BACKGROUND: Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs). METHODS: A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2 * and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression. RESULTS: Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata ( P <0.001) and compacta ( P <0.001), SN ( P <0.001), red nucleus (RN, P <0.001), globus pallidus ( P <0.001), putamen (PUT, P = 0.021), and thalamus ( P = 0.029) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT ( P <0.001), RN ( P = 0.003), SN ( P = 0.017), and caudate nucleus ( P = 0.017) than MSA patients, and lower iron content in RN ( P = 0.001), PUT ( P <0.001), globus pallidus ( P = 0.004), SN ( P = 0.015), and caudate nucleus ( P = 0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.86). CONCLUSIONS: Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD. REGISTRISION PROSPERO (CRD42022344413).
Humans ; Parkinson Disease/diagnostic imaging* ; Magnetic Resonance Imaging/methods* ; Iron/metabolism*

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective To modify the method for establishing mouse models of middle cerebral artery occlusion(MCAO)-induced focal cerebral ischemia using electrocoagulation.Methods Forty-six C57/BL6J male mice were divided into MCAO model group(n=34)and sham-operated group(n=12).In the model group,MCAO was induced by permanent coagulation of the right middle cerebral artery(MCA)using a coagulator,and cerebral blood flow perfusion was monitored before and at 20 min and 1 day after modeling.Neurological deficits of the mice at 1,7,and 14 days after modeling were evaluated using Longa score,mNSS score,beam walking test,cylinder test and corner test.TTC staining was used to measure the cerebral infarct size,and Western blotting was performed to detect the expressions of BDNF,GFAP and DCX proteins in the ischemic cortex.Results The mice in the model group showed significantly reduced cerebral blood flow in the MCA on the ischemic side and obvious neurological deficits with increased forelimb use asymmetry on days 1,7 and 14 after modeling(P<0.05).In the cerebral cortex on the ischemic side of the model mice,the expressions of GFAP and DCX increased significantly at 1,7,and 14 days(P<0.05)and the expression of BDNF increased at 1 day after modeling ischemia(P<0.05).Conclusion We successfully prepared mouse models of MCAO using a modified method by changing the electrocoagulation location from the distal location of the junction between the MCA and the inferior cerebral vein to a 2 mm segment medial to the junction between the MCA and the olfactory bundle.

OBJECTIVE To rapidly analyze the chemical constituents of Rubus sachalinensis Leveille by HPLC-Q-Exactive-MS/MS. METHODS Chromatographic separation was carried out on CAPCELL PAK MGII C18(4.6 mm×250 mm, 5 μm) column at the temperature of 30 ℃. The mobile phase was acetonitrile-0.1% formic acid by gradient elution, with a flow rate of 1.0 mL∙min−1, and the injection volume of 20 µL. The MS spectrum was acquired in negative ion modes using HESI ion source. RESULTS The molecular and structural formulae of the compounds were determined based on the exact mass number and ChemSpider and PubChem databases. By comparing the retention time of the corresponding reference standards and those reported in the literature, primary mass spectra, and secondary mass spectrometry pyrolysis fragments, combined with fragmentation regularity of such compounds, a total of 71 compounds were identified from Rubus sachalinensis Leveille, including 30 organic acids, 22 flavonoids, 7 triterpenoid saponins, 5 coumarins, 1 lignan, 1 gallotannin and 2 aromatic compounds. CONCLUSION This method can quickly and accurately identify the complex chemical constituents in Rubus sachalinensis Leveille, and provide scientific basis for the basic research on the medicinal substances of Rubus sachalinensis Leveille.

Objective:To analyze the application value of serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9 and CA242 in screening colorectal cancer with a meta-analysis.Methods:A literature search was conducted in the databases of Pubmed, Embase, Cochrane, CNKI, Wanfang and VIP to identify studies on applying CEA, CA19-9 and CA242 for detection of colorectal cancer from the establishment of the databases to October 2023. The Quality Evaluation Tool of Diagnostic Accuracy Studies (QUADAS-2) was used to evaluate the quality of the literature. Stata17.0 statistical software was used for meta-analysis. Deeks funnel plot was used to analyze publication bias.Results:A total of 34 articles of case-control studies met the criteria. Meta-analysis revealed that the diagnostic accuracy and sensitivity of CEA, CA19-9 and CA242 were all low, the area under the curve (AUC) of summary receiver operating characteristic curve was 0.62, 0.63 and 0.73, the sensitivity was 0.42, 0.27 and 0.36, respectively. The combined detection of CEA+CA19-9+CA242 significantly improved the pooled diagnostic accuracy (AUC: 0.92(95% CI: 0.89-0.94) and sensitivity: 0.75(95% CI: 0.65-0.83)), the specificity was mildly reduced (dropped from above 0.95 to 0.90(95% CI 0.87-0.93)). The Deek′s test indicated no publication bias. Conclusions:Combined detection of CEA+CA19-9+CA242 can significantly improve the diagnostic accuracy and sensitivity in screening colorectal cancer with a compromised specificity. However, due to the lack of data, whether it can meet the demand for opportunistic screening in the physical examination population needs to be confirmed.

Objective:To investigate the clinical features and therapeutic efficacy of patients with hereditary leiomyomatosis and renal cell carcinoma(RCC) syndrome-associated RCC (HLRCC-RCC) in China.Methods:The clinical data of 119 HLRCC-RCC patients with fumarate hydratase (FH) germline mutation confirmed by genetic diagnosis from 15 medical centers nationwide from January 2008 to December 2021 were retrospectively analyzed. Among them, 73 were male and 46 were female. The median age was 38(13, 74) years. The median tumor diameter was 6.5 (1.0, 20.5) cm. There were 38 cases (31.9%) in stage Ⅰ-Ⅱand 81 cases (68.1%) in stage Ⅲ-Ⅳ. In this group, only 11 of 119 HLRCC-RCC patients presented with skin smooth muscle tumors, and 44 of 46 female HLRCC-RCC patients had a history of uterine fibroids. The pathological characteristics, treatment methods, prognosis and survival of the patients were summarized.Results:A total of 86 patients underwent surgical treatment, including 70 cases of radical nephrectomy, 5 cases of partial nephrectomy, and 11 cases of reductive nephrectomy. The other 33 patients with newly diagnosed metastasis underwent renal puncture biopsy. The results of genetic testing showed that 94 patients had FH gene point mutation, 18 had FH gene insertion/deletion mutation, 4 had FH gene splicing mutation, 2 had FH gene large fragment deletion and 1 had FH gene copy number mutation. Immunohistochemical staining showed strong 2-succinocysteine (2-SC) positive and FH negative in 113 patients. A total of 102 patients received systematic treatment, including 44 newly diagnosed patients with metastasis and 58 patients with postoperative metastasis. Among them, 33 patients were treated with tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI), 8 patients were treated with bevacizumab combined with erlotinib, and 61 patients were treated with TKI monotherapy. Survival analysis showed that the median progression-free survival (PFS) of TKI combined with ICI was 18 (5, 38) months, and the median overall survival (OS) was not reached. The median PFS and OS were 12 (5, 14) months and 30 (10, 32) months in the bevacizumab combined with erlotinib treatment group, respectively. The median PFS and OS were 10 (3, 64) months and 44 (10, 74) months in the TKI monotherapy group, respectively. PFS ( P=0.009) and OS ( P=0.006) in TKI combined with ICI group were better than those in bevacizumab combined with erlotinib group. The median PFS ( P=0.003) and median OS ( P=0.028) in TKI combined with ICI group were better than those in TKI monotherapy group. Conclusions:HLRCC-RCC is rare but has a high degree of malignancy, poor prognosis and familial genetic characteristics. Immunohistochemical staining with strong positive 2-SC and negative FH can provide an important basis for clinical diagnosis. Genetic detection of FH gene germ line mutation can confirm the diagnosis. The preliminary study results confirmed that TKI combined with ICI had a good clinical effect, but it needs to be confirmed by the results of a large sample multi-center randomized controlled clinical study.

Objective To modify the method for establishing mouse models of middle cerebral artery occlusion(MCAO)-induced focal cerebral ischemia using electrocoagulation.Methods Forty-six C57/BL6J male mice were divided into MCAO model group(n=34)and sham-operated group(n=12).In the model group,MCAO was induced by permanent coagulation of the right middle cerebral artery(MCA)using a coagulator,and cerebral blood flow perfusion was monitored before and at 20 min and 1 day after modeling.Neurological deficits of the mice at 1,7,and 14 days after modeling were evaluated using Longa score,mNSS score,beam walking test,cylinder test and corner test.TTC staining was used to measure the cerebral infarct size,and Western blotting was performed to detect the expressions of BDNF,GFAP and DCX proteins in the ischemic cortex.Results The mice in the model group showed significantly reduced cerebral blood flow in the MCA on the ischemic side and obvious neurological deficits with increased forelimb use asymmetry on days 1,7 and 14 after modeling(P<0.05).In the cerebral cortex on the ischemic side of the model mice,the expressions of GFAP and DCX increased significantly at 1,7,and 14 days(P<0.05)and the expression of BDNF increased at 1 day after modeling ischemia(P<0.05).Conclusion We successfully prepared mouse models of MCAO using a modified method by changing the electrocoagulation location from the distal location of the junction between the MCA and the inferior cerebral vein to a 2 mm segment medial to the junction between the MCA and the olfactory bundle.

Objective:To compare the effects of extrafine-particle versus fine-particle inhaled corticosteroids (ICS) combined with formoterol on clinical symptoms, airway inflammation and airway function in patients with bronchial asthma (referred to as asthma).Methods:This prospective, randomized controlled clinical trial enrolled a total of 111 patients diagnose of asthma and cough variant asthma with forced expired volume in one second (FEV 1) percentage of predicted (FEV 1%pred) >70% in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from November 2020 to October 2022. The patients were divided into observation group (57 cases) and control group (54 cases) by random digits table method. The patients in observation group were treated with extrafine-particle ICS combined with formoterol, while the patients in control group were treated with fine-particle ICS combined with formoterol. Both groups were treated for 4 weeks. During treatment 10 patients lost follow up and a total of 101 patients complete the final study: 52 cases in observation group and 49 cases in control group. At baseline, the asthma control test (ACT) score was calculated to evaluate the clinical symptoms, fractional exhaled nitric oxide (FeNO) was applied to evaluate the airway inflammatory level, and the pulmonary function test and bronchodilation test were perfromed. The symptom relief time was record. After treatment, all of the parameters were reevaluated. Results:The FEV 1, peak expiratory flow (PEF), forced expired flow at 50% of forced vital capacity (MEF 50), forced expired flow at 25% of forced vital capacity (MEF 25), maximal expiratory flow-volume curve (MMEF) and ACT score after treatment in both groups were significantly improved compared to baseline, and there were statistical differences ( P<0.01). The improvement of ACT score in observation group was significantly higher than that in control group: (5.90 ± 2.25) scores vs. (4.10 ± 2.18) scores, and there was statistical difference ( P<0.01); there were no statistical differences in the symptom relief time and the improvement rates of FEV 1, PEF, MEF 50, MEF 25, MMEF between the two groups ( P>0.05). Further subgroup analysis was performed on 78 patients with small airway dysfunction, 39 patients were treated with extrafine-particle ICS combined with formoterol (observation subgroup), and 39 patients were treated with fine-particle ICS combined with formoterol (control subgroup). The improvement of ACT score in observation subgroup was significantly higher than that in control subgroup: (6.05 ± 2.22) scores vs. (3.95 ± 2.19) scores, and there was statistical difference ( P<0.01); there were no statistical differences in the symptom relief time and the improvement rates of FEV 1, PEF, MEF 50, MEF 25, MMEF between the two subgroups ( P>0.05). Spearman correlation analysis result showed that the improvement rates of MEF 50, MEF 25 and MMEF after treatment were positive correlated with baseline bronchodilator responses of FEV 1, FEV 1/FVC, MEF 50, MEF 25, MMEF ( r = 0.22 to 0.58, P<0.05), but not with baseline bronchodilator responses of PEF ( P>0.05). In terms of safety, neither of the two treatments had major adverse reactions that affect treatment. Conclusions:For asthma patients with baseline FEV 1%pred>70%, the extrafine-particle ICS combined with formoterol has more significantly improved of clinical symptoms compared to fine-particle ICS combined with formoterol, and potentially with better safety profile. The improvement ratio of small airway function parameters in baseline bronchodilation test could potentially predict treatment response.

Objective:To investigate a 3D method of radiological evaluation of extra-articular scapular fracture and the treatment outcomes.Methods:A total of 19 patients with extra-articular scapular fracture were operatively treated and completely followed up at Department of Orthopaedics and Traumatology, Beijing Jishuitan Hospital from January 2014 to January 2020. They were 17 males and 2 females with an average age of 41 years (from 24 to 65 years). The medial-lateral displacement, antero-posterior angulation and glenopolar angle were measured on images of 3D reconstruction of the fractured scapulae by Mimics software. 3D reconstructions of the intact scapulae were made as controls in the patients with proximal humerus fracture matched in time and age (17 males and 2 females with an average age of 41 years). Operations were carried out via the modified Judet approach in the experimental group. The treatment outcomes in the experimental group were evaluated by the Constant-Murley absolute value scoring at 6 months after operation.Results:All the patients in the experimental group obtained a mean follow-up of 48 months (from 11 to 73 months). All fractures in the experimental group acquired anatomical reduction and fixation intraoperatively and bony union within 6 months after operation. In the experimental group, the medial-lateral displacement averaged 17.9 mm and the antero-posterior angulation 26.9° before operation while the anteflexion lifting angle 162.2°, the lateral external rotation 41.6°, and the Constant-Murley absolute value scores 93.2 points at 6 months after operation. Pre-operatively, the glenopolar angles were 34.4°±6.3° and 40.6°±6.6° for the experimental and control groups respectively, showing a significant difference between the 2 groups ( P<0.05). At 6 months after operation, the glenopolar angle was 38.4°±5.0° for the experimental group, showing a significant difference between pre- and post-operation ( P<0.05). Conclusions:3D reconstruction measurements with Mimics software help accurate characterization of extra-articular scapular fracture and evaluation of surgical indications. Open reduction and internal fixation of scapular fractures via the modified Judet approach may promise a satisfactory union rate and functional outcomes.

Objective:To analyze the treatment of scapular glenoid fractures via the modified Judet approach.Methods:A retrospective study was conducted of the 25 patients who had been treated for scapular glenoid fractures via the modified Judet approach and completely followed up at Department of Orthopaedic Trauma, Beijing Jishuitan Hospital from January 2014 to January 2020. They were 19 males and 6 females with an average age of 46 years (from 29 to 66 years). According to the Goss-Ideberg classification, 8 cases were diagnosed as type Ⅱ, 2 cases as type Ⅳ, 10 cases as type Ⅴ and 5 cases as type Ⅵ. 3D reconstruction of the CT scans by software Mimics 16.0 was made to confirm the diagnoses and classifications of the fractures. Articular step-off and displacement of the scapular glenoid were calculated and recorded. The functional outcomes were evaluated by Constant-Murley scoring system at 6 months postoperatively.Results:Preoperatively, the mean articular step-off was 5.8 mm (from 1.2 to 6.3 mm) and the mean displacement 7.7 mm (from 2.1 to 12.9 mm). All fractures obtained bony union within postoperative 6 months. The mean follow-up period was 58.8 months (from 7 to 92 months). The forward flexion was 158.6° (from 125° to 180°) and the external rotation 39.0° (from 30° to 45°) at 6 months postoperatively. The mean Constant-Murley score was 92.6 (from 75 to 100) at 6 months post-operatively; 19 cases were excellent (76%), 5 were good (20%) and one was fair (4%), giving an excellent to good rate of 96% (24/25).Conclusion:For scapular glenoid fractures of Goss-Ideberg types Ⅱ/Ⅳ/Ⅴ/Ⅵ, surgery via the modified Judet approach may promise satisfactory reduction and fixation and fine clinical outcomes.