early warning and diagnosis. Follow-up observation was performed on cirrhosis patients. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was adopted to detect the serums of patients, and the serum polypeptides with a potential value in early HCC warning and diagnosis were screened. Electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-Q-TOF-MS/MS) was exploited to identify these screened polypeptides. Moreover, the serum marker concentration was determined by ELISA to validate the clinical value of the serum marker. Among 109 cirrhosis patients followed up for two years, 29 patients (26.6%) finally progressed into HCC. MALDI-TOF MS shows that the concentration of a 3155.66Da polypeptide was significantly different between the patients that progressed into HCC and those not. Through MS/MS identification, it is confirmed that the polypeptide is inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4). The serum ITIH4 concentrations in two groups were measured with ELISA and compared with Alpha-fetoprotein (AFP). Results show that serum ITIH4 and AFP concentrations were negatively correlated (r=-0.263, p=0.0006), and the ITIH4 concentration had a significant intergroup difference (p=0.000). Receiver operating characteristic (ROC) curve indicates that its predictive value (area under the curve, AUC) is 0.667, superior to AFP. For the patients progressing into HCC, serum samples were separately collected when they were recruited and diagnosed as cirrhosis. Measurement on these samples reveals that ITIH4 was declining during the progression of HCC (p=0.006). By virtue of mass spectrometry, we discovered and identified a biomarker valuable for early HCC warning and diagnosis. This marker overperforms the commonly used AFP, demonstrating a bright prospect.
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http://dx.doi.org/10.1007/s12253-017-0285-4DOI Listing
July 2018

21 cases reports on haemangioma of spleen.

J Cancer Res Ther 2016 Oct-Dec;12(4):1323

Biomedical Engineering Center, Beijing University of Technology, Beijing, China.

The growing activity of hemangioma of spleen keeps unknown. To search theoretical basis for whether to take the operation, this study analyzed clinical data of 21 hemangioma patients, and 16 surgical specimens were analyzed immunohistochemistry of Ki-67, Bcl-2 and vascular endothelial growth factor (VEGF). Both 14 cases of cavernous hemangioma were positive for VEGF, and negative in capillary hemangioma, there was statistical significant difference between two types of hemangioma (P < 0.05). The most tumors had a low expression of Ki-67 with a mean ± standard deviation (SD) of 6.62 ± 6.24%, whereas the mean ± SD of Bcl-2 labeling index was 36.06 ± 19.05%. According to the statistical results, the expression of Ki-67 and Bcl-2 did not correlate with age, gender, tumor size, amount of tumor and angiomatous types. Hemangioma of spleen was one benign tumor with a tendency of slow growth. Therefore, operation should be strictly selected, we recommend observation of patients with small, asymptomatic splenic lesions, which meet the radiologic criteria for hemangiomas.
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http://dx.doi.org/10.4103/0973-1482.199575DOI Listing
March 2017

Primary Germinoma Originating from the Insular Lobe: A Case Report and Review of the Literature.

World Neurosurg 2017 Feb 19;98:871.e1-871.e7. Epub 2016 Dec 19.

Biomechanics and Medical Information Institute, Beijing University of Technology, Beijing, China.

Background: Primary intracranial germinomas occurring in the cerebral hemisphere are extremely rare, with only a few reported cases in the literature. We describe an unusual case of a primary germinoma that developed in the insular lobe, with little involvement in the basal frontal lobe.

Case Description: A 19-year-old man presented with headache and vomiting. Magnetic resonance imaging showed a solitary, ring-like enhanced lesion in the left hemisphere, and a preliminary diagnosis of glioma was made. Surgery was performed, and the diagnosis of germinoma was made based on the histopathologic results.

Conclusions: The causes of ectopic germinomas of the midline structures of the brain are still unclear, but the theory of misplacement may partially clarify this phenomenon. Reflecting a lack of definitive management guidelines for atypical germinoma, the present patient was treated with focal radiotherapy around the lesion after surgery and achieved remission by 34 months postoperatively.
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http://dx.doi.org/10.1016/j.wneu.2016.12.004DOI Listing
February 2017

Clinical and imaging analysis of subclinical hemophilia combined with coxarthrosis: case report and literature review.

Springerplus 2016 1;5(1):2058. Epub 2016 Dec 1.

Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing, 100022 China.

Introduction: The incidence of subclinical hemophilic arthritis is low, with this case reports and literature review, we hope clinicians could pay more attention to the diagnosis of subclinical hemophilic arthritis and prevent the misdiagnosis and mistreatment.

Case Presentation: We analyzed the imaging feature, and therapy of a subclinical hemophilia case with hip lesion by reporting its clinical manifestations, imaging features and therapy procedure, and reviewing literatures.

Results: Hemophilia is a sex-linked recessive hereditary hemorrhagic disease, and the pathogenesis of subclinic hemophilia is concealed, which often involves joint lesion. The imaging of joint lesion of hemophilia cases is typical, which facilitates the differential diagnosis with other joint diseases. The current treatment is mainly supplementary or replacement therapy.

Conclusion: Hemophilic arthritis cases, especially the mild or subclinical cases without family history and with an older age of onset, are not common. The disease should be further understood, and early diagnosis and treatment is crucial to prevent the progressive development of joint diseases.
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http://dx.doi.org/10.1186/s40064-016-3727-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133214PMC
December 2016

The role of relative membrane capacitance and time delay in cerebellar Purkinje cells.

Biomed Tech (Berl) 2017 Oct;62(5):529-536

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The membrane capacitance of a neuron can influence the synaptic efficacy and the speed of electrical signal propagation. Exploring the role of membrane capacitance will help facilitate a deeper understanding of the electrical properties of neurons. Thus, in this paper, we investigated the neuronal firing behaviors of a two-compartment model in Purkinje cells. We evaluated the influence of membrane capacitance under two different circumstances: in the absence of time delay and in the presence of time delay. Firstly, we separately studied the influence of somatic membrane capacitance Cs and dendritic membrane capacitance Cd on neuronal firing patterns. Through numerical simulation, we observed that they had two different types of period-adding scenarios, i.e. with and without chaotic bursting. Secondly, our results indicated that when the time delay was included in the model, periodic motions were more inclined to be destroyed, while at the same time, corresponding new chaotic motions were induced. These findings suggested that membrane capacitance and time delay play a pivotal functional role in modulating dynamical firing properties of neurons, especially aspects which lead to behaviors which result in changes to bursting patterns.
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http://dx.doi.org/10.1515/bmt-2015-0212DOI Listing
October 2017

Coding Properties of Three Intrinsically Distinct Retinal Ganglion Cells under Periodic Stimuli: A Computational Study.

Front Comput Neurosci 2016 23;10:102. Epub 2016 Sep 23.

Biomedical Engineering Center, Beijing University of Technology Beijing, China.

As the sole output neurons in the retina, ganglion cells play significant roles in transforming visual information into spike trains, and then transmitting them to the higher visual centers. However, coding strategies that retinal ganglion cells (RGCs) adopt to accomplish these processes are not completely clear yet. To clarify these issues, we investigate the coding properties of three types of RGCs (repetitive spiking, tonic firing, and phasic firing) by two different measures (spike-rate and spike-latency). Model results show that for periodic stimuli, repetitive spiking RGC and tonic RGC exhibit similar spike-rate patterns. Their spike- rates decrease gradually with increased stimulus frequency, moreover, variation of stimulus amplitude would change the two RGCs' spike-rate patterns. For phasic RGC, it activates strongly at medium levels of frequency when the stimulus amplitude is low. While if high stimulus amplitude is applied, phasic RGC switches to respond strongly at low frequencies. These results suggest that stimulus amplitude is a prominent factor in regulating RGCs in encoding periodic signals. Similar conclusions can be drawn when analyzes spike-latency patterns of the three RGCs. More importantly, the above phenomena can be accurately reproduced by Hodgkin's three classes of neurons, indicating that RGCs can perform the typical three classes of firing dynamics, depending on the distinctions of ion channel densities. Consequently, model results from the three RGCs may be not specific, but can also applicable to neurons in other brain regions which exhibit part(s) or all of the Hodgkin's three excitabilities.
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http://dx.doi.org/10.3389/fncom.2016.00102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033956PMC
September 2016

Estimation of shear stress by using a myocardial bridge-mural coronary artery simulating device.

Cardiol J 2017 7;24(5):530-538. Epub 2016 Oct 7.

Biomechanics and Medical Information Institute, Beijing University of Technology, Beijing, China.

Background: This study was aimed at developing a myocardial bridge-mural coronary artery simulative device and analyzing the relationship between shear stress on the mural coronary artery and atherosclerosis.

Methods: A myocardial bridge-mural coronary artery simulative device was used to simulate experiments in vitro. In the condition of maintaining any related parameters such as system temperature, average flow rate, and heart rate, we calculated and observed changes in proximal and distal mean values, and oscillatory value of shear stress on the mural coronary artery by regulating the compression level of the myocardial bridge to the mural coronary artery.

Results: Under 0% compression, no significant differences were observed in distal and proximal mean values and oscillatory value of the shear stress on the mural coronary artery. With the increase in the degree of compression, the mean shear stress at the distal end was greater than that at the proximal end, but the oscillatory value of the shear stress at the proximal end was greater than that at the distal end.

Conclusions: The experimental results of this study indicate that myocardial bridge compression leads to abnormal hemodynamics at the proximal end of the mural coronary artery. This abnormal phenomenon is of great significance in the study of atherosclerosis hemodynamic pathogenesis, which has potential clinical value for pathological effects and treatments of myocardial bridge.
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http://dx.doi.org/10.5603/CJ.a2016.0084DOI Listing
June 2018

Characteristics of Rosai-Dorfman Disease Primarily Involved in the Central Nervous System: 3 Case Reports and Review of Literature.

World Neurosurg 2017 Jan 28;97:58-63. Epub 2016 Sep 28.

Biomechanics and Medical Information Institute, Beijing University of Technology, Beijing, China. Electronic address:

Objective: This study aimed to summarize the clinical characteristics of Rosai-Dorfman disease primarily involving the central nervous system and to explore diagnosis and treatment.

Methods: We analyzed the clinical, imaging, and pathologic characteristics; treatment; and prognosis in 3 cases of Rosai-Dorfman disease primarily involving the central nervous system. We also performed a literature review.

Results: The largest of multiple intracranial lesions was totally resected, and steroid administration and radiotherapy were performed in phases for the remaining lesions. During the 1-year follow-up period, the excised lesion did not recur, and no obvious variations were observed in the other lesions. Subtotal resection was performed of the largest of another group of multiple intracranial lesions, and the residual did not show any obvious variations during the 1-year follow-up period. The isolated lesion was totally resected and did not recur during a 2-year follow-up period.

Conclusions: Rosai-Dorfman disease with multiple lesions primarily involving the central nervous system is rare. Imaging characteristics are similar to meningiomas, and the pathological features include lymphocytes and plasma cells reaching tissue cells with large volume and abundant cytoplasm. Surgery is the preferred treatment, as the effects of steroid administration and radiotherapy are not apparent.
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http://dx.doi.org/10.1016/j.wneu.2016.09.084DOI Listing
January 2017

Effective treatment via early cranioplasty for intractable contralateral subdural effusion after standard decompressive craniectomy in patients with severe traumatic brain injury.

Clin Neurol Neurosurg 2016 Oct 2;149:87-93. Epub 2016 Aug 2.

Biomechanics and Medical Information Institute, Beijing University of Technology, Beijing 100022, PR China. Electronic address:

Objective: This study aimed to introduce an effective treatment for intractable contralateral subdural effusion after standard decompressive craniectomy in patients with severe traumatic brain injury (TBI) and to analyze the underlying mechanism.

Methods: A retrospective analysis was performed in 13 patients with severe traumatic craniocerebral injury showing complicated intractable contralateral subdural effusion after standard decompressive craniectomy, in whom satisfactory results were not obtained from treatments, including compression bandaging, head-down bed rest (HDBR), continuing lumbar drainage, and Ommaya catheter drainage. Among these patients, 6 underwent temporal muscle sticking, while 7 underwent early cranioplasty. The postoperative changes in the subdural effusion were observed.

Results: In the 6 patients who underwent temporal muscle sticking and the 7 who underwent early cranioplasty, the subdural effusion completely resolved or was significantly reduced within one month, and no recurrence was observed in the 6-month follow-up period. However, secondary bilateral cranioplasty was still necessary in the postoperative 3-6 months for the patients who underwent temporal muscle sticking. In the early cranioplasty group, there were three total operations, and the average length of stay (ALOS) was 76days. In the temporal muscle sticking group, there were four total operations, and the ALOS was 56.1days. A retrospective analysis of surgical pain showed that 100% of the patients in the first group experienced unacceptable suffering, while 14.3% of the patients in the second group experienced pain.

Conclusion: Early cranioplasty is an effective, economical, and less painful treatment for intractable contralateral subdural effusion after standard decompressive craniectomy.
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http://dx.doi.org/10.1016/j.clineuro.2016.08.004DOI Listing
October 2016

Regression models for near-infrared measurement of subcutaneous adipose tissue thickness.

Physiol Meas 2016 07 31;37(7):1024-34. Epub 2016 May 31.

College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, People's Republic of China. China-Japan Friendship Hospital, Beijing 100029, People's Republic of China.

Obesity is often associated with the risks of diabetes and cardiovascular disease, and there is a need to measure subcutaneous adipose tissue (SAT) thickness for acquiring the distribution of body fat. The present study aimed to develop and evaluate different model-based methods for SAT thickness measurement using an SATmeter developed in our laboratory. Near-infrared signals backscattered from the body surfaces from 40 subjects at 20 body sites each were recorded. Linear regression (LR) and support vector regression (SVR) models were established to predict SAT thickness on different body sites. The measurement accuracy was evaluated by ultrasound, and compared with results from a mechanical skinfold caliper (MSC) and a body composition balance monitor (BCBM). The results showed that both LR- and SVR-based measurement produced better accuracy than MSC and BCBM. It was also concluded that by using regression models specifically designed for certain parts of human body, higher measurement accuracy could be achieved than using a general model for the whole body. Our results demonstrated that the SATmeter is a feasible method, which can be applied at home and in the community due to its portability and convenience.
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http://dx.doi.org/10.1088/0967-3334/37/7/1024DOI Listing
July 2016

Quantification of MRI and MRS characteristics changes in a rat model at different stage of cerebral ischemia.

Neurol Res 2016 Jul 23;38(7):640-6. Epub 2016 May 23.

b Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University , Beijing , China.

Background: A better understanding the mechanisms of cerebral ischemia is important both for diagnosis and treatment.

Objective: The study aimed to quantify several characteristics of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to indicate the brain tissue changes at different stage of cerebral ischemia in rats.

Methods: In the present study, a rat model of cerebral ischemia was established by middle cerebral artery occlusion (MCAO) in the left hemisphere. MRI and MRS were performed on 15 Sprague Dawley rats 4 H, 24 H, and 1 W after MCAO. Apparent diffusion coefficient (ADC), relative ADC including FNR, PNR, PNF, and metabolite ratio NCC were proposed to reflect the changes of water diffusion and metabolism in brain tissue.

Results: ADCs of focal zone and penumbra zone from 1 W group were significantly larger than those from 4H group, respectively (both p < 0.05). PNR and PNF of 24H and 1 W groups were significantly less than 4H group (all p < 0.01). NCCs of focal zone and penumbra zone were significantly less than the normal zone within 4H, 24H, and 1 W groups, respectively (both p < 0.01). While NCCs of penumbra zone from 24H and 1 W groups were significantly larger than 4H group (both p < 0.01).

Conclusion: We conclude that combination of MRI and MRS characteristics can provide significant indicators for ischemic damage at different stage of cerebral ischemia in a rat model.
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http://dx.doi.org/10.1080/01616412.2016.1181345DOI Listing
July 2016

Anti-hMAM monoclonal antibodies evaluated in breast and non-breast tissues for differential diagnosis implication.

Tumori 2016 Jun 21;2016(3):264-9. Epub 2016 Apr 21.

Affiliated 307 Hospital, Academy of Military Medical Sciences, Beijing - China.

Purpose: Human mammaglobin (hMAM) is a breast tissue-specific marker that may have potency for the diagnosis of breast cancer. However, there is a lack of commercialization of anti-hMAM antibody made in China.

Methods: Immunoreactivities of 2 self-made monoclonal anti-hMAM antibodies, MEF521 and MDA822, were evaluated by immunohistochemistry staining and compared with imported monoclonal antibody ab81611. A total of 48 cases of primary breast cancers, 36 cases of benign or normal breast tissues, 52 cases of lymph nodes or organ metastases from breast cancer, and 90 cases of non-breast primary carcinoma tissues were analyzed.

Results: All 3 anti-hMAM antibodies showed high positive expression of hMAM in primary breast cancers, benign, and normal breast tissues. The positive ratio for MEF521 (33.3%) or MDA822 (44.4%) was much higher than that of ab81611 (16.7%) in lymph node metastasis from breast cancer (p = 0.038). There was no correlation between hMAM expression and clinicopathologic features of breast cancer in the 3 groups of antibodies. In 90 cases of non-breast primary carcinoma tissues, no hMAM-positive ones were observed in the MEF521 or MDA822 group, but 48 (53.3%) in the ab81611 group were positive, indicating that breast tissue specificity of the 2 self-made anti-hMAM monoclonal antibodies much higher than that of ab81611 (p<0.001).

Conclusions: Our results showed that MDA822 and MEF521 are more specific to breast cancer as measured by means of immunohistochemistry. Therefore, the 2 self-made anti-hMAM antibodies may have good prospects for clinical application in the differential diagnosis of breast tumor and breast cancer metastases.
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http://dx.doi.org/10.5301/tj.5000496DOI Listing
June 2016

Clinical report of intra-arterial interventional chemotherapy for synovial sarcoma on limbs.

J Cancer Res Ther 2016 Jan-Mar;12(1):73-6

Biomechanics and Medical Information Institute, Beijing University of Technology, Beijing, China.

Objective: The efficiency of implantable intra-arterial interventional chemotherapy before the operation for synovial sarcoma on limbs was evaluated.

Materials And Methods: Drug delivery device (chemotherapy pumps) was implanted percutaneously for 36 patients, and the interventional chemotherapy was conducted for 3-4 cycles. The surgical resection was carried out after obvious improvement was observed by clinical and imaging examination. The evaluation standard for the efficiency of chemotherapy was tumor cell necrosis rate obtained from postoperative pathological test.

Results: The response rate (RR) of pain alleviation was 91% (32/36), and the RR of the changing of lesion imaging was 83% (30/36). Thirty cases received extensive tumor excision, and six cases received amputation because of poor response to tumor chemotherapy and local carcinelcosis. The postoperative pathological test showed 81% moderate and severe chemotherapy response (29/36). The average follow-up time was 39 months. There were three cases presenting with local tumor recurrence, and seven deaths due to pulmonary metastasis.

Conclusion: Intra-arterial interventional chemotherapy before operation for synovial sarcoma can effectively control pain. After chemotherapy, the imaging performance significantly changed, and tumor cells were necrotized extensively. The pathological changes were obvious.
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http://dx.doi.org/10.4103/0973-1482.148662DOI Listing
December 2016

Methods of intra-operative treatment of cranioplasty in patients with abnormal bone window flap pressure after decompressive craniectomy.

Clin Neurol Neurosurg 2016 May 6;144:44-7. Epub 2016 Mar 6.

Biomechanics and Medical Information Institute, Beijing University of Technology, Beijing 100022, PR China. Electronic address:

Objective: This study was performed to investigate the method of cranioplasty in patients with abnormal bone window pressure after decompressive craniectomy.

Methods: We performed a retrospective analysis for 25 cases after decompressive craniectomy in patients with abnormal flap pressure of clinical data.

Results: Flap pressure increased in 15 cases, including 6 cases of hydrocephalus, 5 cases of contralateral subdural effusion, 2 cases of subdural effusion bone window, 2 cases of bone window cystic encephalomalacia communicating with the ventricle; Flap pressure decreased in 10 cases, including 6 cases of hydrocephalus after ventriculoperitoneal shunt, and 4 cases of low intracranial pressure. ALL of patients were treated by appropriate measures to make the operation smoothly.

Conclusion: Our data suggest that after analysis of the factors for abnormal bone window flap pressure by decompressive craniectomy and symptomatic treatment, the difficulty of operation and operative complications can be reduced.
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http://dx.doi.org/10.1016/j.clineuro.2016.03.001DOI Listing
May 2016

A model-based analysis of physiological properties of the striatal medium spiny neuron.

Neurol Res 2015 ;37(12):1074-81

1 School of Mathematics, South China University of Technology , Guangzhou 510640, China.

As the principal cell of the striatum, medium spiny neurons (MSNs) are closely associated with various motor dysfunctional diseases. In this paper, we describe an electric compartment model constructed in NEURON with a realistic morphology. Based on a 554-compartment computational model, we researched the influence of external current stimuli, different ions conductance, and the removal of partial dendrites on the physiological properties of the MSN. The main results are the following: (1) in the case of external current stimuli, various firing patterns appear in the MSN and the model produces a clear period-adding bifurcation phenomenon; (2) the effect of distinct types of ion channels vary and significant differences in discharge rhythm exist even among ion channels of the same type; (3) the closer the removed dendrite was to the soma, the larger the impact this had on the discharge pattern of the MSN.
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http://dx.doi.org/10.1080/01616412.2015.1110304DOI Listing
October 2016

Repair of rabbit cartilage defect based on the fusion of rabbit bone marrow stromal cells and Nano-HA/PLLA composite material.

Artif Cells Nanomed Biotechnol 2017 Feb 2;45(1):115-119. Epub 2016 Feb 2.

a Department of Sports Medical , the Affiliated Clinical College Shenzhen Second People's Hospital, Anhui Medical University , Hefei , PR China.

Objective To assess the effect of the fusion of rabbit bone marrow stromal cells (rBMSCs) and Nano-hydroxyapatite/poly (l-lactic acid) (Nano-HA/PLLA) in repairing the rabbit knee joint with full-thickness cartilage defect. Method The rBMSCs were isolated and cultured in vitro, and the third generation of rBMSCs was co-cultured with the Nano-HA/PLLA to construct the tissue-engineered cartilage (TEC). Eighteen New Zealand white rabbits were selected and randomly divided into three groups, namely, TEC group, Nano-HA/PLLA group, and control group. A cartilage defect model with the diameter of 4.5 mm and depth of 5 mm was constructed on the articular surface of medial malleolus of rabbit femur. General observation, histological observation, and Wakitani's histological scoring were conducted in the 12th and 24th week postoperatively. Results The results of TEC group indicated that new cartilage tissue was formed on the defect site and subchondral bone achieved physiological integration basically. Histological and immunohistochemical analyses indicated the generation of massive extracellular matrix. In contrast, limited regeneration and reconstruction of cartilage was achieved in the Nano-HA/PLLA group and control group, with a significant difference from the TEC group (p < 0.05). Moreover, the effect of cartilage repair was positively correlated with time. Conclusion The porous Nano-HA/PLLA combined with BMSCs promoted the repair of weight-bearing bone of adult rabbit's knee joint with cartilage defect.
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http://dx.doi.org/10.3109/21691401.2016.1138482DOI Listing
February 2017

Influence of bone mineral density and hip geometry on the different types of hip fracture.

Bosn J Basic Med Sci 2016 Jan 1;16(1):35-8. Epub 2016 Jan 1.

Department of Orthopedics, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.

The aim of this study was to assess the influence of bone mineral density and hip geometry on the fragility fracture of femoral neck and trochanteric region. There were 95 menopausal females of age ≥ 50 years with fragility fracture of hip, including 55 cases of femoral neck fracture and 40 cases of trochanteric fracture. Another 63 non-fractured females with normal bone mineral density (BMD) were chosen as control. BMD, hip axis length, neck-shaft angle and structural parameters including cross surface area, cortical thickness and buckling ratio were detected and compared. Compared with control group, the patients with femoral neck fracture or trochanteric fractures had significantly lower BMD of femoral neck, as well as lower cross surface area and cortical thickness and higher buckling ratio in femoral neck and trochanteric region. There were no significant differences of BMD and structural parameters in the femoral neck fracture group and intertrochanteric fracture group. Hip axis length and neck-shaft angle were not significantly different among three groups. The significant changes of BMD and proximal femur geometry were present in the fragility fracture of femoral neck and trochanteric region. The different types of hip fractures cannot be explained by these changes.
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http://dx.doi.org/10.17305/bjbms.2016.638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765937PMC
January 2016