1.Comparative study on diagnostic efficacy of 3 Tesla magnetic resonance imaging with zero echo time versus high resolution computed tomography for pulmonary nodule detection and Lung-RADS classification in sub-health populations
Li-jun YANG ; Kai SU ; Peng-fei YANG ; Ming-xia JIANG ; Rong-ping SHI ; Huan-pu GE ; Qiong WU
Chinese Medical Equipment Journal 2025;46(9):52-59
Objective To explore the efficacy differences between 3 Tesla magnetic resonance imaging with zero echo time(3T MRI ZTE)and high resolution computed tomography(HRCT)in the detection of pulmonary nodules and the classification diagnosis of the lung imaging reporting and data system(Lung-RADS)in sub-health populations.Methods Clinical and imaging data of 93 patients with pulmonary nodules(126 nodules in total)admitted to some hospital from July to December 2023 were retrospectively analyzed.The 126 nodules were categorized into a benign nodule group(n=51)and a malignant nodule group(n=75)using pathological findings as the gold standard.All the patients underwent examinations by 3T MRI ZTE and HRCT to compare the detection rates of the two measures for pulmonary nodules;the missed and misdiagnosis rates of 3T MRI ZTE,HRCT and Lung-RADS grading were contrasted with the postoperative pathological diagnosis results as the gold standard;comparison analyses of 3T MRI ZTE signs and HRCT signs were performed between the two groups and the patients with different Lung-RADS grades;3T MRI ZTE,HRCT and Lung-RADS grading were compared with the receiver operating characteristic(ROC)curve in terms of diagnosis efficacy for pulmonary nodules,and the consistency analysis was carried out.Results No discernible statistical variation was observed in the detection rates of pulmonary nodules between 3T MRI ZTE and HRCT(P>0.05).Lung-RADS grading had the highest rates of missed diagnosis and misdiagnosis,and 3T MRI ZTE and HRCT had similar detection rates.The malignant nodule group was different from the benign nodule group in the 3T MRI ZTE and HRCT signs in terms of lesion size,spiculation sign,lobulation sign,calcifica-tion,pleural indentation sign,cavity sign,boundary and bronchial cut-off sign,with the differences being statistically signi-ficant(all P<0.05).For the patients of Lung-RADS grade 3,the 3T MRI ZTE and HRCT signs had significant differences in terms of lesion size,spiculation sign,lobulation sign,calcification,pleural indentation sign,cavity sign and bronchial cut-off sign(all P<0.05).For the patients of Lung-RADS grade 4A,the 3T MRI ZTE and HRCT signs had significant differen-ces in terms of lesion size,calcification,boundary and bronchial cut-off sign(all P<0.05).For the patients of Lung-RADS grade 4B,the 3T MRI ZTE and HRCT signs had significant differences in terms of lesion size and calcification(all P<0.05).For the patients of Lung-RADS grade 4X,there were no significant differences found between the 3T MRI ZTE and HRCT signs(all P>0.05).HRCT had the highest sensitivity,specificity,accuracy,AUC value,predictive values and Kappa value for benign and malignant nodules,3T MRI ZTE had the values slightly lower than those of HRCT,and Lung-RADS grading had the lowest values when compared with HRCT and 3T MRI ZTE.Conclusion HRCT and 3T MRI ZTE are complementary for the evaluation of pulmonary nodules,and the differences in imaging signs between them show graded dependence.3T MRI ZTE and HRCT have no significant differences in the detection rate of pulmonary nodules,while HRCT gains advanta-ges in differentiating benign and malignant pulmonary nodules,and references are provided for the screening and clinical early diagnosis of pulmonary nodules.[Chinese Medical Equipment Journal,2025,46(9):52-59]
2.Comparative study on diagnostic efficacy of 3 Tesla magnetic resonance imaging with zero echo time versus high resolution computed tomography for pulmonary nodule detection and Lung-RADS classification in sub-health populations
Li-jun YANG ; Kai SU ; Peng-fei YANG ; Ming-xia JIANG ; Rong-ping SHI ; Huan-pu GE ; Qiong WU
Chinese Medical Equipment Journal 2025;46(9):52-59
Objective To explore the efficacy differences between 3 Tesla magnetic resonance imaging with zero echo time(3T MRI ZTE)and high resolution computed tomography(HRCT)in the detection of pulmonary nodules and the classification diagnosis of the lung imaging reporting and data system(Lung-RADS)in sub-health populations.Methods Clinical and imaging data of 93 patients with pulmonary nodules(126 nodules in total)admitted to some hospital from July to December 2023 were retrospectively analyzed.The 126 nodules were categorized into a benign nodule group(n=51)and a malignant nodule group(n=75)using pathological findings as the gold standard.All the patients underwent examinations by 3T MRI ZTE and HRCT to compare the detection rates of the two measures for pulmonary nodules;the missed and misdiagnosis rates of 3T MRI ZTE,HRCT and Lung-RADS grading were contrasted with the postoperative pathological diagnosis results as the gold standard;comparison analyses of 3T MRI ZTE signs and HRCT signs were performed between the two groups and the patients with different Lung-RADS grades;3T MRI ZTE,HRCT and Lung-RADS grading were compared with the receiver operating characteristic(ROC)curve in terms of diagnosis efficacy for pulmonary nodules,and the consistency analysis was carried out.Results No discernible statistical variation was observed in the detection rates of pulmonary nodules between 3T MRI ZTE and HRCT(P>0.05).Lung-RADS grading had the highest rates of missed diagnosis and misdiagnosis,and 3T MRI ZTE and HRCT had similar detection rates.The malignant nodule group was different from the benign nodule group in the 3T MRI ZTE and HRCT signs in terms of lesion size,spiculation sign,lobulation sign,calcifica-tion,pleural indentation sign,cavity sign,boundary and bronchial cut-off sign,with the differences being statistically signi-ficant(all P<0.05).For the patients of Lung-RADS grade 3,the 3T MRI ZTE and HRCT signs had significant differences in terms of lesion size,spiculation sign,lobulation sign,calcification,pleural indentation sign,cavity sign and bronchial cut-off sign(all P<0.05).For the patients of Lung-RADS grade 4A,the 3T MRI ZTE and HRCT signs had significant differen-ces in terms of lesion size,calcification,boundary and bronchial cut-off sign(all P<0.05).For the patients of Lung-RADS grade 4B,the 3T MRI ZTE and HRCT signs had significant differences in terms of lesion size and calcification(all P<0.05).For the patients of Lung-RADS grade 4X,there were no significant differences found between the 3T MRI ZTE and HRCT signs(all P>0.05).HRCT had the highest sensitivity,specificity,accuracy,AUC value,predictive values and Kappa value for benign and malignant nodules,3T MRI ZTE had the values slightly lower than those of HRCT,and Lung-RADS grading had the lowest values when compared with HRCT and 3T MRI ZTE.Conclusion HRCT and 3T MRI ZTE are complementary for the evaluation of pulmonary nodules,and the differences in imaging signs between them show graded dependence.3T MRI ZTE and HRCT have no significant differences in the detection rate of pulmonary nodules,while HRCT gains advanta-ges in differentiating benign and malignant pulmonary nodules,and references are provided for the screening and clinical early diagnosis of pulmonary nodules.[Chinese Medical Equipment Journal,2025,46(9):52-59]
3.Retrospective clinical study on cryopreservation-free integrated autologous hematopoietic stem cell transplantation model for newly diagnosed multiple myeloma
Xi YANG ; Chenglong LI ; Jiao CHEN ; Feifei CHE ; Rong XIAO ; Hui LI ; Juan HUANG ; Tao JIANG ; Haiqing YANG ; Huan WANG ; Xiaochuan KUANG ; Xiaobing HUANG
Chinese Journal of Hematology 2024;45(5):488-494
Objective:To explore the efficacy and safety of cryopreservation-free integrated autologous hematopoietic stem cell transplantation (HSCT) model for patients with multiple myeloma.Methods:A total of 96 patients with newly diagnosed multiple myeloma (NDMM) between July 31, 2020, and December 31, 2022, were retrospectively analyzed, of which 41 patients in the observation group received integrated non-cryopreserved transplantation mode. After hematopoietic stem cells were mobilized and collected, melphalan was started immediately for pre-transplant conditioning, and non-cryopreserved grafts from the medical blood transfusion refrigerator were directly injected intravenously into the patient within 24-48 h after the melphalan conditioning. The control group consisted of 55 patients who received traditional transplantation mode. After hematopoietic stem cells were collected, stem cell cryopreservation was performed in liquid nitrogen, and then the transplant plans were started at the right time. All patients received mobilization of autologous hematopoietic stem cells using the G-CSF combined with the plerixafor.Results:① A total of 34 patients (82.9% ) with VGPR plus CR in the observation group were significantly higher than 33 patients (60.0% ) in the control group ( P=0.016). ②Compared with the control group, the incidence of grade 1 oral mucosal inflammation was higher in the observation group ( P<0.001) ; however, the incidence of grades 2 and 3 oral mucosal inflammation was lower ( P=0.004, P=0.048), and neither group experienced grade 4 or above oral mucosal inflammation. The incidence of grade 1 diarrhea was higher in the observation group ( P=0.002), whereas the incidence of grade 3 diarrhea was lower ( P=0.007). No statistically significant difference was observed in the incidence of grade 4 diarrhea ( P=0.506), and neither group experienced grade 5 diarrhea. ③ The incidence of bacterial infection in the observation group was lower than that in the control group (34.1% vs 65.5%, P=0.002), whereas no statistically significant difference was observed in the incidence of fungal infection (29.3% vs 31.4%, P=0.863) and viral infection (4.88% vs 3.64%, P=0.831). ④No statistically significant difference was observed in the implantation time of granulocytes and platelets between the observation and control groups [10 (8-20) days vs 11 (8-17) days, P=0.501; 13 (10-21) days vs 15 (10-20) days, P=0.245]. ⑤ All patients did not receive lenalidomide treatment 100 days post-transplantation. At 30 days post-transplantation, the CTL, NK, and Th cell counts in the observation group were lower than those in the control group ( P<0.001, P=0.002, P=0.049), and the NKT cell counts were higher than those in the control group ( P=0.024). At 100 days post-transplantation, the CTL, NKT, and Th cell counts in the observation group were higher than those in the control group ( P=0.025, P=0.011, P=0.007), and no statistically significant difference in NK cell counts was observed between the two groups ( P=0.396). ⑥ The median follow-up was 18 (4-33) months. The overall 2-year survival rates of the observation and control groups post-transplantation were 91.5% and 78.2%, respectively ( P=0.337). The recurrence-free survival rates were 85.3% and 77.6%, respectively ( P=0.386), and the cumulative recurrence rates were 9.8% and 16.9%, respectively ( P=0.373) . Conclusion:In NDMM, the cryopreservation-free integrated autologous HSCT model can achieve similar therapeutic effects as traditional transplantation models, with lower rates of severe mucosal inflammation and infection compared with traditional transplantation models.
4.Expert consensus on the diagnosis and treatment of insomnia in specified populations
Guihai CHEN ; Liying DENG ; Yijie DU ; Zhili HUANG ; Fan JIANG ; Furui JIN ; Yanpeng LI ; Chun-Feng LIU ; Jiyang PAN ; Yanhui PENG ; Changjun SU ; Jiyou TANG ; Tao WANG ; Zan WANG ; Huijuan WU ; Rong XUE ; Yuechang YANG ; Fengchun YU ; Huan YU ; Shuqin ZHAN ; Hongju ZHANG ; Lin ZHANG ; Zhengqing ZHAO ; Zhongxin ZHAO
Chinese Journal of Clinical Pharmacology and Therapeutics 2024;29(8):841-852
Clinicians need to focus on various points in the diagnosis and treatment of insomnia.This article prescribed the treatment protocol based on the unique features,such as insomnia in the elderly,women experiencing specific physiologi-cal periods,children insomnia,insomnia in sleep-breathing disorder patients,insomnia in patients with chronic liver and kidney dysfunction.It pro-vides some reference for clinicians while they make decision on diagnosis,differentiation and treat-ment methods.
5.Advances in pharmacological mechanism and toxicology of gambogic acid.
Ke-Rong TU ; Shang-Qin YANG ; Qi-Qi XU ; Liang-Liang LYU ; Xian-Mei JIANG ; Yao QI ; Huan-Huan DING ; Hong-Mei LIU ; Lu-Lu CAI ; Qiang SUN
China Journal of Chinese Materia Medica 2024;49(24):6593-6603
Gambogic acid, a caged xanthone compound derived from Garcinia, has been proven to be an important substance basis for the pharmacological effects of the plant. In recent years, it has received continuous attention due to its broad and significant pharmacological activities. Modern pharmacological investigations have demonstrated that gambogic acid endows various therapeutic effects such as anti-inflammatory, antioxidant, and anti-tumor activities, as well as benefits in retinopathy, organ protection, anti-microbial infection, bone protection, and neuropathic pain relief. Nevertheless, there is currently a lack of systematic summary and integration of the pharmacological effects and mechanisms of gambogic acid, which is critical for advancing the clinical application of this natural product. In addition, current research has raised concerns about potential safety risks associated with gambogic acid, such as organ toxicity, developmental toxicity, and hemolysis. Given this, this paper systematically reviewed and summarized the pharmacological effects, mechanisms, and toxicological profiles of gambogic acid, aiming to provide reference and data support for its clinical translation.
Xanthones/toxicity*
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Humans
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Animals
;
Drugs, Chinese Herbal/toxicity*
;
Garcinia/chemistry*
6.To compare the efficacy and incidence of severe hematological adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia.
Xiao Shuai ZHANG ; Bing Cheng LIU ; Xin DU ; Yan Li ZHANG ; Na XU ; Xiao Li LIU ; Wei Ming LI ; Hai LIN ; Rong LIANG ; Chun Yan CHEN ; Jian HUANG ; Yun Fan YANG ; Huan Ling ZHU ; Ling PAN ; Xiao Dong WANG ; Gui Hui LI ; Zhuo Gang LIU ; Yan Qing ZHANG ; Zhen Fang LIU ; Jian Da HU ; Chun Shui LIU ; Fei LI ; Wei YANG ; Li MENG ; Yan Qiu HAN ; Li E LIN ; Zhen Yu ZHAO ; Chuan Qing TU ; Cai Feng ZHENG ; Yan Liang BAI ; Ze Ping ZHOU ; Su Ning CHEN ; Hui Ying QIU ; Li Jie YANG ; Xiu Li SUN ; Hui SUN ; Li ZHOU ; Ze Lin LIU ; Dan Yu WANG ; Jian Xin GUO ; Li Ping PANG ; Qing Shu ZENG ; Xiao Hui SUO ; Wei Hua ZHANG ; Yuan Jun ZHENG ; Qian JIANG
Chinese Journal of Hematology 2023;44(9):728-736
Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult
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Humans
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Adolescent
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Imatinib Mesylate/adverse effects*
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Incidence
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Antineoplastic Agents/adverse effects*
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Retrospective Studies
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Pyrimidines/adverse effects*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy*
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Treatment Outcome
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Benzamides/adverse effects*
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Leukemia, Myeloid, Chronic-Phase/drug therapy*
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Aminopyridines/therapeutic use*
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Protein Kinase Inhibitors/therapeutic use*
7.Geniposide promotes skin ulcer wound healing in diabetic rats through the PI3K/Akt pathway
Wenwen JIANG ; Huan LIU ; Xiaoyan CHEN ; Xiaojuan RONG ; Yanling LIU ; Wei ZENG
Chinese Journal of Comparative Medicine 2023;33(12):14-20
Objective To investigate the protective effect of geniposide against diabetic rats with skin ulcer and the mechanism.Methods Rats were divided into a normal group,model group,and geniposide subgroups(Gen(L):200 mg/kg;Gen(H):500 mg/kg).Diabetic rats were treated with normal saline or geniposide by intragastric administration(n=6).Treatments were administered once a day,and the wound healing and inflammation of each group were recorded every day.After 7 days of treatment for diabetic skin ulcers,the wound area,tissue sections,TUNEL staining and Western blot were used to quantitatively analyze changes in wound healing,apoptosis,and related regulatory protein expression.Results Compared with the model group,the group receiving orally administered geniposide(200 and 500 mg/kg)showed significantly improved wound healing and increased contraction of the injured area.In terms of skin wound apoptosis in diabetic rats,TUNEL-positive cells were significantly reduced in geniposide subgroups(P<0.05).Geniposide significantly inhibited skin inflammation and promoted wound repair,which may be related to promotion of PI3K and Akt phosphorylation.Conclusions Geniposide promoted skin wound repair in diabetic rats by inhibiting inflammatory responses and apoptosis.
8.Regulation Effect of Myeloid Leukemia No.1 Chinese Herb Medicine Prescription Combined with Chemotherapy on Th17 Cells in Bone Marrow of Patients with Acute Myeloid Leukemia.
Guo-Liang ZHANG ; Ming PAN ; Yan-Zhi WANG ; Jian-Xia HUANG ; Gang-Shou GU ; Yan WANG ; Qing WU ; Li-Teng YAO ; Huan-Rong XIE ; Xing-Jiang HU
Journal of Experimental Hematology 2021;29(2):328-332
OBJECTIVE:
To explore the regulation effect of myeloid leukemia No.1 Chinese herb medicine prescription combined with chemotherapy on Th17 cells in bone marrow fluid of AML patients, so as to provide guidance for improving AML treatment effect and patients' long-term survival.
METHODS:
Seventy patients with AML who were hospitalized in Department of Hematology, Wuwei People's Hospital from April 2017 to August 2019 were selected and enrolled in AML group, 25 healthy volunteers were selected and enrolled in control group; then according to therapeutic regimen, AML patients were divided into 2 groups: combined therapy group (myeloid leukemia NO.1 Chinese herb medicine prescription combined with chemotherapy) and non-combined therapy group (chemotherapy alone). Flow cytometry was used to detect the ratio of CD3
RESULTS:
The ratio of CD3
CONCLUSION
Th17 cells expression in bone marrow of newly diagnoses and relapsed AML patients significantly increase, and decrease significantly after treatment. Myeloid leukemia No.1 Chinese herb prescription combined with chemotherapy can significantly increase the CR rate and reduce the RL rate for AML.
Bone Marrow
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China
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Humans
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Leukemia, Myeloid, Acute/drug therapy*
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Medicine
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Prescriptions
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Th17 Cells
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Vascular Endothelial Growth Factor A
9.High Expression of Bone Marrow VEGF in Patients with Acute Leukemia and Its Correlation with Prognosis.
Ming PAN ; Guo-Liang ZHANG ; Yan-Zhi WANG ; Jian-Xia HUANG ; Gang-Shou GU ; Yan WANG ; Qing WU ; Li-Teng YAO ; Huan-Rong XIE ; Xing-Jiang HU
Journal of Experimental Hematology 2021;29(2):428-432
OBJECTIVE:
To detect the level of vascular endothelial growth factor (VEGF) in bone marrow of patients with non-M3 acute leukemia (AL), and estimate its relationship with prognosis.
METHODS:
From January 2016 to December 2019, 114 patients with AL in department of Hematology, Wuwei People's Hospital were selected as study group, and 25 healthy volunteers were enrolled as control group. The concentration of VEGF in bone marrow was detected by ELISA. The patients were divided into high and low concentration group according to the level of VEGF. The overall survival (OS) and event-free survival (EFS) were compared among different groups.
RESULTS:
The level of VEGF in patients with AL was significantly higher than that in the control group. The median OS and EFS in the low concentration group was 34.5 and 32 months, respectively, while, in the high concentration group was 30 and 26 months, respectively. The differences between the two groups were statistically significant (P=0.010). There were significant differences in OS rate (P=0.035) and EFS rate (P=0.026) between low and high concentration group. Multivariate analysis showed that high VEGF concentration was an independent risk factor affecting OS (HR=2.619, 95%CI 1.070-6.406, P=0.035) and EFS (HR=2.221, 95%CI 1.074-4.552, P=0.031) in AL patients.
CONCLUSION
VEGF highly expresses in the bone marrow of patients with AL at initial diagnosis and relapse, and shows adverse effects on the prognosis.
Bone Marrow
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Disease-Free Survival
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Humans
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Leukemia, Myeloid, Acute
;
Prognosis
;
Vascular Endothelial Growth Factor A
10.Abnormal striatum functional connectivity in major depression and schizophrenia: a resting state functional magnetic resonance imaging study
Cheng CHEN ; Huiling WANG ; Gaohua WANG ; Tianzi JIANG ; Yuan ZHOU ; Huan HUANG ; Shihao WU ; Bei RONG
Chinese Journal of Psychiatry 2021;54(1):17-24
Objective:To compare and explore the characteristics of striatum functional connectivity in major depression and schizophrenic.Methods:Thirty-six patients with major depressive disorder (MDD), schizophrenia, and health controls were recruited in this study. All subjects underwent rest-stating functional magnetic resonance imaging (rs-fMRI). Routine preprocessing of rs-fMRI data was performed. The regional homogeneity (ReHo), and fractional amplitude of low frequency fluctuation (fALFF) values of the three groups were calculated, separately. Based on the results of one-way analysis of covariance, different brain areas were superimposed to obtain the overlapping regions (the left striatum). Next, the superimposed brain region (the left striatum) was used as the region of interest (ROI), and the customized ROI method was used for the whole-brain functional connectivity analysis. Finally, Pearson correlation analysis was performed between the functional connectivity of the brain regions and clinical features of MDD and schizophrenia.Result:Among the three groups, left striatum extending to the insula and Rolland′s insula showed significant differences of the ReHo values ( P<0.001, AlphaSim correction, voxel number >99);while left superior parietal areas and bilateral insula extending to lentiform nucleus showed significant differences of fALFF values (AlphaSim correction, P<0.001, voxel number >90). The left striatum were superimposed and revealed significant ReHo and fALFF values. The ROI analysis showed that the brain area with different functional connections in the three groups was left inferior temporal gyrus (AlphaSim correction, P<0.001, volume element number>42). The pairwise comparative analysis showed that compared with healthy controls (0.24±0.03), patients with MDD (0.15±0.02) and schizophrenia (0.09±0.01) showed decreased functional connections between the left striatum and the inferior temporal gyrus, and the decline was more significant in patients with schizophrenia. The functional connectivity value of left inferior temporal gyrus was not correlated with HAMD score in MDD( r=-0.02, P=0.93). The functional connectivity value of left inferior temporal gyrus was positively correlated with PANSS positive score in patients with schizophrenia ( r=-0.40, P=0.02). Conclusion:Both MDD and schizophrenia patients may have abnormal function connections of the striatum and the abnormal function connection with the left temporal inferior gyrus may closely related to clinical symptoms of schizophrenia. The brain function activity of striatum and its abnormal connection with the left temporal inferior gyrus may play an important role in the neuropathology of schizophrenia and MDD.

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