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18 June 2019, Volume 51 Issue 3
  • Role and mechanism of muscarinic acetylcholine receptor in the regulation of submandibular gland secretion
    Xin CONG,Sai-nan MIN,Li-ling WU,Zhi-gang CAI,Guang-yan YU
    2019, (3):  390-396.  doi: 10.19723/j.issn.1671-167X.2019.03.003    
    Abstract ( 31 )   HTML ( 9 )   PDF (2036KB) ( 23 )   Save
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    SUMMARY Muscarinic acetylcholine receptors (mAChRs), including M1-M5 subtypes, are classic receptors in regulating water, ion, and solute transport in salivary gland. Our work focuses on the studies on the expression pattern and function of mAChR in the submandibular gland (SMG), and the under-lying mechanism involved in the mAChR-regulated secretion, together with the effect of parasympathectomy on the salivary secretion. Microvascular autotransplantation of SMG into the temporal fossa provides a continuous and endogenous source of fluids, and is currently an effective method for treating severe keratoconjunctivitis sicca. By using RT-PCR, Western blotting, and immunofluorescence, our data demonstrated that the expression of M1 and M3 subtypes were decreased in latent period in rabbit SMG autotransplantation model, whereas carbachol stimulation promoted the salivary secretion, as well as M1 and M3 expressions. By contrast, mAChRs were hypersensitive in epiphora SMGs, whereas atropine gel and botulinum toxin A application significantly inhibited the hypersecretion in both animal models and patients. Furthermore, the possible intracellular signal molecules involved in the mAChR-modulated saliva-ry secretion were explored. Activation of mAChR upregulated the expression of aquaporin 5 (AQP5), the main transporter that mediated water secretion through transcellular pathway, and led to AQP5 trafficking from lipid rafts to non-lipid microdomain. Extracellular signal-regulated kinase 1/2 (ERK1/2) was involved in the mAChR-regulated AQP5 content. mAChR activation also modulated the expression, distribution, and function of tight junction proteins, and increased paracellular permeability. ERK1/2/β-arrestin2/clathrin/ubiquitin signaling pathway was responsible for the mAChR-regulated downregulation of tight junction molecule claudin-4. Cytoskeleton filamentous actin (F-actin) was also involved in the distribution and barrier function of epithelial tight junctions. Besides, endothelial tight junctions were opened by mAChR agonist-evoked salivation in the mice. Furthermore, parasympathetic denervation increased resting salivary secretion in the long terminrats and minipigs. Taken together, our work demonstrated that mAChR regulated saliva secretion via transcellular and paracellular pathways in SMG epithe-lium as well as tight junction opening in SMG endothelium. Modulation of mAChR might be a promising strategy to ameliorate SMG dysfunction.

    Discovery of a new division system in brain and the regionalized drainage route of brain interstitial fluid
    Hong-bin HAN
    2019, (3):  397-401.  doi: 10.19723/j.issn.1671-167X.2019.03.004    
    Abstract ( 27 )   HTML ( 3 )   PDF (4038KB) ( 15 )   Save
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    SUMMARY Brain extracellular space (ECS) is a narrow, irregular space, which provides immediate living environment for neural cells and accounts for approximately 15%-20% of the total volume of living brain. Twenty-five years ago, as an interventional radiologist, the author was engaged in investigating early diagnosis and treatment of cerebral ischemic stroke, and the parameters of brain ECS was firstly derived and demonstrated during the study of the permeability of blood-brain barrier (BBB) and its diffusion changes in the cerebral ischemic tissue. Since then, the author and his team had been working on developing a novel measuring method of ECS: tracer-based magnetic resonance imaging (MRI), which could measure brain ECS parameters in the whole brain scale and make the dynamic drainage process of the labelled brain interstitial fluid (ISF) visualized. By using the new method, the team made a series of new findings about the brain ECS and ISF, including the discovery of a new division system in the brain, named regionalized ISF drainage system. We found that the ISF drainage in the deep brain was regiona-lized and the structural and functional parameters in different interstitial system (ISS) divisions were disparate. The ISF in the caudate nucleus could be drained to ipsilateral cortex and finally into the subarachnoid space, which maintained the pathway of ISF- cerebrospinal fluid (CSF) exchange. However, the ISF in the thalamus was eliminated locally in its anatomical division. After verifying the nature of the barrier structure between different drainage divisions, the author proposed the hypothesis of “regionalized brain homeostasis”. Thus, we demonstrated that the brain was protected not only by the BBB, which avoided potential exogenous damage through the vascular system, but was also protected by an internal ISF drainage barrier to avoid potentially harmful interference from other ECS divisions in the deep brain. With the new findings and the proposed hypothesis, an innovative therapeutic method for the treatment of encephalopathy with local drug delivery via the brain ECS pathway was esta-blished. By using this new administration method, the drug was achieved directly to the space around neurons or target regions, overwhelming the impendence from the blood-brain barrier, thus solved the obstacles of low efficiency in traditional drug investigation. At present, new methods and discoveries developed by the author and his team have been widely applied in several frontier fields including neuroscience, new drug research and development, neurodevelopment aerospace medicine, clinical encephalopathy treatment,new neural network modeling and so on.

    Expression and clinical significance of chemokine CXCL10 and its receptor CXCR3 in hepatocellular carcinoma
    Jing ZHANG,Jie CHEN,Gui-wen GUAN,Ting ZHANG,Feng-min LU,Xiang-mei CHEN
    2019, (3):  402-408.  doi: 10.19723/j.issn.1671-167X.2019.03.005    
    Abstract ( 39 )   HTML ( 10 )   PDF (3479KB) ( 39 )   Save
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    Objective: To explore the expression and clinical significance of chemokine CXCL10 and CXCR3 in hepatocellular carcinoma (HCC).Methods: The expression and prognostic of CXCL10 and CXCR3 in HCC tumor tissues and non-tumor tissues were analyzed in two different publicly available databases the Cancer Genome Atlas (TCGA) and Liver Cancer Institute (LCI). In addition, quantitative real-time PCR (qPCR) was used to detect the mRNA expression of CXCL10 and CXCR3 in 45 HCC cli-nical samples with HBV infection background. Pearson correlation and Spearman rank correlation were used to determine the correlation between the expression level of CXCL10 and CXCR3 in tumor and non-tumor tissues. Results: In TCGA database, the expression of CXCL10 in HCC tumor tissues was significantly higher than that in non-tumor tissues (nonpaired samples: 3.379±2.081 vs. 2.213±2.274, P<0.001; paired samples: 3.159±2.267 vs. 2.213±2.274, P=0.018). Similarly in LCI datebase (7.625±1.683 vs. 7.287±1.328, P=0.009). And higher CXCL10 expression was significantly associated with a better prognosis in the patients with HCC both in TCGA and LCI database (P=0.107, P=0.002). In TCGA database, the expression of CXCR3 in HCC tumor tissues was significantly higher than that in non-tumor tissues (nonpaired samples: -0.906±1.697 vs. -1.978±1.629, P<0.001; paired samples: -1.329±1.732 vs. -1.978±1.629, P=0.037), while lower in LCI database (3.989±0.339 vs. 4.074±0.309, P=0.003). In both databases, higher CXCR3 expression was significantly associated with a better prognosis in the HCC patients (P=0.004, P=0.014). Furthermore, in TCGA database, the expression level of CXCL10 and CXCR3 was positively correlated both in HCC tumor tissues and matched non-tumor tissues (r=0.584, P<0.001; r=0.776, P<0.001). The qPCR assay showed that the expression of CXCL10 in HBV-related HCC tumor tissues was significantly higher than those in normal liver tissues [0.479(0.223, 1.094) vs. 0.131(0.106, 0.159), P=0.010], and the expression in HBV-related non-tumor tissues was also significantly higher than those in normal liver tissues [0.484(0.241, 0.846) vs. 0.131(0.106, 0.159), P<0.001]. The same was true as CXCR3 [0.011(0.006, 0.019) vs. 0.002(0.001, 0.004), P=0.004; 0.016(0.011, 0.021) vs. 0.002(0.001, 0.004), P<0.001]. However there was no significant difference of CXCL10 and CXCR3 between tumor tissues and matched non-tumor tissues (P=1.000, P=0.374).Conclusion: Expression of CXCL10 was up-regulated in HCC tissues, expression of CXCR3 was down-regulated in HBV-related HCC tissues, and the higher expression of both genes was correlated with better overall survival in HCC patients.
    Haploidentical allogenetic hematopoietic stem cell transplantation for X-linked adrenoleukodystrophy
    Yao Chen,Xiao-hui ZHANG,Lan-ping XU,Kai-yan LIU,Jiong QIN,Yan-ling YANG,Xiao-jun HUANG
    2019, (3):  409-413.  doi: 10.19723/j.issn.1671-167X.2019.03.006    
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    Objective: X-linked adrenoleukodystrophy (ALD) is a severe inherited disorder leading to rapid neurological deterioration and premature death. Allogeneic hematopoietic stem cell transplantation (HSCT) is still the only treatment that halts the neurologic symptoms in ALD. However, many patients lack suitable human leukocyte antigen (HLA) matched related donors and must rely on alternative donors for a source of stem cells. The purpose of this study was to explore the outcomes of haploidentical allogeneic stem cell transplantation for ALD patients.Methods: Between December 2014 and December 2018, eight children with ALD lacking HLA matched related or unrelated donors were treated with haploidentical allogeneic hematopoietic stem cell transplantation. The patients received conditioning regimen with busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg and fludarabine 90 mg/m 2. Graft-versus-host disease (GVHD) prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil and short course of methotrexate. Results: All the 8 children received allogeneic stem cell transplants from their fathers. The median age of the recipients was 8 (range: 5-12) years. The median age of the donors was 36 (range: 32-40) years. All the recipients received granulocyte colony-stimulating factor (G-CSF) mobilized bone marrow and peripheral blood-derived stem cells. The median number of total mononuclear cells dose and CD34 + dose was 10.89 (range: 9.40-12.16)×10 8/kg and 7.06 (range: 0.74-7.80)×10 6/kg, respectively. Neutrophil engraftment occurred a median of 11 days (range:8-13 days) after transplantation. Platelet engraftment occurred a median of 10 days (range:8-12 days) after transplantation. All the patients achieved complete donor chimerism at the time of engraftment. Four patients had grades Ⅱ-Ⅳ acute GVHD and 1 had chronic graft-versus-host disease. No severe chronic GVHD occurred. Among all the children, 2 had cytomegalovirus (CMV) DNAemia and 2 Epstein-Barr virus (EBV) DNAemia. Overall, seven of them survived and had no major complications related to transplantation. One died of cerebral hernia after epilepsy 125 days after transplantation. Conclusion: The preliminary observation demonstrates that haploidentical allogeneic stem cell transplantation with this novel regimen could successfully achieve full donor chimerism in ALD patients. According to our experience, haploidentical allogeneic hematopoietic stem cell transplantation is safe and feasible in the treatment of X-linked adrenoleukodystrophy.
    Hemodynamic changes in standing-up test of children and adolescents with postural tachycardia syndrome
    Chun-yan TAO,Hong-xia LI,Xue-ying LI,Chao-shu TANG,Hong-fang JIN,Jun-bao DU
    2019, (3):  414-421.  doi: 10.19723/j.issn.1671-167X.2019.03.007    
    Abstract ( 14 )   HTML ( 2 )   PDF (2112KB) ( 4 )   Save
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    Objective: To explore the hemodynamic changes in standing-up test of children and adolescents with postural tachycardia syndrome (POTS) and to compare hemodynamic parameters of POTS patients with decreased cardiac index (CI) and those with not-decreased CI.Methods: A retrospective study was conducted to show the trends of CI, total peripheral vascular resistance index (TPVRI), heart rate and blood pressure in standing-up test of 26 POTS patients and 12 healthy controls, and to compare them between the two groups. The POTS patients were divided into two groups based on CI decreasing or not in standing-up test, namely decreased CI group (14 cases) and not-decreased CI group (12 cases). The trends of the above mentioned hemodynamic parameters in standing-up test were observed and compared between decreased CI group and not-decreased CI group.Results: In standing-up test for all the POTS patients, CI (F=6.936, P=0.001) and systolic blood pressure (F=6.049, P<0.001) both decreased significantly, and heart rate increased obviously (F=113.926, P<0.001). However, TPVRI (F=2.031, P=0.138) and diastolic blood pressure (F=2.018, P=0.113) had no significant changes. For healthy controls, CI (F=3.646, P=0.016), heart rate (F=43.970, P<0.001), systolic blood pressure (F=4.043, P=0.020) and diastolic blood pressure (F=8.627, P<0.001) all increased significantly in standing-up test. TPVRI (F=1.688, P=0.190) did not change obviously. The changing trends of CI (F=6.221, P=0.001), heart rate (F=6.203, P<0.001) and systolic blood pressure (F=7.946, P<0.001) over time were significantly different between the patients and healthy controls, however, no difference was found in TPVRI and diastolic blood pressure (P > 0.05). Among the POTS patients, CI was significantly different between decreased CI group and not-decreased CI group (F=14.723, P<0.001). Systolic blood pressure of the former decreased obviously (F=8.010, P<0.001), but it did not change obviously in the latter (F=0.612, P=0.639). Furthermore, none of the changes of TPVRI, heart rate and diastolic blood pressure in standing-up test were significantly different between the two groups (P > 0.05). Age was an independent factor for decreased CI patients (P=0.013, OR=2.233; 95% CI, 1.183 to 4.216).Conclusion: POTS patients experience vital hemodynamic changes in standing-up test, part of them suffering from decreased CI, but others from not-decreased CI. Age is an independent factor for patients suffering from decreased CI.
    Photosensitive tonic-clonic seizures:a continuum between focal and generalized seizures
    Jiao-yang LU,Jiao XUE,Pan GONG,Hai-po YANG,Zhi-xian YANG
    2019, (3):  422-429.  doi: 10.19723/j.issn.1671-167X.2019.03.008    
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    Objective: To investigate whether the tonic-clonic seizure(TCS) induced by intermittent photic stimulation(IPS)was generalized tonic-clonic seizure (GTCS)or partial secondarily tonic-clonic seizure(PGTCS),and to analyze the relationship between them. Methods: Video-electroencephalogram(VEEG)database of Peking University First Hospital from March 2010 to October 2018 were reviewed. Fifteen cases with idiopathic epilepsy who had TCS induced by IPS were included in this study, and their clinical and electroencephalogram(EEG)characteristics were retrospectively analyzed. Results: In this study, 4 of the 15 cases were boys and 11 were girls. The age of seizure onset ranged from 1 to 13 years. According to the medical records: 12 cases were considered as GTCS,while the remaining 3 cases were considered as PGTCS. The age at VEEG monitoring ranged from 2.5 to 16.0 years. All backgrounds of the VEEG were normal. Interictal discharges:generalized discharges in 11 cases,of which 4 cases coexisted with posterior discharges, 2 cases coexisted with Rolandic discharges, the other 5 cases merely had generalized discharges;merely focal discharges in two cases,one in the Rolandic area and the other in the posterior area;no interictal discharge in the remaining 2 cases. IPS induced photoparoxysmal response(PPR)results: 2 cases without PPR,the remaining 13 cases with PPR of generalized discharges,and 6 of the 13 cases coexisted with posterior discharges. IPS induced photoconvulsive response(PCR)results:GTCS in one case (contradictory to medical history),PGTCS in 11 cases (consistent with medical history),and GTCS and PGTCS hardly to distinguish in the remaining 3 cases. Of the three conditions above, there were generalized myoclonic seizures induced by IPS before TCS in 7 cases. Conclusion: The medical history was unreliable in determining whether TCS was generalized or focal. Myoclonic seizures can coexist with PGTCS, and sometimes GTCS was indistinguishable from PGTCS, indicating that the dicho-tomy of seizure types need to be improved. Photosensitive TCS should be regarded as a continuum between focal and generalized seizures.

    Prediction of syncope with nonlinear dynamic analysis during head-up tilt in vasovagal syncope patients
    Fan LI,Han-bin WANG,Qing PENG,Yun-chuang SUN,Ran ZHANG,Bo PANG,Jing FANG,Jue ZHANG,Yi-ning HUANG
    2019, (3):  430-438.  doi: 10.19723/j.issn.1671-167X.2019.03.009    
    Abstract ( 18 )   HTML ( 2 )   PDF (2145KB) ( 9 )   Save
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    Objective: To quantify the relationship between cerebral blood flow velocity and peripheral blood pressure during hypotension period, aiming to predict the brain hypotension before symptomatic occurrence.Methods: Twenty vasovagal syncope (VVS) patients who had a previous clinical history were selected in groups and 20 pair-matched control subjects underwent 70° tilt-up test. The subjects remained supine for 30 minutes before recordings when Doppler probes, electrodes and Finapres device were prepared. After continuous baseline recordings for 10 min, the subjects underwent head up tilt (HUT) test (70°), and were standing upright for 30 minutes or until syncope was imminent. For ethical reasons, the subjects were turned back to supine position immediately after SBP dropped to ≥20 mmHg, when their consciousness persisted. The point of syncope was synchronized for all the subjects by the point SBP reached the minima. Their beat-to-beat blood pressures (BP) were recorded continuously and bilateral middle cerebral artery (MCA) flow velocities were obtained with two 2 MHz Doppler probes from a transcranial Doppler ultrasonography (TCD) system. A nonlinear dynamic method——multimodal pressure flow (MMPF) analysis was introduced to access cerebral autoregulation during different time intervals. We introduced a new indicator——syncope index (SI), which was extracted from blood flow velocity (BFV) signal to evaluate the variation of cerebral vascular tension, and could reflect the deepness of dicrotic notch in BFV signal. Results: Compared with the syncope index of the baseline value at the beginning of the tilt test, SI in VVS group showed significantly lower when the VVS occurred (0.16±0.10 vs.0.27±0.10,P<0.01),while there was no significant difference in syncope index between the control group at the end of the tilt test and the baseline value at the beginning of the tilt test. For those VVS patients, pulse index and resistance index had no significant change. Syncope index decreased significantly 3 minutes before the point of syncope (0.23±0.07 vs.0.29±0.07,P<0.01).Conclusion: Dynamic regulation is exhausted when vasovagal syncope occurred. Tension decrease of small vessels could have some relationship with loss of the cerebral autoregulation capability. The proposed syncope index could be a useful parameter in predicting syncope of VVS patients since it decreased significantly up to 3 minutes earlier from the point of syncope.
    Family history of rheumatic diseases in patients with rheumatoid arthritis: a large scale cross-sectional study
    Xiao-ying ZHANG,Jia-yang JIN,Jing HE,Yu-zhou GAN,Jia-li CHEN,Xiao-zhen ZHAO,Jia-jia LIU,Xu-jie YOU,Xue LI,Jian-ping GUO,Xiao-feng LI,Jing LI,Ru LI,Zhan-guo LI
    2019, (3):  439-444.  doi: 10.19723/j.issn.1671-167X.2019.03.010    
    Abstract ( 21 )   HTML ( 1 )   PDF (3792KB) ( 18 )   Save
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    Objective: To determine the associations between the family history of rheumatic diseases and clinical features in patients with rheumatoid arthritis (RA).Methods: In total, eight hundred and ninety patients with RA were enrolled. The demographic and clinical data were collected, including gender, age, height, body weight, age of disease onset, history of smoking and drinking, family history of rheumatic diseases, clinical and laboratory features, pain and global visual analogue scale (VAS), and multi-dimensional health assessment questionnaire (MDHAQ). Finally, 803 patients were completed the dataset and were included in the study. Results: In this cohort, the male/female ratio was 1 ∶3.5, and the age of onset was (45.09±14.50) years. A total of 123 (15.32%) patients were accompanied with family history of rheumatic diseases, including RA, spondyloarthritis, Sj?gren’s syndrome, systemic lupus erythematosus and systemic sclerosis. The percentages of first degree, second degree and both first and second degree relatives were 91 (73.98%), 22 (17.89%), and 10(8.13%) respectively. The most common disease was RA (70.73%), followed by other rheumatic diseases (21.95%), and RA combined with other rheumatic diseases (7.32%). The clinical and laboratory characteristics were compared between the patients with and without family history. The onset-age of the subjects was significantly different between those with and without family history of rheumatic diseases (39.97 ±13.68 vs. 46.01±14.46; P<0.01), which meant that the onset-age in patients with family history was 6.04 years earlier than that in patients without family history. The patients with family history had higher positive rate of rheumatoid factor (RF) compared with those without family history (78.48% vs. 66.67%, P<0.05). By adjusting with gender, body mass index (BMI), smoking and alcohol drinking, anti-cyclic citrullinated peptide (CCP) antibody and RF level, the age at disease onset in the patients with family history was 4.54 years earlier than that in the patients without family history (β=-4.54;95%CI:-8.70, -0.38;P<0.05). Further hierarchical regression analysis showed that, the age at onset of the RA patients with family history was 10.02 years earlier than that without family history among the smoking patients (β= -10.02;95%CI:-17.60, -2.43;P=0.01), while the age at onset of the RA patients with family history was 3.27 years earlier than that without family history among the never smoking patients (β=-3.27;95%CI:-8.37, 1.82;P=0.21).Conclusion: The family history of rheumatic diseases is a risk factor for early onset of RA, and may interact with smoking.
    Role of erythroblast-like Ter cells in the pathogenesis of collagen-induced arthritis
    Ping WANG,Jing SONG,Xiang-yu FANG,Xin LI,Xu LIU,Yuan JIA,Zhan-guo LI,Fan-lei HU
    2019, (3):  445-450.  doi: 10.19723/j.issn.1671-167X.2019.03.011    
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    Objective: To explore the role of Ter cells in the development of the collagen-induced arthritis (CIA), we detected their quantity changes in the spleen of different stages of CIA mice and analyzed the correlation between Ter cells and the joint scores, and we also analyzed the correlation between Ter cells and the frequencies of T and B cell subsets, so as to further understand the pathogenesis of rheumatoid arthritis.Methods: The six to eight weeks DBA/1 mice were used to prepare CIA model. After the second immunization, we began to evaluate the joint score. According to the time of CIA onset and the joint score, the CIA mice were divided into three stages: early, peak and late stages. According to the final joint score, the CIA mice at the peak stage were subdivided into the high score group (score>8) and the low score group (score≤8). The frequencies of Ter cells in the spleen of the na?ve mice and the CIA mice at various stages and the frequencies of T and B cell subsets in the spleen of the CIA mice at the peak stage were detected by flow cytometry, then we carried on the correlation analysis. Results: The frequencies of Ter cells in the spleen of the CIA mice was significantly higher than those of the na?ve mice (8.522%±2.645% vs. 1.937%±0.725%, P<0.01), the frequencies of Ter cells in the spleen of the high score group mice was significantly lower than those of the low score group (6.217%±0.841% vs. 10.827%±0.917%, P<0.01). The frequencies of Th1 cells in the spleen of the high score group mice was significantly higher than those of the low score group mice (1.337%±0.110% vs. 0.727%±0.223%, P<0.05). The frequencies of Th17 cells in the spleen of the high score group mice was higher than those of the low score group mice (0.750%±0.171% vs. 0.477%±0.051%, P=0.099). The frequencies of germinal center B cells in the spleen of the high score group mice was significantly higher than those of the low score group mice (1.243%±0.057% vs. 1.097%±0.015%, P<0.05). Correlation analysis results showed that the frequencies of Ter cells in the spleen of the CIA mice at the peak stage was strongly negatively correlated with the frequencies of CD4 + T, Th1, Th17, and germinal center B cells, and was strongly positively correlated with the frequencies of B10 cells, indicating that these cells might have a protective effect in CIA. Studies on dynamic changes showed that the frequencies of Ter cells in the spleen of the CIA mice at the late stage was significantly lower than those at the peak stage (0.917%±0.588% vs. 8.522%±2.645%, P<0.001), suggesting the protective effect of these cells in arthritis. Conclusion: Ter cells were significantly increased in the spleen of the CIA mice at peak stage, and were negatively correlated with joint scores and pathogenic immune cells, and positively correlated with protective immune cells. Ter cells were significantly decreased in the spleen of the CIA mice at the late stage. What we mentioned above suggests that Ter cells might be involved in the progression of rheumatoid arthritis as an immunomodulatory cell,but further in vivo and in vitro experiments are needed to verify its specific effects and mechanism.
    Clinicopathological and molecular characteristics of Epstein-Barr virus associated gastric cancer: a single center large sample case investigation
    Yang YANG,Yi-qiang LIU,Xiao-hong WANG,Ke JI,Zhong-wu LI,Jian BAI,Ai-rong YANG,Ying HU,Hai-bo HAN,Zi-yu LI,Zhao-de BU,Xiao-jiang WU,Lian-hai ZHANG,Jia-fu JI
    2019, (3):  451-458.  doi: 10.19723/j.issn.1671-167X.2019.03.012    
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    Objective: Epstein-Barr virus associated gastric cancer (EBVaGC) is different from the traditional gastric cancer (Epstein-Barr virus non-associated gastric cancer, EBVnGC), and has unique clinicopathological features. This study investigated the largest single center cancer series so as to establish the clinicopathological and molecular characteristics of EBVaGC in China.Methods: A retrospective analysis was conducted on EBVaGC and EBVnGC patients diagnosed at Peking University Cancer Hospital from 2003 to 2018 by comparing their clinicopathological features and prognosis. The gastric cancer (GC) dataset of public database was analyzed to obtain differentially expressed genes. The expression of important genes and their association with prognosis of GC were verified in GC tissues from our hospital. Results: In this study, 3 241 GC patients were included, and a total of 163 EBVaGC (5.0%) patients were identified. Compared with EBVnGC, EBVaGC was higher in male and younger patients, and positively associated with remnant GC, poorly differentiated adenocarcinoma, and mixed type GC. EBVaGC was inversely related to lymph node metastasis. The 5-year survival rate of EBVnGC and EBVaGC was 59.6% and 63.2% respectively (P<0.05). In order to explore molecular features of EBVaGC, the Cancer Genome Atlas (TCGA) dataset was analyzed (n=240), and 7 404 significant differentially expressed genes were obtained, involving cell proliferation, apoptosis, invasion and metastasis. The down-regulated invasion/metastasis gene SALL4 and the up-regulated immune checkpoint gene PD-L1 were important molecular features of EBVaGC. Validation of these two genes in large GC series showed that the majority of the EBVaGC was SALL4 negative (1/92, 1.1%, lower than EBVnGC, 303/1 727, 17.5%), and that PD-L1 was mostly positive in EBVaGC (81/110, 73.6%, higher than EBVnGC, 649/2 350, 27.6%). GC patients with SALL4 negative and PD-L1 positive were often associated with better prognosis.Conclusion: EBVaGC is a unique subtype of GC with less metastasis and a good prognosis. It also has a distinct molecular background. The down-regulation of invasion/metastasis gene SALL4 and up-regulation of immune checkpoint gene PD-L1 are important molecular features.
    Trans-ethnic analysis of susceptibility variants in IgA nephropathy
    Yu-qi KANG,Yue-miao ZHANG,Ping HOU,Su-fang SHI,Li-jun LIU,Xu-jie ZHOU,Ji-cheng LV,Hong ZHANG
    2019, (3):  459-466.  doi: 10.19723/j.issn.1671-167X.2019.03.013    
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    Objective: To compare the genetic architecture of susceptibility variants of IgA nephropathy (IgAN) in Chinese and Europeans.Methods: We selected the independent genome-wide significant variants of IgAN in European population as candidate variants. Their associations, risk alleles, risk allele frequencies, odds ratios and population attributable risk scores were derived and calculated, then compared with those in the current Chinese population, including 1 194 IgAN patients and 902 controls. Using the significant variants, genetic risk scores were calculated and compared between the East Asians and the Europeans. The correlation between the genetic risk scores and clinical manifestations was also evaluated. Results: There were 16 independent single nucleotide polymorphisms (SNPs) located in 11 loci showing significantly association with susceptibility to IgAN in the Europeans. 93.75% (15/16) of them also showed significant associations in the Chinese (P<0.05). The effects of all the associated SNPs were in the same direction, either risk or being protective for IgAN, between the Chinese and the Europeans. On the contrary, remarkable higher risk allelic odds ratio (P=1.94×10 -2), higher risk allele frequency (P=3.09×10 -2), and higher population attributable risk (P=3.03×10 -4) were observed for most of the associated SNPs in the Chinese than in the Europeans. Furthermore, genetic risk scores were significantly larger in the Asian populations compared with the Europeans (P=1.78×10 -163). While there was no significance among the subpopulations in both the East Asians and the Europeans. Compared with the healthy controls, the genetic risk score in the IgAN patients was significantly larger (P=3.60×10 -27). Clinical analysis showed the genetic risk score was positively associated with serum levels of IgA and IgA1, phases of chronic kidney disease and Haas grades. Conclusion: Our study provides further evidence in the shared genetic architecture between Chinese and Europeans, while diffe-rences with respect to the effect sizes and risk allele frequencies across ethnicities, contributing partially to the differences of disease prevalence.
    Spectrometric analyses of larotaxel and larotaxel liposomes quantification by high performance liquid chromatography
    Xue-qi LI,Jian-wei LI,Qiu-hong LI,Yan YAN,Jia-lun DUAN,Yi-nuo CUI,Zhan-bo SU,Qian LUO,Jia-rui XU,Ya-fei DU,Gui-ling WANG,Ying XIE,Wan-liang LU
    2019, (3):  467-476.  doi: 10.19723/j.issn.1671-167X.2019.03.014    
    Abstract ( 9 )   HTML ( 1 )   PDF (3602KB) ( 4 )   Save
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    Objective: Larotaxel is a new chemical structure drug, which has not been marketed worldwide. Accordingly, the standard identification and quantification methods for larotaxel remain unclear. The spectrometric analyses were performed for verifying weight molecular formula, molecular weight and chemical structure of larotaxel. Besides, a quantification method was developed for measuring larotaxel in the liposomes.Methods: The molecular formula, molecular weight and chemical structure of larotaxel were studied by using mass spectrometry (MS), infra-red (IR), nuclear magnetic resonance (NMR) and ultraviolet-visible (UV-vis) spectrometric techniques. The absorption wavelength of larotaxel was investigated by UV-vis spectrophotometry full-wavelength scanning. Besides, a quantification method was developed by high performance liquid chromatography (HPLC), and then validated by measuring the encapsulation efficacy of larotaxel liposomes. Results: The four spectral characteristics of larotaxel were revealed and the corresponding standard spectra were defined. It was confirmed that larotaxel had the structure of tricyclic diterpenoids, with the molecular formula of C45H53NO14, the molecular weight of 831.900 1, and the maximum absorption wavelength of 230 nm. The quantitative method of larotaxel was established by using HPLC with a reversed phase C18 column (5 μm, 250 mm×4.6 mm), a mobile phase of acetonitrile-water (75 ∶25, volume/volume), and a detection wavelength of 230 nm. The validation study exhibited that the established HPLC method was stable, and had a high recovery and precision in the quantitative measurement of larotaxel in liposomes. In addition, a new kind of larotaxel liposomes was also successfully prepared. The particle size of the liposomes was about 105 nm, with an even size distribution. And the encapsulation efficiency of larotaxel in the liposomes was above 80%.Conclusion: The present study offers reference standard spectra of larotaxel, including MS, IR, NMR, and UV-vis, and confirms the molecular formula, molecular weight and chemical structure of larotaxel. Besides, the study develops a rapid HPLC method for quality control of larotaxel liposomes.
    Preparation and characterization of paclitaxel microspheres in situ gel and its antitumor efficacy by local injection
    Ying ZHAN,Yi-tian DU,Zhen-zhen YANG,Chun-li ZHANG,Xian-rong QI
    2019, (3):  477-486.  doi: 10.19723/j.issn.1671-167X.2019.03.015    
    Abstract ( 15 )   HTML ( 1 )   PDF (10786KB) ( 8 )   Save
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    Objective: The current difficulties in the treatment of tumor include repeated administration and high recurrence rate after tumor resection. In order to reduce the number of doses, avoid side effects of chemotherapeutic drugs, suppress tumor growth and delay tumor recurrence after surgery, a temperature-sensitive in situ gel with paclitaxel microspheres (PTX/M gel) was prepared. PTX/M gel was administered by intratumoral injection once a month.Methods: First of all, paclitaxel microspheres (PTX/M) were prepared by emulsion solvent evaporation method. A laser particle size distribution analyzer was used to investigate the size, distribution, specific surface area of microspheres. Paclitaxel content was determined by high performance liquid chromatography (HPLC). Then encapsulation efficiency of paclita-xel was calculated and in vitro release characteristics were studied. Secondly, PTX/M gel was prepared by cold dissolution method. The phase transition temperature, elastic modulus, dissolution curve, correlation between dissolution and release were measured. Finally, U87 MG and 4T1 subcutaneous tumor mo-dels were established respectively to study the efficacy of PTX/M gel in suppressing tumor growth and delaying tumor recurrence after surgery.Results: The median diameter of the selected PTX/M was (32.24±1.09) μm, the specific surface area was (206.61±10.23) m 2/kg, the encapsulation efficiency was 85.29%±1.34%, and the cumulative release percentage of paclitaxel from PTX/M was 33.56%±3.33% in one month. Phase transition temperature of PTX/M gel was 33 ℃. The elastic modulus of PTX/M gel at 25 ℃ and 37 ℃ were 4.2×10 3 Pa and 18×10 3 Pa, respectively. The gel could stay in the body for up to 48 hours. It could be seen from the results of animal experiments that were compared with the saline group and the Taxol group, and the tumor-bearing mice of the PTX/M gel group had the slowest tumor growth (P<0.05). Similarly, in the tumor recurrence experiments, the mice of PTX/M gel group had the latest tumor recurrence after surgery. Conclusion: As a local sustained-release preparation, PTX/M gel can effectively suppress tumor growth and delay postoperative recurrence of tumors. It has potential advantages in tumor treatment.
    Fluorescence assay for the detection of apurinic/apyrimidinic endonuclease 1 (APE1) activity in human blood samples
    Jia-yu WANG,Mei-ping ZHAO
    2019, (3):  487-492.  doi: 10.19723/j.issn.1671-167X.2019.03.016    
    Abstract ( 16 )   HTML ( 2 )   PDF (3646KB) ( 8 )   Save
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    Objective: To develop a simple, sensitive and robust method for rapid detection of human apurinic/apyrimidinic endonuclease 1 (APE1) in various biological samples.Methods: An abasic site-containing DNA probe with a sequence of 5'-T*T*C*C*T*C*T(ROX)AGAGXCGTT(BHQ2)C*A*C*T*G*T*AGTTTATA*C*A*G*T* GAATCTCTCTAG*T*C*T-3'[“X” represents AP site; The phosphorothioated nucleotides (at 3’ side) are indicated with an asterisk after the nucleotides; ROX is 6-carboxy-X-rhodamine and BHQ2 is Black Hole quencher 2] was synthesized and used for the detection. In the presence of APE1, the DNA probe could be specifically hydrolyzed by the enzyme and release the fluorophore, resulting in strong fluorescence emission. The activity of APE1 was determined according to the rate of increase in fluorescence intensity. In this work, we modified the reaction buffer and significantly improved the performance of the method. Moreover, the method was further extended to measure the contents of APE1 in the protein extraction from peripheral blood mononuclear cells (PBMCs) extracted from human whole blood samples by density gradient centrifugation. The assay was also applied to measure the activity of APE1 in human serum samples. Results: With a new reaction buffer composed of 0.04% (V/V) Triton X-100, 50 mmol/L KAc, 20 mmol/L Tris-Ac, 10 mmol/L Mg(Ac)2 and 1 mmol/L dithiothreitol (DTT), the method achieved a detection limit of 0.005 U/mL (3 pg/mL) and a linear response ranging from 6 pg/mL to 1.2 ng/mL. The contents of APE1 in the protein extraction from PBMCs of eight blood samples were measured to be in the range from 0.061 to 0.40 ng/μg protein, with an average of 0.16 ng/μg protein. The recovery was 98%±5% (n=3). The levels of APE1 in the sera from 102 normal individuals (51 male and 51 female, age range: 59-75 years) were observed to be from 0.13 to 0.34 ng/mL, with a recovery of 96%±15% (n=3).Conclusion: The new fluorescence assay was simple, rapid and sensitive, providing a practical tool to measure the activity of APE1 in serum samples and cell extracts. It also holds great potential in measurement of APE1 in many other biological samples for clinical test and laboratory research.
    Proximal femoral nails antirotation and dynamic hip screws for fixation of unstable intertrochanteric fractures of femur: A meta-analysis
    Yi-ran ZHANG,Feng RAO,Wei PI,Pei-xun ZHANG,Bao-guo JIANG
    2019, (3):  493-500.  doi: 10.19723/j.issn.1671-167X.2019.03.017    
    Abstract ( 33 )   HTML ( 11 )   PDF (2062KB) ( 21 )   Save
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    Objective: To evaluate the efficacy and safety of proximal femoral nail antirotation (PFNA) and dynamic hip screw (DHS) for unstable intertrochanteric fractures using meta-analysis. Methods: The PubMed, Embase, Cocharane Central Register of Controlled Trials, Google Scholar, China Science and Technology Papers and Citation Database (CSTPCD) and China Journal Full-text Database (CNKI) were searched for published randomized controlled trials before January 1, 2019. Two researchers independently screened the literature in the light of the inclusion and exclusion criteria, evaluated the quality of the studies and extracted the data which were consisted of clinical efficacy indexes, such as incision length, operation time,intraoperative blood loss, weight-bearing time,fracture-healing time, Harris hip score and safety indicators like complications. Meta-analysis was performed with the Revman 5.3 software provided by Cochrane Community in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standard. Results: Nine randomized controlled trials met the requirement with a total of 779 patients, of whom 383 were fixed with PFNA and 396 with DHS. Meta-analysis demonstrated that PFNA was associated with smaller surgical incision length [MD=-7.43, 95%CI (-9.31, -5.55), P<0.05], shorter operation time [MD=-22.76, 95%CI (-29.57, -11.95), P<0.05], less intraoperative blood loss [MD=-216.34, 95%CI (-275.18, -157.49), P<0.05], earlier weight bearing after surgery [MD=-12.34, 95%CI (-17.71, -6.97), P<0.05], shorter fracture healing time [MD=-5.00, 95%CI (-7.73, -2.26), P<0.05], higher postoperative Harris hip score [MD=12.22, 95%CI (3.88, 20.55), P<0.05], higher rate of excellent Harris hip score [OR=3.56, 95%CI (1.44, 8.81), P<0.05] and lower incidence rate of postoperative complications [OR=0.48, 95%CI (0.33, 0.70), P<0.05], such as hip varus, wound infection, urinary tract infection, pulmonary infection, pressure sore, deep vein thrombosis, pulmonary embolism, heart failure and cerebral infraction when compared with DHS. No statistical difference was shown between the groups when it came to subgroup analysis by age. However, there was no significant difference (P>0.05) in the duration of hospitalization and the complications resulting in the occurrences of internal fixation loosening, such as femoral shaft fracture (during or post operation), internal fixation fracture, cut-out, displacement or retraction. Conclusion: Current published evidence supports the superiority of PFNA to DHS for unstable intertrochanteric fractures in terms of clinical efficacy. The conclusion was limited because of the relatively low quality of evidence with low strength of confidence. Large scale and high-quality randomized controlled trials are required to validate the safety of PFNA and DHS for unstable intertrochanteric fractures.
    Analysis of prophylactic effect of extended-duration anticoagulant drugs in elderly patients undergoing hip fracture
    Wei ZHANG,Pei-xun ZHANG
    2019, (3):  501-504.  doi: 10.19723/j.issn.1671-167X.2019.03.018    
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    Objective: To evaluate the prophylactic effect of extended-duration anticoagulant drugs on venous thromboembolism, and to explore the time of drug prevention for venous thromboembolism after hip fracture.Methods: A retrospective analysis of 143 patients undergoing hip fractures from November 2017 to October 2018 in Peking University People’s Hospital was conducted to investigate the relationship between the extended-duration anticoagulant drug and the morbidity of venous thromboembolism and bleeding during the treatment. All the drug prevention programs for the patients included in the study were implemented in accordance with the 2016 edition of the Guidelines for Prevention of Venous Thrombosis in Orthopaedic Surgery by Orthopaedic Society of Chinese Medical Association. The patients in the two groups were followed up for venous thromboembolism and bleeding during the medication within 5 weeks after the fracture. Venous thromboembolism included symptomatic and asymptomatic deep venous thrombosis of the lower extremities, pulmonary thromboembolism, and all the patients with deep venous thrombosis of the lower extremities required vascular ultrasound results to obtain clear evidence. The results of vascular ultrasound were the basis for determining deep venous thrombosis. Bleeding conditions were included, but not limited to gastrointestinal bleeding, wound bleeding, intracranial hemorrhage, intraspinal hematoma, and fundus hemorrhage. Results: There were no pulmonary thromboembolism in both groups after surgery. The morbidity of deep venous thrombosis was 22.09% and 8.77% in the 2-week and 4-week groups (P=0.037), the time to deep venous thrombosis in the two groups was (17.32±7.75) days and (29.20±0.17) days after surgery. One case of bleeding occurred during the use of anticoagulant drugs in both groups, the morbidity of bleeding during the treatment was 1.16% and 1.75% (P=0.769), respectively.Conclusion: Extended-duration anticoagulant drugs to 4 weeks after surgery can significantly reduce the morbidity of postoperative venous thromboembolism, and does not increase the risk of bleeding. Patients with a risk of bleeding should carefully assess the risks and benefits of drug prevention and choose the best treatment.
    Mid-to-long term outcomes and influence factors of postoperative concurrent chronic ankle instability and posterior ankle impingement
    Dong JIANG,Yue-lin HU,Chen JIAO,Qin-wei GUO,Xing XIE,Lin-xin CHEN,Feng ZHAO,Yan-bin PI
    2019, (3):  505-509.  doi: 10.19723/j.issn.1671-167X.2019.03.019    
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    Objective: To investigate the mid-to-long-term efficacy of patients with chronic ankle instability combined with posterior impingement syndrome after 3-9 years of follow-up, and to analyze the influencing factors.Methods: From February 2010 to December 2015, 46 patients underwent concurrent lateral ankle ligament repair with posterior ankle arthroscopic surgery at the Institute of Sports Medicine, Peking University Third Hospital. The patient was first placed in a prone position and underwent arthroscopic debridement for the posterior impingement. After finishing the posterior arthroscopy, the surgeon and assistants first translated the patient to the affected side, then turned to the healthy side, and changed the position to the supine position. During the turning over, another assistant held the arthroscope and the instrument to ensure that it was sterile and could be used without replacement. The anterior ankle arthroscopy was operated if necessary and the lateral ankle ligament repair was anatomic repaired with anchors. The 42 patients were followed up, including 26 males and 16 females. The average age was (28.9±10.0) years. The patient’s clinical symptoms, joint stability, mobility and motor function were compared by questionnaire and physical examination. The preoperative and postoperative visual analogue scale (VAS) scores, American Orthopaedic Foot and Ankle Society (AOFAS) scores, Tegner scores were compared, and the clinical scores and the patient age, gender, height and weight were compared. The correlations between body mass index (BMI), preoperative duration, surgery duration, and cartilage injury were analyzed. Results: The mean follow-up time was (71.8±22.8) months. The postoperative VAS scores (1.0 vs. 5.0, P<0.001), AOFAS scores (92 vs. 80, P<0.001), and Tegner scores (6.5 vs. 2, P<0.001) were significantly superior to the preoperative levels. The excellent and good rate was 97.6%. The postoperative VAS score (t=2.719, P=0.10), AOFAS score (t=-2.853, P=0.10), Tegner score (t=-3.443, P=0.001) and time to return exercise (t=2.814, P=0.008) were negatively correlated with the patient age, and the postoperative VAS score was negatively correlated with cartilage injury (Z=-2.195, P=0.028).Conclusion: The mid-to-long-term clinical outcomes of the chronic ankle ligament instability combined with the posterior impingement were good. The age of the patients was negatively correlated with the clinical outcome. The combined cartilage injury could aggravate the postoperative pain.
    Association of malnutrition-inflammation-cardiovascular disease with cognitive deterioration in peritoneal dialysis patients
    Li-ping DUAN,Zhao-xia ZHENG,Yu-hui ZHANG,Jie DONG
    2019, (3):  510-518.  doi: 10.19723/j.issn.1671-167X.2019.03.020    
    Abstract ( 28 )   HTML ( 6 )   PDF (1361KB) ( 28 )   Save
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    Objective: To investigate the relationship between malnutrition-inflammation-atherosclerosis (MIA) syndrome and deterioration of global and specific domains of cognitive function in peritoneal dialysis (PD) patients.Methods: This was a multi-center prospective cohort study. The PD patients who met the inclusion criteria were examined with general and specific cognitive function between March 2013 and November 2013. The patients were divided into MIA0, MIA1 and MIA2 groups, according to items of “Yes” for whether or not having cardiovascular disease, serum albumin≤35 g/L or high-sensitive C-reactive protein (hs-CRP) ≥3 mg/L. After 2 years, the patients maintained on PD would be repeatedly measured with cognitive function. The Chi-square test, One-way ANOVA, Kruskal-wallis H rank sum test were used to compare the differences of clinical characteristics, biochemical data, and global and specific cognitive function parameters among the three groups at baseline, and two years later, respectively. The Bonferroni method was applied to adjust the significance level for further comparison between each two different groups. The change of score in each cognitive parameter of global and specific domains was used as dependent variable. Age, gender, education level, depression index, body-mass index, diabetes mellitus, serum sodium levels and MIA (MIA0 was control, MIA1 and MIA2 as dummy variables) were all included in the multivariable linear regression models to analyze the risk factors of the deterioration of cognitive function. The analysis for each cognitive domain was adjusted for the baseline score of the corresponding cognitive parameter. All the analyses were performed using SPSS for Windows, software version 25.0 (SPSS Inc., Chicago, IL). Results: Over two-year follow up, the prevalence of cognitive impairment increased from 20.0% to 24.7%, absolute decrease of 3MS scores were more significantly decreased in MIA2 (-3.9±12.0 vs. 1.1±6.7, P<0.01) and MIA1 group (-2.3±11.8 vs. 1.1±6.7, P<0.05) than those in MIA0 group respectively. Specific cognitive functions, included executive function (trail-making tests A and B, P=0.401,P=0.176), immediate memory (P=0.437), delayed memory (P=0.104), visuospatial skill (P=0.496), and language ability (P=0.171) remained unchanged. Advanced age, lower education, diabetes mellitus and depression were all correlated with the deterioration of one or more cognitive domains, and the patients having one item of MIA syndrome were prone to develop the deterioration of 3MS (P=0.022). Furthermore, the patients having two or more items of MIA syndrome were more likely to develop the deterioration of not only 3MS (P <0.001), but also delayed memory, visuospatial skill, and language ability (P=0.002, P=0.007, P=0.004, respectively).Conclusion: Patients with one item or above of MIA syndrome were at high-risk for the deterioration of global cognitive function. The more MIA syndrome items there were, the more specific cognitive domains deteriorated.
    Effect of clinical characteristics on relapse of alcohol dependence: a prospective cohort study
    Ran ZHU,Zhao-jun NI,Shun ZHANG,Liang-jun PANG,Chuan-sheng WANG,Yan-ping BAO,Hong-qiang SUN
    2019, (3):  519-524.  doi: 10.19723/j.issn.1671-167X.2019.03.021    
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    Objective: To investigate whether craving and demographic factors to predict relapse in alcohol dependence.Methods: This study was a prospective cohort study. From August 2017 to August 2018, 158 Han male inpatients who met the diagnositic and statistical manual disorders-fourth version(DSM-Ⅳ) alcohol dependence diagnostic criteria were recruited from three mental hospitals in China. The participants were interviewed at baseline and followed up by telephone after 3 months for assessment. The baseline assessment after the acute withdrawal period included demographic data and alcohol-related data, clinical institute withdrawal assessment-advanced revised (CIWA-Ar), withdrawal and cue-induced craving on visual analog scale (VAS), Michigan alcoholism screening test (MAST), self-rating anxiety scale (SAS), self-rating depression scale (SDS) and alcohol urge questionnaire (AUQ). According to the follow-up results, “relapse” was defined as the consumption of beverages containing ethanol at any time during the follow-up study, and “time to relapse” was defined as the number of days from the first drinking to the baseline. Whether relapse occurred and the time to relapse were the primary endpoints. Cox proportional hazard regression model was used to analyze the factors affecting the relapse of alcohol dependence. Results: In the study, 158 alcohol dependence patients were finally included, age from 21 to 60 years, with the mean age of (40.31±9.14) years. The relapse rate was 63.7% three months after baseline assessment. According to Cox univariate analysis and multivariate analysis, the age (OR=0.975, P=0.030) and CIWA-Ar scores (OR=1.126, P=0.010) significantly predicted relapse. And there was no significant difference in education level, marital status, withdrawal and cue-induced craving on VAS, SAS and SDS between the relapse group and the non-relapse group (P>0.05).Conclusion: Age and severity of alcohol-dependent withdrawal symptoms during hospitalization are significantly related to relapse for alcohol in alcohol-dependent patients. To be exact, the older age is a protective factor, that is to say, the younger patients are prone to relapse, while the risk of relapse is raised by the higher se-verity of withdrawal symptoms. However, neither cue-induced nor withdrawal craving can predict relapse of alcohol-dependent patients.
    Quantitative evaluation of image quality of megavoltage computed tomography for guiding helical tomotherapy
    Yu-liang HUANG,Chen-guang LI,Kai MAO,Jian-an WU,Tian-tian DAI,Yuan-yuan HAN,Hao WU,Hai-yang WANG,Yi-bao ZHANG
    2019, (3):  525-529.  doi: 10.19723/j.issn.1671-167X.2019.03.022    
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    Objective: To quantitatively analyze image quality of two sets of phantom (CatPhan504 and Cheese) Megavoltage computed tomography (MVCT) images acquired by Helical Tomotherapy with three scanning modes (Fine, Normal and Coarse), and to explore and validate a semi-automatic quality assurance procedure for MVCT images of Helical Tomotherapy.Methods: On Helical Tomotherapy, CatPan504 and Cheese phantoms were scanned with three pitch levels (Fine, Normal, Coarse: 4 mm, 8 mm, 12 mm/circle) respectively. Pylinac, Matlab and Eclipse were used to calculate and compare spatial resolution, noise level and low contrast resolution of images obtained under three scanning modes respectively. The spatial resolution can be evaluated by the blurring of line-pair CT value in the images of CatPhan504’s CTP528 module. The noise level can be evaluated by the integral non-uniformity in the images of Cheese’s uniformity module. the low contrast resolution can be evaluated by contrast-to-noise ratio of both phantoms’ plug-in module, or visibility of the region of interest (Supra-Slice) in the images of CatPhan504’s CTP515 module. Results: Analyses on CatPhan504’s line pair module(CTP528 module) showed that the first three line pairs(the gap size are 0.500 cm, 0.250 cm and 0.167 cm respectively) could be clearly observed but blurring began to occur from the fourth line pair(the gap size is 0.125 cm) under Coarse mode. Meanwhile, the first four line pairs were all observable under the Normal and Fine modes. Integral non-integrity index(the value negatively correlated with the noise level) were 0.155 7, 0.136 8 and 0.122 9 for Coarse, Normal and Fine modes respectively. None of the Supra-Slice in CatPhan504’s CTP515 module could be observed under three imaging modes. Low contrast contrast-to-noise ratio of Cheese phantom was similar under three modes and the insert visibility exhibited nearly linear growth with the increasing difference between CT average value of the insert material and background.Conclusion: Superiority and inferiority of three image modes in terms of the three image quality index was not consistent. Evaluation results above could provide reference for more rational decision on scanning modes selection of helical tomotherapy, which was based on image visualization demands in clinical practice. The proposed method could also provide guidance for similar image quality assessment and periodic quality assurance.
    Application of diffusion tensor imaging combined with virtual reality three-dimensional reconstruction in the operation of gliomas involved eloquent regions
    Su-hua CHEN,Jun YANG,Hong-bin HAN,De-hua CUI,Jian-jun SUN,Chang-cheng MA,Qing-yuan HE,Guo-zhong LIN,Yun-feng HAN,Chao WU,Kai-ming MA,Yi-bo ZHANG
    2019, (3):  530-535.  doi: 10.19723/j.issn.1671-167X.2019.03.023    
    Abstract ( 8 )   HTML ( 2 )   PDF (3741KB) ( 4 )   Save
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    Objective: To investigate the values of diffusion tensor imaging (DTI) and virtual reality(VR) techniques in design surgery program of gliomas near eloquent regions.Methods: In this study, 35 cases were retrospectively analyzed with gliomas involved language areas or rolandic regions operated in Department of Neurosurgery, Peking University Third Hospital from January 2015 to January 2019. Surgery programs were performed by Dextroscope virtual reality system. The pre-operative data, such as the magnetic resonance imaging(MRI), magnetic resonance arteriography (MRA) and DTI was transferred into the VR computer for restitution,Tumors, neural fiber tracts and blood vessels were reconstructed to simulate operation and design individual surgical plan. Neurological function was evaluated 1 week, 1 month and 3 months after operation.Results: Virtual reality three-dimensional images of the 35 cases were successfully achieved, including neural fiber tracts,blood vessels and the lesions. The displacement and destruction of fiber tracts,the anatomic relationship between tumor and important fiber bundle, artery and vein could be shown clearly. Surgical simulation and surgery program of VR of the 35 patients were successfully performed. The 3D images obtained from virtual reality near to the real surgery. Ten of the 35 cases were defined as rolandic regions tumors, 14 of the 35 cases were defined as language areas tumors and 11 of the 35 cases involved both language areas and rolandic regions. Complete resection of enhancing tumor (CRET) was achieved in 30 cases (85.7%), subtotal resection in 5 cases (14.3%), neurological function improved in 34 cases (97.1%) after operation,and 1 case had no improvement compared with that before(2.9%). Thirteen cases without neurological deficit pre-operation,showed transient neurological deficit ,which were recovered about 10 days post-operation, 12 of 22 cases with pre-operative neurologic deficit, improved one week postoperation, 9 of 22 cases with pre-operative neurologic deficit improved one month after operation, the rest 1 case was recurrent with glioblastoma with aggravated hemiplegia symptom after operation, who died of cerebral hernia 2 months later.Conclusion: Dextroscope virtual reality system can clearly expose and quantify the 3D anatomic relationship of tumors, neural fiber tracts and blood vessels surrounding gliomas near eloquent regions, which is helpful to design the best individualized surgery program, to improve surgical effect.
    Anti-Müllerian hormone as a new marker of the ovarian reserve function preservation by goserelin during (neo)adjuvant chemotherapy for young breast cancer patients
    Si-yuan WANG,Shu WANG
    2019, (3):  536-541.  doi: 10.19723/j.issn.1671-167X.2019.03.024    
    Abstract ( 23 )   HTML ( 2 )   PDF (1904KB) ( 21 )   Save
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    Objective: To observe the dynamic change of anti-Müllerian hormone (AMH) in 1 year after chemotherapy which is the best biochemical marker of ovarian reserve in reproductive medicine setting and to evaluate the effect of gonadotropin-releasing hormone agonist (GnRHa)goserelin to prevent ovarian reserve function during (neo)adjuvant chemotherapy for young breast cancer patients.Methods: Between December 2015 and June 2017, 101 breast cancer patients of age ≤ 45 years with stagesⅠtoⅢ had been enrolled. The patients were assigned without interference to receive either (neo)adjuvant chemotherapy with goserelin (goserelin group) or without goserelin (chemotherapy group) as their own selection. AMH and menstrual status were evaluated before, during and 0.5 year, 1 year after chemotherapy. Primary end point was the incidence of low AMH value (<0.4 μg/L) at the end of 1 year. Secondary end point was the incidence of amenorrhea(the absence of menses in the preceding 12 months after assignment). Results: In the study, 51 patients chose to join the chemotherapy group, while the other 50 patients selected goserelin to preserve their ovarian reserve function. More unmarried or childless, hormone receptors negative,receiving breast conservation therapy patients with earlier stage selected goserelin before chemotherapy. The incidence of low AMH value was significantly higher in chemotherapy group than in goserelin group (74.5% vs. 38.0%, P<0.001) in 1 year after chemotherapy. The incidence of amenorrhea was consistent with AMH (56.9% vs. 24.0%, P=0.001). And more patients’ menstruation (78.9% vs. 54.5%) and AMH value (71.0% vs. 53.8%) recovered in goserelin group within 6 months after chemotherapy. In sub-group analysis, AMH and menstruation seemingly recovered more in goserelin group independent of age, chemotherapy regimen and use of tamoxifen. Especially, AMH value of 36.4% (8/22) patients in chemotherapy group and 18.4% (7/38) patients in goserelin group still maintained low level (<0.4 μg /L) although their menstruation had recovered 1 year after chemotherapy. In addition, 41 patients (20 patients in chemotherapy group, 21 patients in goserelin group) could be evaluated for the dynamic change of AMH and menstrual status during chemotherapy. The mean level of AMH in chemotherapy group declined rapidly to very low level before the 3rd cycle, while 70% of the patients kept presence of menstruation. At the same time, the mean level of AMH in goserelin group was still above 0.4 μg /L, but all of the patients had menopause.Conclusion: Our study has offered evidence that Goserelin with chemotherapy could protect against ovarian reserve failure for young breast cancer patients, now that more patients’ AMH value recovered earlier who had selected co-treatment. AMH may be a more precise marker than menstrual status to clinically evaluate ovarian reserve function pre-, during and post- chemotherapy.
    Detection of preoperative chemoradiotherapy sensitivity molecular characteristics of rectal cancer by transcriptome second generation sequencing
    Wei ZHANG,Ying-jiang YE,Xian-wen REN,Jing HUANG,Zhan-long SHEN
    2019, (3):  542-547.  doi: 10.19723/j.issn.1671-167X.2019.03.025    
    Abstract ( 19 )   HTML ( 2 )   PDF (3425KB) ( 11 )   Save
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    Objective: To detect the preoperative chemoradiotherapy sensitivity molecular characteristics of rectal cancer by transcriptome second generation sequencing.Methods: The clinicopathological data of 30 patients with locally advanced rectal cancer were collected prospectively, including 9 indicators (general conditions, imaging data before radiotherapy and chemotherapy, pathological data of biopsy before radiotherapy and chemotherapy, and tumor differentiation degree, etc.), in order to analyze the correlation between them and tumor regression grading (TRG) after radiotherapy and chemotherapy for rectal cancer. At the same time, frozen specimens of colonoscopy biopsy before neoadjuvant therapy were collected from these 30 patients, and transcriptome second-generation sequencing was performed for bioinformatics analysis to screen out the genes that might drive the radio chemotherapy sensitivity of rectal can-cer. Results: Among the 30 patients with rectal cancer, 9 had complete pathological remission, 12 had partial remission, and 9 had poor remission. The degree of pathological TRG remission after radiotherapy and chemotherapy for rectal cancer was negatively correlated with the preoperative MRI T stage (P=0.046), and positively correlated with preoperative MRI rectal cancer extravascular invasion (EMVI) (P=0.003). Transcriptome second-generation sequencing of the obtained 217 transcripts (P<0.05) for signal pathway enrichment analysis, and multiple cell signal transduction pathways related to antigen presentation could be found. The high expression of HSPA1A, HSPA1B and EXOSC2 was positively correlated with postoperative pathological remission (P<0.05). The high expression of DNMBP, WASH8P, FAM57A, and SGSM2 was positively correlated with postoperative pathological remission (P<0.05).Conclusion: Preoperative NMR detection of extra-tumoral vascular invasion (EMVI-positive) in patients with rectal cancer was significantly better than that of EMVI-negative patients after chemoradiotherapy. Patients with high expressions of HSPA1A, HSPA1B and EXOSC2 had poor postoperative pathological remission, while patients with high expressions of genes, such as DMNMB, WASH8P, FAM57A, and SGSM2 had good postoperative pathological remission. Based on the molecular characte-ristics of rectal cancer radiotherapy and chemotherapy, attempts to block or enhance the molecular pathways associated with chemosensitivity of rectal cancer, are to be made to further explore new candidate therapeutic targets that can increase the sensitivity of radiotherapy and chemotherapy for rectal cancer.
    Quality assessment of global guidelines on colorectal cancer screening
    Le GAO,Shu-qing YU,Ji-chun YANG,Jun-ling MA,Si-yan ZHAN,Feng SUN
    2019, (3):  548-555.  doi: 10.19723/j.issn.1671-167X.2019.03.026    
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    Objective: To systematically review and assess the quality of guidelines on colorectal cancer screening worldwide to provide guidance for the development of high-quality colorectal cancer screening guidelines in mainland China.Methods: CNKI, WanFang Data, VIP, SinoMed, PubMed, Embase, and Web of Science were systematically searched to identify guidelines on colorectal cancer screening from inception to Jun. 20 th, 2018, and so were some websites and major search engines about the deve-lopment of the guidelines from the existing literature (search date: Aug. 3 rd, 2018). Two experienced reviewers independently examined these abstracts and then extracted information, and the Appraisal of Guidelines for Research and Evaluation Ⅱ (AGREE Ⅱ) were used to evaluate the methodological quality of these guidelines by four well trained reviewers. Results: In this study, 46 guidelines published from 1994 to 2018 were finally included in our analysis from 10 countries and 5 regions, among which 5 were from mainland China. The quality of these guidelines was relatively high in domain 1 (scope and purpose) and domain 4 (clarity of presentation), and medium in domain 2 (stakeholder involvement). While in the other three domains (domain 3: rigour of development; domain 5: applicability; domain 6: editorial independence), the results were quite different among these guidelines. The quality of evidence-based guidelines (defined by the criteria based on World Health Organization guideline development handbook) was generally higher than that of the common guidelines. Existing guidelines from mainland China were not evidence-based guidelines, which were of low quality.Conclusion: The colorectal cancer screening guidelines all over the world are generally large in number, low in quality, different in statements, and so are the guidelines in China. There are no evidence-based guidelines in mainland China, which cannot provide effective guidance for colorectal cancer screening, so we need to pay more attention to the establishment of guidelines with high quality and high credibility for colorectal cancer screening as well as for cancer screening based on the national condition, in order to provide reasonable guidance for practice in public health and improve the health conditions in our society.
    Analysis of single-nucleotide polymorphism of Sonic hedgehog signaling pathway in non-syndromic cleft lip and/or palate in the Chinese population
    Jie-ni ZHANG,Feng-qi SONG,Shao-nan ZHOU,Hui ZHENG,Li-ying PENG,Qian ZHANG,Wang-hong ZHAO,Tao-wen ZHANG,Wei-ran LI,Zhi-bo ZHOU,Jiu-xiang LIN,Feng CHEN
    2019, (3):  556-563.  doi: 10.19723/j.issn.1671-167X.2019.03.027    
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    Objective: To study the relationship between Sonic hedgehog (Shh) associated single-nucleotide polymorphism (SNP) and non-syndromic cleft lip and/or palate (NSCL/P), and to explore the risk factors of cleft lip and/or palate. Many studies suggest that the pathogenesis of NSCL/P could be related to genes that control early development, in which the Shh signaling pathway plays an important role.Methods: Peripheral blood was collected from 197 individuals (100 patients with NSCL/P and 97 healthy controls). Haploview software was used for haplotype analysis and Tag SNP were selected, based on the population data of Han Chinese in Beijing of the international human genome haplotype mapping project. A total of 27 SNP were selected for the 4 candidate genes of SHH, PTCH1, SMO and GLI2 in the Shh signaling pathway. The genotypes of 27 SNP were detected and analyzed by Sequenom mass spectrometry. The data were analyzed by chi-squared test and an unconditional Logistic regression model. Results: The selected SNP basically covered the potential functional SNP of the target genes, and its minimum allele frequency (MAF) was >0.05: GLI2 73.5%, PTCH1 91.0%, SMO 100.0%, and SHH 75.0%. It was found that the genotype frequency of SNP (rs12674259) located in SMO gene and SNP (rs2066836) located in PTCH1 gene were significantly different between the NSCL/P group and the control group. Linkage disequilibrium was also found on 3 chromosomes (chromosomes 2, 7 and 9) where the 4 candidate genes were located. However, in the analysis of linkage imbalance haplotype, there was no significant difference between the disease group and the control group.Conclusion: In China, NSCL/P is the most common congenital disease in orofacial region. However, as it is a multigenic disease and could be affected by multiple factors, such as the external environment, the etiology of NSCL/P has not been clearly defined. This study indicates that Shh signaling pathway is involved in the occurrence of NSCL/P, and some special SNP of key genes in this pathway are related to cleft lip and/or palate, which provides a new direction for the etiology research of NSCL/P and may provide help for the early screening and risk prediction of NSCL/P.
    Exploring the association between SPRY gene family and non-syndromic oral clefts among Chinese populations using data of a next-generation sequencing study
    Ren ZHOU,Hong-chen ZHENG,Wen-yong LI,Meng-ying WANG,Si-yue WANG,Nan LI,Jing LI,Zhi-bo ZHOU,Tao WU,Hong-ping ZHU
    2019, (3):  564-570.  doi: 10.19723/j.issn.1671-167X.2019.03.028    
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    Objective: To explore the association between SPRY gene family and the risk of non-syndromic oral clefts among Chinese populations, in respect of single nucleotide polymorphisms (SNPs) association and parent-of-origin effects.Methods: Based on case-parent design, this study used the data of SPRY gene family in a next generation sequencing study of 183 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios (549 participants) recruited from 2016 to 2018, to analyze the effects of SNP association and parent-of-origin. The sequencing study adopted a two-stage design. In the first stage, whole exome sequencing was conducted among 24 NSCL/P trios with family history to explore potential signals. Then in the second stage, another 159 NSCL/P trios were used as validation samples to verify the signals found in the first stage. The data of general information, disease features and parental environmental exposures for participants were collected through questionnaires. Blood samples were collected from each participant for DNA extraction and sequencing. Transmission disequilibrium tests (TDT) were conducted to test for the association between SNPs and NSCL/P, while Z score tests were applied to analyze parent-of-origin effects. The analyses were performed using Plink (v1.07). TRIO package in R (v3.5.1). Besides, famSKAT analyses were conducted in the first stage to combine the effect of SNPs located on the same gene, using famSKAT package in R(V3.5.1). Bonferroni method was adopted to correct multiple tests in the second stage. Results: Twenty-two SNPs in SPRY gene family were included for analyses after the quality control process in the first stage. Based on the variants annotation, functional prediction and statistical analysis, rs1298215244 (SPRY1) and rs504122 (SPRY2) were included in the second verification stage. TDTs in the verification stage revealed that rs1298215244: T>C, rs504122: G>C and rs504122: G>T were associated with the risk of NSCL/P after Bonferroni corrections, where rs504122: G>T was a rare variation. Although the test for parent-of-origin effect of rs1298215244: T>C reached nominal significance level, no SNP showed significant association with NSCL/P through parent-of-origin effect after Bonferroni corrections.Conclusion: This study found that SNPs (including both common and rare variants) among the SPRY gene family were associated with the risk of NSCL/P among Chinese populations. This study failed to detect parent-of-origin effects among the SPRY gene family.
    Application of digital mandibular movement record and masticatory muscle electromyography in the evaluation of stomatognathic function in patients with mandibular tumor
    Jing WANG,Jun-peng CHEN,Yang WANG,Xiang-liang XU,Chuan-bin GUO
    2019, (3):  571-578.  doi: 10.19723/j.issn.1671-167X.2019.03.029    
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    Objective: To study the clinical characteristics of mandibular movement and masticatory muscle function in preoperative and postoperative patients with unilateral mandibular tumors in the region of mandibular body and ramus by combining digital mandibular movement records with electromyography, and to preliminarily explore the relationship and mechanism between movement and masticatory muscle function.Methods: Six preoperative patients with tumor in unilateral body and ramus of mandible were included, and three postoperative patients with unilateral segmental resection and reconstruction of mandibular bone were included. The mandibular movement recording system and surface electromyography system were used to collect the movement trajectory of the patients’ mandibular marginal movement and chewing movement, and the surface electromyography of bilateral masseter and temporalis was recorded concurrently. The surface electromyography of bilateral masseter and temporalis was collected when the patients were at relaxation and at maximal voluntary clenching (MVC). The motion trajectory was observed on the digital virtual model, and the motion amplitude and direction of mandibular marginal movements were analyzed. The characteristics of masticatory electromyogram (EMG) activity in affected and unaffected sides at relaxation, MVC and bilateral mastication were analyzed, and the asymmetry indexes and activity indexes were calculated. Results: The preoperative mean maximum opening of the patients was (35.20±6.87) mm. Three patients had mild mouth opening limitation, and all the patients’ mouth opening trajectory was skewed to the affected side. During lateral movements, the mean range of motion of the affected side [(10.34±1.27) mm] and that of the healthy side [(6.94±2.41) mm] were significantly different. The maximum opening of the postoperative patients was (30.65±17.32) mm, and the mandibular marginal movement characteristics were consistent with those of the patients before surgery. During MVC in the preoperative patients, the median EMG activities of the masseter muscle [44.20 (5.70, 197.90) μV] and the temporalis muscle [42.15 (22.90, 155.00) μV] on the affected side were slightly lower than those of the masseter [45.60 (7.50, 235.40) μV] and the temporalis muscle [63.30 (44.10, 126.70) μV] on the healthy side. In the postoperative patients, individualized changes occurred. Some patients suffered from weakened electromyographic activity on the affected side, while some other ones showed hyperelectromyographic activity on the affected side.Conclusion: Both benign and malignant tumors as well as their surgery can cause abnormal mandibular movements and change of electromyographic activity of bilateral masseter and temporalis muscles.
    Two procedures for ridge preservation of molar extraction sites affected by severe bone defect due to advanced periodontitis
    Li-ping ZHAO,Wen-jie HU,Tao XU,Ya-lin ZHAN,Yi-ping WEI,Min ZHEN,Cui WANG
    2019, (3):  579-585.  doi: 10.19723/j.issn.1671-167X.2019.03.030    
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    Objective: To evaluate and to compare dimensional alterations of hard and soft tissues in molar extraction sites with irregular deficiency of bone plates due to advanced periodontitis receiving two different procedures, namely the flapped and flapless techniques with Bio-Gide? membrane covering the Bio-Oss? material for ridge preservation. Methods: Twenty-three patients with 24 infected-molar extraction sites received ridge preservation procedure, the first consecutive 12 sites belonged to the flap group (a full thickness mucoperiosteal flap and primary soft tissue closure) and the following 12 sites belonged to the flapless group (minimal flap with a collagen sponge and a secondary soft tissue closure). Width of keratinized tissue was evaluated before tooth extraction and after 6-month healing. Parallel periapical radiographs were taken immediately and 6 months after extraction to evaluate vertical bone changes. The width of the ridge was measured in the center of the ridge at the time of tooth extraction and after 6 months at implant placement. Results: After 6 months, width of keratinized tissue decreased (1.6±1.5) mm in the flap group (P=0.004) when compared with (0.3±1.6) mm in the flapless group (P>0.05). Both groups showed increases in ridge height from the central aspect, (5.53±4.20) mm for flap group and (7.70±4.35) mm for flapless group. These differences between the groups were not statistically significant (P=0.226). The ridge widths were (9.5±2.2) mm for flap group and (9.3±1.0) mm for flapless group at the time of implant insertion, and no statistical significance was observed between the flap and flapless groups. Conclusion: The study points out that both ridge preservation techniques were effective in increasing ridge height and minimizing ridge resorption after tooth extraction, and the ridge width allowed the placement of implants 6 months after ridge preservation. The flapless technique gave positive outcome in terms of the keratinized gingival width than that of the flap technique.
    Anatomical and finite element analysis of anterior cruciate ligament reconstruction within biomechanical insertion
    Jia-hao ZHANG,Shuang REN,Jia-yi SHAO,Xing-yue NIU,Xiao-qing HU,Ying-fang AO
    2019, (3):  586-590.  doi: 10.19723/j.issn.1671-167X.2019.03.031    
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    Objective: To provide new concepts of anterior cruciate ligament (ACL) reconstruction by anatomical gross observation of ACL tibial insertion and finite element analysis of distribution of ACL mechanical insertion.Methods: In the anatomical study, ten fresh adult cadaveric knees were dissected, including 6 males and 4 females, all knees were generally observed through standard medial parapatellar approaches, paying attention to the close anatomical relationship of tibial insertion and anterior horn of lateral meniscus, and ACL was exposed and gradually removed from the inside. The shape of tibial insertion of ACL was observed and recorded, and anterior-posterior diameters and left-right diameters of tibial insertion were measured with vernier caliper. For the study of finite element analysis, three-dimensional thin-layer magnetic resonance imaging of normal knee joint was used to establish knee joint model. Three-dimensional reconstruction software MIMICS and finite element analysis software ANSYS were used to establish knee joint model, subsequently, clinical physical examination Lachman test and pivot-shift test were simulated to observe the force distribution of ACL tibial insertion and femoral insertion. Results: The ACL tibial mechanical insertion was rather flat and long similar as an arc shape without a clear separation between anterior medial bundle (AMB) and posterolateral bundle (PLB) in gross observation. The dense fibers lies belonged to the medial intercondylar ridge and ended up anterior with the osseous landmark of anterior ridge. Its average anterior-posterior diameter was (13.8±2.0) mm, the average left-right diameter of midsubstance was (5.3±0.6) mm, and the average left-right diameter of anterior margin was (11.5±1.2) mm. The finite element analysis showed that distribution on the femoral side was oval shape mainly below the residents’ ridge, while the tibial side was rather flat mainly along the medial intercondylar ridge, which was consistent with the anatomical observation. The biomechanical characteristics of ACL attachments were verified theoretically.Conclusion: Anatomical study and finite element analysis have confirmed the flat arc shape of ACL tibial insertion. The ideal reconstruction technique of ACL should be based on its biomechanical insertion. Based on anatomical study and biomechanical analysis, we have proposed the idea of ACL biomechanical insertion reconstruction (BIR) and established a surgical model with oval femoral tunnel and rounded-rectangle tibial tunnel.
    Efficacy and peripheral immunity analysis of allogeneic natural killer cells therapy in patients with hepatocellular carcinoma
    Yun-bo XIE,Ji-yuan ZHANG,Mei-ling DU,Fan-ping MENG,Jun-liang FU,Li-min LIU,Song-shan WANG,Rui QU,Fang LIAN,Fei QIAO,Yang-liu CHEN,Ying-ying GAO,Ruo-nan XU,Ming SHI,Fu-sheng WANG
    2019, (3):  591-595.  doi: 10.19723/j.issn.1671-167X.2019.03.032    
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    Objective: To evaluate the safety and efficacy of allogeneic natural killer (NK) cells in the treatment of primary hepatocellular carcinoma (HCC), and to elucidate the mechanism of NK cells therapy.Methods: Twenty-one patients with primary HCC treated with allogeneic NK cells at the Fifth Medical Center of the PLA General Hospital were followed up for 1 year. Peripheral blood mononuclear cells (PBMCs) were isolated from patient-related donors and cultured in vitro for 15 days and infused to the patients in two consecutive days. Clinical data and laboratory data were collected and analyzed, including survival, clinical features, imaging changes, hematology, immunology, and biochemical indicators to evaluate the safety and efficacy of allogeneic NK cell therapy. The changes of peripheral blood lymphocyte subsets after treatment were also analyzed to explore the possible anti-tumor mechanisms. Results: (1) Of the 21 patients with primary HCC, 11 patients were treated once, 5 patients were treated twice, and 5 patients were treated 3 times. After allogeneic NK cells infusion, 10 patients had fever, 1 patient had slight hepatalgia and 1 patient had slight headache, no other adverse events occurred including acute and chronic graft-versus-host disease (GVHD). They resolved spontaneously within 8 hours without other treatment. (2) The total disease control rate was 76.2% during one-year follow-up. Among them, the patients with Barcelona clinic liver cancer (BCLC) stage A had a disease control rate of 100%, stable disease (SD) in 10 cases; BCLC stage B patients had a disease control rate of 60%, partial response (PR) in 1 case, and SD 2 in cases; BCLC stage C patients had a disease control rate of 50%, complete response (CR) in 1 case, and 2 cases of PR. (3) The frequencies of NK cells and CD8+ T cells in peripheral blood were significantly lower than that before at 24 hours after treatment, and the frequencies of CD4+ T cells and CD4/CD8 were significantly higher than the baseline.Conclusion: Allogeneic NK cells have good safety and efficacy in the treatment of primary HCC. The anti-tumor effect of the allogeneic NK cells may play an important role in the activation of the patient’s natural immune system and delay disease progression, suggesting that allogeneic NK cells combined with sorafenib may be a very effective treatment for advanced HCC, and further large-sample multicenter randomized controlled clinical trials are needed to validate this result.
    Application of U-shaped convolutional neural network in auto segmentation and reconstruction of 3D prostate model in laparoscopic prostatectomy navigation
    Ye YAN,Hai-zhui XIA,Xu-sheng LI,Wei HE,Xue-hua ZHU,Zhi-ying ZHANG,Chun-lei XIAO,Yu-qing LIU,Hua HUANG,Liang-hua HE,Jian LU
    2019, (3):  596-601.  doi: 10.19723/j.issn.1671-167X.2019.03.033    
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    Objective: To investigate the efficacy of intraoperative cognitive navigation on laparoscopic radical prostatectomy using 3D prostatic models created by U-shaped convolutional neural network (U-net) and reconstructed through Medical Image Interaction Tool Kit (MITK) platform. Methods: A total of 5 000 pieces of prostate cancer magnetic resonance (MR) imaging discovery sets with manual annotations were used to train a modified U-net, and a set of clinically demand-oriented, stable and efficient full convolutional neural network algorithm was constructed. The MR images were cropped and segmented automatically by using modified U-net, and the segmentation data were automatically reconstructed using MITK platform according to our own protocols. The modeling data were output as STL format, and the prostate models were simultaneously displayed on an android tablet during the operation to help achieving cognitive navigation. Results: Based on original U-net architecture, we established a modified U-net from a 201-case MR imaging training set. The network performance was tested and compared with human segmentations and other segmentation networks by using one certain testing data set. Auto segmentation of multi-structures (such as prostate, prostate tumors, seminal vesicles, rectus, neurovascular bundles and dorsal venous complex) were successfully achieved. Secondary automatic 3D reconstruction had been carried out through MITK platform. During the surgery, 3D models of prostatic area were simultaneously displayed on an android tablet, and the cognitive navigation was successfully achieved. Intra-operation organ visualization demonstrated the structural relationships among the key structures in great detail and the degree of tumor invasion was visualized directly. Conclusion: The modified U-net was able to achieve automatic segmentations of important structures of prostate area. Secondary 3D model reconstruction and demonstration could provide intraoperative visualization of vital structures of prostate area, which could help achieve cognitive fusion navigation for surgeons. The application of these techniques could finally reduce positive surgical margin rates, and may improve the efficacy and oncological outcomes of laparoscopic prostatectomy.
    Application of recurrent neural network in prognosis of peritoneal dialysis
    Wen TANG,Jun-yi GAO,Xin-yu MA,Chao-he ZHANG,Lian-tao MA,Ya-sha WANG
    2019, (3):  602-608.  doi: 10.19723/j.issn.1671-167X.2019.03.034    
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    Objective: Deep learning models, including recurrent neural network (RNN) and gated recurrent unit (GRU), were used to construct the clinical prognostic prediction models for peritoneal dialysis (PD) patients based on routine clinical data. The performance of the RNN and GRU were compared with logistic regression (LR), which is commonly used in medical researches. The possible underlining clinical implications based on the result from the GRU model were also investigated.Methods: We used the clinical data from the PD center of Peking University Third Hospital as the data source. Both the baseline data at the beginning of dialysis, and the follow-up and prognostic data of the patients were used by the RNN and GRU prediction models. The hyper-parameters were tuned based on the 10-fold cross-validation. The risk prediction performance of each model was evaluated via area under the receiver ope-ration characteristic curve (AUROC), recall rate and F1-score on the testset. Results: A total of 656 patients with the 261 occurrences of death were included in the experiment. The total number of all diagnostic records were 13 091. The results on the testset showed that the AUROC of the LR model, RNN mo-del, and GRU model was 0.701 4, 0.786 0, and 0.814 7, respectively. The predictive performances of the GRU and RNN models were significantly better than that of the LR model. The performances of the GRU and RNN models assessed by recall rate and F1-score were also significantly better than that of the LR model, in which the GRU model reached the best performance. In addition, the recall rates were different among different causes of death or by different prediction time windows.Conclusion: The recurrent neural network model, especially the GRU model, is more effective in predicting PD patients’ prognosis as compared with the LR model. This new model may be helpful for clinicians to provide timely intervention, thus improving the quality of care of PD.
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