Matrix Stiffness Affects Mitochondrial Heterogeneity of Tibial Plateau Chondrocytes in Knee Osteoarthritis / 医用生物力学

Objective To investigate the difference of matrix stiffness in different regions of tibial plateau in osteoarthritis (OA) and its effects on morphology of the cartilage and mitochondria. Methods The tibial plateau cartilage specimens of OA were obtained for nanoindentation test, transmission electron microscopy and histological analysis. The stiffness of cartilage matrix in different regions of OA tibial plateau was detected by nano-indentation. The morphology of cartilage mitochondria in different regions was observed by transmission electron microscopy, and the changes of mitochondrial plane area, shape and ridge volume density were quantitatively analyzed. Cartilage injury in different regions of OA tibial plateau was observed by histological staining. Results The cartilage of OA tibial plateau showed regional heterogeneity, and the cartilage and mitochondria on medial side of varus knee OA were more severe, and the matrix stiffness was higher. The OA scores were positively correlated with matrix stiffness. There was also a significant correlation between OA scores and mitochondrial morphology: the higher OA scores, the larger and rounder mitochondrial plane area, and the lower cristae volume density. Conclusions The differences of tibial plateau revealed the correlation between cartilage matrix stiffness, OA scores and mitochondrial morphological parameters. The increased cartilage matrix stiffness may be the main cause of chondrocyte mitochondrial injury, and further aggravate the progression of OA.

Differences in clinicopathological features, gene mutations, and prognosis between primary gastric and intestinal gastrointestinal stromal tumors in 1061 patients / 中华胃肠外科杂志

Objective: To analyze the clinicopathological features and gene mutations of primary gastrointestinal stromal tumors (GISTs) of the stomach and intestine and the prognosis of intermediate- and high-risk GISTs. Methods: This was a retrospective cohort study. Data of patients with GISTs admitted to Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2019 were collected retrospectively. Patients with primary gastric or intestinal disease who had undergone endoscopic or surgical resection of the primary lesion and were confirmed pathologically as GIST were included. Patients treated with targeted therapy preoperatively were excluded. The above criteria were met by 1061 patients with primary GISTs, 794 of whom had gastric GISTs and 267 intestinal GISTs. Genetic testing had been performed in 360 of these patients since implementation of Sanger sequencing in our hospital in October 2014. Gene mutations in KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were detected by Sanger sequencing. The factors investigated in this study included: (1) clinicopathological data, such as sex, age, primary tumor location, maximum tumor diameter, histological type, mitotic index (/5 mm2), and risk classification; (2) gene mutation; (3) follow-up, survival, and postoperative treatment; and (4) prognostic factors of progression-free survival (PFS) and overall survival (OS) for intermediate- and high-risk GIST. Results: (1) Clinicopathological features: The median ages of patients with primary gastric and intestinal GIST were 61 (8-85) years and 60 (26-80) years, respectively; The median maximum tumor diameters were 4.0 (0.3-32.0) cm and 6.0 (0.3-35.0) cm, respectively; The median mitotic indexes were 3 (0-113)/5 mm² and 3 (0-50)/5 mm², respectively; The median Ki-67 proliferation indexes were 5% (1%-80%) and 5% (1%-50%), respectively. The rates of positivity for CD117, DOG-1, and CD34 were 99.7% (792/794), 99.9% (731/732), 95.6% (753/788), and 100.0% (267/267), 100.0% (238/238), 61.5% (163/265), respectively. There were higher proportions of male patients (χ²=6.390, P=0.011), tumors of maximum diameter > 5.0 cm (χ²=33.593, P<0.001), high-risk (χ²=94.957, P<0.001), and CD34-negativity (χ²=203.138, P<0.001) among patients with intestinal GISTs than among those with gastric GISTs. (2) Gene mutations: Gene mutations were investigated in 286/360 patients (79.4%) with primary gastric GISTs and 74/360 (20.6%) with primary intestinal GISTs. Among the 286 patients with gastric primary GISTs, 79.4% (227/286), 8.4% (24/286), and 12.2% (35/286), had KIT mutations, PDGFRA mutations, and wild-type, respectively. Among the 74 patients with primary intestinal GISTs, 85.1% (63/74) had KIT mutations and 14.9% (11/74) were wild-type. The PDGFRA mutation rate was lower in patients with intestinal GISTs than in those with gastric GISTs[ 0% vs. 8.4%(24/286), χ²=6.770, P=0.034], whereas KIT exon 9 mutations occurred more often in those with intestinal GISTs [22.2% (14/63) vs. 1.8% (4/227), P<0.001]. There were no significant differences between gastric and intestinal GISTs in the rates of KIT exon 11 mutation type and KIT exon 11 deletion mutation type (both P>0.05). (3) Follow-up, survival, and postoperative treatment: After excluding 228 patients with synchronous and metachronous other malignant tumors, the remaining 833 patients were followed up for 6-124 (median 53) months with a follow-up rate of 88.6% (738/833). None of the patients with very low or low-risk gastric (n=239) or intestinal GISTs (n=56) had received targeted therapy postoperatively. Among 179 patients with moderate-risk GISTs, postoperative targeted therapy had been administered to 88/155 with gastric and 11/24 with intestinal GISTs. Among 264 patients with high-risk GISTs, postoperative targeted therapy had been administered to 106/153 with gastric and 62/111 with intestinal GISTs. The 3-, 5-, and 10-year PFS of patients with gastric or intestinal GISTs were 96.5%, 93.8%, and 87.6% and 85.7%, 80.1% and 63.3%, respectively (P<0.001). The 3-, 5-, and 10-year OS were 99.2%, 98.8%, 97.5% and 94.8%, 92.1%, 85.0%, respectively (P<0.001). (4) Analysis of predictors of intermediate- and high-risk GISTs: The 5-year PFS of patients with gastric and intestinal GISTs were 89.5% and 73.2%, respectively (P<0.001); The 5-year OS were 97.9% and 89.3%, respectively (P<0.001). Multivariate analysis showed that high risk (HR=2.918, 95%CI: 1.076-7.911, P=0.035) and Ki-67 proliferation index > 5% (HR=2.778, 95%CI: 1.389-5.558, P=0.004) were independent risk factors for PFS in patients with intermediate- and high-risk GISTs (both P<0.05). Intestinal GISTs (HR=3.485, 95%CI: 1.407-8.634, P=0.007) and high risk (HR=3.753,95%CI:1.079-13.056, P=0.038) were independent risk factors for OS in patients with intermediate- and high-risk GISTs (both P<0.05). Postoperative targeted therapy was independent protective factor for PFS and OS (HR=0.103, 95%CI: 0.049-0.213, P<0.001; HR=0.210, 95%CI:0.078-0.564,P=0.002). Conclusions: Primary intestinal GIST behaves more aggressively than gastric GISTs and more frequently progress after surgery. Moreover, CD34 negativity and KIT exon 9 mutations occur more frequently in patients with intestinal GISTs than in those with gastric GISTs.

Clinical features of fundus lesions of 74 patients with acquired immunodeficiency syndrome in Shenyang / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the clinical features and factors of fundus lesions in patients with acquired immunodeficiency syndrome(AIDS)in Shenyang and the relationship between fundus lesions and CD4+T cell count.METHODS: Retrospective case study. A total of 74 cases with AIDS who were treated in the Central Hospital of Liaoning Electric Power Supply Co., Ltd., from January 2021 to December 2021 were selected. The fundus manifestation and CD4+T cell count of the patients were analyzed.RESULTS: The total detection rate of fundus lesions in AIDS patients was 58%. CD4+T cell count in the patients with fundus lesions was significantly lower than that in the patients with normal fundus [29(6, 55)/μL vs. 76(35, 103)/μL, P<0.01]. The rate of fundus lesions was the highest in the patients with CD4+T cell count ≤ 50/μL(74%). Logistic regression analysis showed that as the CD4+T cell count increased, the incidence of fundus lesions decreased(OR=0.977, 95%CI 0.964～0.991, P<0.01).CONCLUSION: Fundus lesions in AIDS patients related to CD4+T cell count. Decreasing CD4+T cell count was a risk factor of fundus lesions for AIDS patients. Routine fundus examination is important for the early diagnosis of fundus lesions in AIDS patients.

Study on the correlation between early three-dimensional gait analysis and clinical efficacy after robot-assisted total knee arthroplasty / 中华创伤杂志(英文版)

PURPOSE@#Robot-assisted technology is a forefront of surgical innovation that improves the accuracy of total knee arthroplasty (TKA). But whether the accuracy of surgery can improve the clinical efficacy still needs further research. The purpose of this study is to perform three-dimensional (3D) analysis in the early postoperative period of patients who received robot-assisted total knee arthroplasty (RATKA), and to study the trend of changes in gait parameters after RATKA and the correlation with the early clinical efficacy.@*METHODS@#Patients who received RATKA in the Center of Joint Surgery, the First Hospital Affiliated to Army Military Medical University from October 2020 to January 2021 were included. The imaging parameters, i.e., hip-knee-ankle angle, lateral distal femoral angle, medial proximal tibial angle, posterior condylar angle were measured 3 months post-TKA. The 3D gait analysis and clinical efficacy by Western Ontario Mac Master University Index (WOMAC) score were performed pre-TKA, 3 and 6 months post-TKA. The differences in spatiotemporal parameters of gait, kinetic parameters, and kinematic parameters of the operated limb and the contralateral limb were compared. The correlation between gait parameters and WOMAC scores was analyzed. Paired sample t-test and Wilcoxon rank-sum test were used to analyze the difference between groups, and Spearman correlation coefficient was used to analyze the correlation.@*RESULTS@#There were 31 patients included in this study, and the imaging indexes showed that all of them returned to normal post-TKA. The WOMAC score at 3 months post-TKA was significantly lower than that pre-TKA, and there was no significant difference between at 3 and 6 months. The 3D gait analysis results showed that the double support time of the operated limb reduced at 3 and 6 months (all p < 0.05), the maximum extension and maximum external rotation of the knee joint increased at stance phase, and the maximum flexion angle, the range of motion and the maximum external rotation increased at swing phase. Compared with the preoperative data, there were significant improvements (all p < 0.05). Compared with the contralateral knee joint, the maximum external rotation of the knee joint at swing phase was smaller than that of the contralateral side, and the maximum flexion and extension moment was greater than that of the contralateral knee. The maximum external rotation moment of the joint was greater than that of the contralateral knee joint (p < 0.05). There was a negative correlation between the single support time pre-TKA and the WOMAC score at 3 months (p = 0.017), and the single support time at 3 months was negatively correlated with the WOMAC score at 6 months (p = 0.043). The cadence at 6 months was negatively correlated with the WOMAC score at 6 months (p = 0.031). The maximum knee extension at stance phase at 6 months was negatively correlated with the WOMAC score at 6 month (p = 0.048). The maximum external rotation at stance phase at 6 months was negatively correlated with the WOMAC score at 6 months (p = 0.024).@*CONCLUSION@#The 3D gait analysis of RATKA patients is more sensitive than WOMAC score in evaluating the clinical efficacy. Trend of changes in gait parameters shows that the knee joint support, flexion and extension function, range of motion, external rotation and varus deformity moment of the patient were significantly improved at 3 months after surgery, and continued to 6 months after surgery. Compared with the contralateral knee, the gait parameters of the operated limb still has significant gaps in functionality, such as the external rotation and flexion and extension. The single support time, cadence, knee extension, and knee external rotation of the operated limb have a greater correlation with the postoperative WOMAC score. Postoperative rehabilitation exercises should be emphasized, which is of great value for improving the early efficacy of RATKA.

Re-evaluation of systematic reviews of acupuncture and moxibustion for childhood autism / 中国针灸

OBJECTIVE@#To re-evaluate the systematic review/Meta-analysis of acupuncture and moxibustion for childhood autism (CA), aiming to provide decision-making basis for clinical diagnosis and treatment.@*METHODS@#The systematic review and/or Meta-analysis of acupuncture and moxibustion for CA were searched in PubMed, EMbase, Cochrane Library, SinoMed, CNKI and Wanfang databases. The retrieval time was from the database establishment to May 5th, 2022. PRISMA (preferred reporting items for systematic reviews and Meta-analyses) was used to evaluate the report quality, and AMSTAR 2 (a measurement tool to assess systematic reviews 2) was used to evaluate the methodological quality, bubble map was used to construct the evidence map and GRADE was used to evaluate the quality of evidence.@*RESULTS@#A total of 9 systematic reviews were included. The PRISMA scores ranged from 13 to 26. The report quality was low, and there was a serious lack in the aspects of program and registration, search, other analysis and funding. The main problems in methodology included not making prespecified protocol, incomplete retrieval strategy, not providing a list of excluded literatures, and incomplete explanation on heterogeneity analysis and bias risk. The evidence map showed that 6 conclusions were valid, 2 conclusions were possible valid and 1 conclusion was uncertain valid. The overall quality of evidence was low, and the main factors leading to the downgrade were limitations, followed by inconsistency, imprecision and publication bias.@*CONCLUSION@#Acupuncture and moxibustion has a certain effect for CA, but the quality of reporting, methodology and evidence in included literature need to be improved. It is suggested to perform high-quality and standardized research in the future to provide evidence-based basis.

The effect of enhanced recovery after surgery protocols combined with laparoscopic radical cystectomy with intracorporeal urinary diversion / 中华泌尿外科杂志

Objective:To explore the effect of enhanced recovery after surgery (ERAS) protocols in patients undergoing laparoscopic radical cystectomy (LRC) and intracorporeal urinary diversion (ICUD).Methods:A total of 83 patients who received LRC+ ICUD in Beijing Chaoyang Hospital from March 2014 to September 2020, were divided into 2 groups based on different perioperative management, including 29 ERAS cases and 54 conventional recovery after surgery (CRAS) cases. The ERAS group included 26 males and 3 females , with an average age of (62.07 ± 9.26) years. There were 26 patients with ASA class Ⅰ-Ⅱ, 3 patients with ASA class Ⅲ, 4 patients received neoadjuvant chemotherapy, and 7 patients had a history of abdominal surgery in ERAS group. The CRAS group included 44 males and 10 females , with an average age of (61.59 ± 10.16) years. There were 50 patients with ASA class Ⅰ-Ⅱ, 4 patients with ASA class Ⅲ, 9 patients received neoadjuvant chemotherapy, and 10 patients had a history of abdominal surgery in CRAS group. There were no statistically significant differences in the baseline characteristics between the two groups. The patients in both groups underwent LRC+ ICUD procedures. The perioperative results and complications between the two groups were compared.Results:In the ERAS group, there were 20 patients who underwent Bricker ileal conduit surgery and 9 patients who underwent Studer orthotopic ileal neobladder surgery. Pathological staging included 3, 3, 7, 7, 5 and 4 cases in stage T a, T is, T 1, T 2, T 3 and T 4a, respectively. There were 23, 2, 3 and 1 patient with pathological stage N 0, N 1, N 2 and N 3, respectively. Pathological diagnosis included 3 cases of low-grade urothelial carcinoma, 24 cases of high-grade urothelial carcinoma, and 2 cases of other histological subtypes. In the CRAS group, there were 31 patients who underwent Bricker ileal conduit surgery and 23 patients who underwent Studer orthotopic ileal neobladder surgery. Pathological staging included 5, 3, 12, 9, 15 and 10 patients in stage T a, T is, T 1, T 2, T 3 and T 4a, respectively. There were 35, 6, 7 and 6 patients with pathological stage N 0, N 1, N 2, and N 3, respectively. Pathological diagnoses included 6 cases of low-grade urothelial carcinoma, 45 cases of high-grade urothelial carcinoma, and 3 cases of other histological subtypes. There were no statistically significant differences ( P>0.05) in surgical methods, pathological staging, or pathological types between the ERAS and CRAS groups. ERAS group presented less albumin loss [(25.73±8.63)% vs. (32.63±9.05)%, P=0.001], shorter hospital stay [9(7, 13)d vs. 12(9, 16)d, P=0.006], less 30-day overall complications [55.2% (16/29) vs. 83.3% (45/54), P=0.009]. In multivariable analysis, maximum albumin loss≥20% was independently associated with 30-day minor complications ( P=0.049), and maximum albumin loss ≥25% was independently associated with hospital of stay≥10 days ( P=0.038), respectively. Conclusions:For patients who received LRC+ ICUD, ERAS was associated with reduced perioperative albumin loss, shorter length of stay, less 30-day complications, accelerated recovery time, improved clinical outcome and less albumin injection.

High mobility group box-1 inhibition reduces expression of matrix metalloproteinase-9 in astrocytes in rats after spinal cord injury / 中华创伤骨科杂志

Objective:To investigate the role and underlying mechanisms of inhibiting high mobility group box-1 (HMGB1) in the expression of matrix metalloproteinase-9 (MMP-9) in spinal cord astrocytes (AS) in rats after spinal cord injury (SCI).Methods:After an SCI model was established in Sprague-Dawley (SD) rats using a modified Allen's Weight-Dropping method and ethyl pyruvate (EP) or glycyrrhizin (GL) was used to inhibit the effect of HMGB1, the rats were divided into a sham group, an SCI group, an SCI+EP (50 mg/kg) group, and an SCI+GL (100 mg/kg) group. The expression levels of glial fibrillary acid protein (GFAP) and MMP-9 in spinal cord AS were observed. After the spinal cord AS in SD rats was cultured and incubated by the oxygen-glucose deprivation/reoxygenation (OGD/R) procedure, the expression of MMP-9 protein was detected at 6 h/R 6 h, 12 h, 24 h, and 48 h after OGD. The time point with the highest expression was chosen in the subsequent experiments as an OGD/R group. HMGB1 was inhibited by HMGB1 shRNA or EP to observe the effect of HMGB1 on the expression of MMP-9 protein in AS treated with OGD/R. Then, toll-like receptor 4 (TLR4) inhibitor, TIR-domain-containing adaptor inducing interferon- β (TRIF) inhibitor, and nuclear factor-kappa B (NF- κB) inhibitor were used to investigate the effects of TLR4/TRIF/NF- κB signaling pathway during the regulation of HMGB1 on MMP-9 in vitro. Results:Western blot showed that the expression of MMP-9 protein in the spinal cord was significantly increased in rats at 1 d after SCI, and the expression of MMP-9 protein in the SCI+EP group and the SCI+GL group was significantly lower than that in the SCI group ( P<0.001). Immunofluorescence showed that GFAP and MMP-9 proteins were co-localized in the spinal cord after SCI, and the expression of GFAP and MMP-9 proteins in the SCI+EP and SCI+GL groups was significantly lower than that in the SCI group ( P<0.05). Since the expression of MMP-9 protein in the spinal cord AS cultured in vitro was significantly higher in the OGD 6h/R 12h group than that in the normal group and the OGD 6h/R 6h, 24, and 48 h groups, the OGD 6h/R 12h was taken as the OGD/R group. The MMP-9 protein expression in AS in the OGD/R+HMGB1 shRNA group and the OGD/R+EP group was significantly lower than that in the OGD/R group ( P<0.001). In the cultured AS, moreover, inhibiting TLR4, TRIF, and NF- κB reduced MMP-9 protein expression after OGD 6 h/R 12 h when compared with that in the OGD/R group ( P<0.001). Conclusions:HMGB1 inhibition may result in a reduction in MMP-9 expression both in the spinal cord AS in SCI rats and in AS after OGD/R treatment in vitro. HMGB1 may regulate MMP-9 protein expression in AS after OGD/R treatment via the TLR4/TRIF/NF- κB signal pathway.

Research progress of vitamin D, monocyte chemoattractant protein-1 and Hashimoto's thyroiditis / 中国医师杂志

Hashimoto thyroiditis (HT) is one of the most common autoimmune thyroid disease, and its pathogenesis has not been fully clarified at present. Most people believe that it is induced by mental stress, overwork, infection, stress, environmental pollution, unreasonable diet structure (such as high iodine diet) and other factors on the basis of genetic defects and genetic susceptibility. Vitamin D is a steroid hormone that maintains the balance of calcium and phosphorus metabolism in the body, regulating bone and mineral salt metabolism. Monocyte chemoattractant protein-1 (MCP-1) is a member of the chemokine CC family. It binds to chemokine receptor (CCR) and participates in immune inflammatory response. In recent years, more and more studies have found that vitamin D and MCP-1 are involved in the occurrence and development of many immune diseases, including Hashimoto thyroiditis. This article reviews the new research progress of the role of vitamin D and MCP-1 in Hashimoto thyroiditis.

Comparative study of umbilical venous blood flow between congenital heart disease and normal fetus / 中华超声影像学杂志

Objective:To investigate the differences of umbilical vein diameter(D), time average peak velocity(TAmax) and blood flow between congenital heart disease and normal fetus.Methods:The umbilical vein diameter and time average peak velocity of 69 fetuses with congenital heart disease (disease group) from 22 to 27 weeks were prospectively studied in Maternal-Fetal Medical Center in Fetal Heart Disease of Beijing Anzhen Hospital from May 2021 to September 2021. Q 1 (umbilical venous blood flow) was calculated according to the formular [Q=0.5TAmax·π·(D/2) 2)], and Q 2 (Q 2=Q 1/weight) was calculated according to the fetal weight. At the same time, 111 normal fetuses with matched gestational age were selected as control group. The differences of fetal umbilical vein D, TAmax, Q 1 and Q 2 between the two groups were analyzed. Results:The inner diameter of umbilical vein D, TAmax, Q 1 and Q 2 in the congenital heart disease group were lower than those in the control group(all P<0.05). In the control group, the inner diameter of umbilical vein D, TAmax and Q 1 increased with the increase of gestational age and showed a positive linear correlation( r=0.608, 0.320, 0.626; all P≤0.001), while there was no obvious linear correlation between Q 2 and gestational age( r=0.189, P=0.047). Conclusions:The decrease of umbilical vein D, TAmax, Q 1 and Q 2 in the fetus with congenital heart disease indicates the decrease of effective blood flow in placenta-fetus circulation, which indirectly reflects the decrease of placental function in the fetus with congenital heart disease.

Neurobiological mechanisms in the regulation of conditioned fear memory by the retrieval-extinction paradigm / 中华行为医学与脑科学杂志

Fear memories are temporarily suppressed after repeated retrieval, a phenomenon known as memory extinction.How to reduce or even eliminate fear memory is the key to the treatment of fear related diseases such as post-traumatic stress disorder(PTSD). A single extinction training based on Pavlov's fear regulation task could only inhibit the expression of conditioned fear memory traces, but it could not eliminate the acquired conditioned fear memory. However, according to the reconsolidation theory based on memory, the retrieval-extinction paradigm has a more lasting effect on the erasure and rewriting of fear memory, and can effectively prevent the return of fear memory. Studies have shown that extraction-regression is closely related to a variety of neurotransmitter receptors such as glutamate receptor(GluR), dopamine receptor(DAR), L-type voltage-gated calcium channels(LVGCs) and cannabinoid. Moreover, its effect is closely related with factors such as retrieval-extinction memory stage. At present, most of the researches on extracted boundary conditions only stay at the level of behavior, with little understanding and exploration on the level of molecular mechanism. From the perspective of molecular neurobiology, with different stages of memory and different types of receptors and molecular mechanisms, this research reviewed the mechanisms of retrieval-extinction in recent years.It provided valuable signaling pathways, molecular targets and research directions for the treatment of fear-related diseases such as PTSD.

Berberine alleviates programmed necrosis of metabolic-associated fatty liver disease via activating Nrf2 pathway in mice / 中华肝脏病杂志

Objective: To investigate the effect of berberine on programmed necrosis of hepatocytes induced by metabolic-associated fatty liver disease (MAFLD) in mice and its related molecular mechanism. Methods: Twenty male C57BL/6N mice were randomly divided into four groups (n=5 in each group): control group (S), fatty liver group (H), berberine group(B), nuclear factor erythroid 2-related factor 2 inhibitor group (Nrf2), and all-trans-retinoic acid (ATRA) group (A). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), triglycerides (TG), total cholesterol (TC), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) concentrations were detected at the end of week 12 to calculate fatty liver index (liver mass/body mass ratio). Liver tissue was stained with HE, Masson and Oil Red O, and SAF score was used to evaluate the degree of liver injury. The expression levels of hepatic programmed necrosis-related proteins, namely receptor-interacting protein kinase 3 (RIPK3), phosphorylated mixed series protease-like domain (p-MLKL) and Nrf2 were detected by Western blot method. One-way ANOVA was used for intragroup comparisons and LSD-t tests were used for intergroup comparisons. Results: Compared with S group, H group serum ALT, AST, LDH, TG, TC, TNF-α, IL-1β levels and fatty liver index were significantly increased. The liver tissue was filled with vacuolar-like changes and inflammatory cell infiltration. Numerous red lipid droplets were observed with oil red O staining. Collagen fiber hyperplasia was evident with Masson staining. SAF scores (6.60 ± 0.55 and 0.80 ± 0.45) were significantly increased. The expressions of RIPK3 and p-MLKL were up-regulated. Nrf2 level was relatively increased, and the differences were statistically significant (P < 0.05). Compared with H group, berberine intervention group liver biochemical indexes, lipid levels, pro-inflammatory mediator expression, fatty liver index, and SAF score were significantly reduced, and the expression of RIPK3 and p-MLKL were down-regulated, while Nrf2 levels were further increased, and the differences were statistically significant (P<0.05). Compared with B group, treatment with Nrf2 inhibitor had antagonized the protective effect of berberine on fatty liver. Serum ALT, AST, LDH, TG, TC and TNF-α, IL-1β levels, fatty liver index, and SAF scores were significantly increased and the expressions of RIPK3 and p-MLKL were relatively increased, and the differences were statistically significant (P < 0.05). Conclusion: Berberine can significantly improve the metabolic-associated fatty liver disease injury in mice, and its mechanism is related to activation of Nrf2 and inhibition of programmed necrosis of hepatocytes.

Analysis of clinicopathological features, gene mutation characteristics and prognosis of 228 cases of primary gastrointestinal stromal tumor of small intestine / 中华消化杂志

Objective:To analyze the clinicopathological features, gene mutation characteristics, and prognostic related factors of patients with primary gastrointestinal stromal tumor (GIST) of small intestine.Methods:From January 1, 2011 to December 30, 2019, surgical resected and pathological diagnosed small intestinal GIST without preoperative adjuvant therapy, at Tianjin Medical University Cancer Institute & Hospital were retrospectively collected. The mutational status of KIT exons 9, 11, 13, and 17 and platelet-derived growth factor receptor alpha ( PDGFRA) exons 12 and 18 were detected by polymerase chain reaction and Sanger direct sequencing. Clinicopathological features and gene mutation characteristics were analyzed. Pearson chi-square test and Bonferroni continuous correction test were used to compare the categorical variables among groups. Kaplan-Meier method and log-rank test were used for univariate survival analysis. The multivariate Cox proportional hazards regression model was used for multivariate survival analysis. Results:The proportions of patients with maximum tumor diameter> 10.0 cm and high-risk GIST located in the jejunum and ileum were higher than those of patients with primary GIST located in the duodenum (18.7%, 28/150 vs. 6.4%, 5/78; 56.7%, 85/150 vs. 43.6%, 34/78), and the differences were statistically significant ( χ2=14.67 and 12.46, P=0.002 and 0.006). The results of gene detection of 58 cases of small intestinal GIST indicated that the percentage of KIT gene mutant and wild type accounted for 84.5% (49/58) and 15.5% (9/58), among which 34 cases (69.4%), 12 cases (24.5%), 2 cases (4.1%) and 1 case (2.0%) were KIT gene exons 11, 9, 13 and 17 mutations, respectively, and none of the case with PDGFRA mutation. The 3-, 5-, and 10-year progression-free survival rates of the patients with small intestinal GIST were 88.1%, 85.0%, and 68.3%, respectively, and the 3-, 5-, and 10-year overall survival rates were 96.6%, 94.5%, and 86.1%, respectively. The results of univariate survival analysis showed that the progression-free survival rate and overall survival rate of patients with very low-risk and low-risk GIST were higher than those of patients with intermediate-risk and high-risk GIST (100.0%, 49/49 vs. 72.3%, 81/112; 100.0%, 49/49 vs. 89.3%, 100/112, respectively), and the differences were statistically significant ( χ2=14.07 and 4.92, P<0.001、=0.027). The results of univariate survival analysis of patients with intermediate-risk and high-risk GIST showed that the epithelioid cell type, mitotic index >5/5 mm 2, Ki-67 proliferation index >5%, and without postoperative adjuvant therapy were all related with progression-free survival time, and the differences were statistically significant ( χ2=8.39, 5.53, 13.73 and 15.44, P=0.004、0.019、<0.001、<0.001). Without postoperative adjuvant therapy was related with poor overall survival time ( χ2=7.06, P=0.008). The results of univariate analysis in patients with intermediate-risk and high-risk GIST and without postoperative adjuvant therapy showed that the epithelioid cell type, high-risk, mitotic index >5/5 mm 2 and Ki-67 proliferation index >10% were all related with progression-free survival time, and the differences were statistically significant ( χ2=10.08, 6.51, 10.37 and 15.72, P=0.001、0.011、0.001、<0.001). The results of multivariate analysis indicated that Ki-67 proliferation index >5% ( HR=5.018, 95% confidence interval(95% CI) 1.745 to 14.430, P=0.003) and without postoperative adjuvant treatment ( HR=0.145, 95% CI 0.051 to 0.414, P<0.001) were independent risk factors of postoperative tumor progression in patients with small intestinal intermediate-risk and high-risk GIST. Ki-67 proliferation index>10% ( HR=8.381, 95% CI 1.364 to 51.487, P=0.022) was an independent risk factor of postoperative tumor progression in patients with small intestinal intermediate-risk and high-risk GIST and without postoperative adjuvant treatment. Conclusions:The most common mutation in small intestinal primary GIST is KIT mutation, followed by wild type, no case of PDGFRA gene mutation has been found. High Ki-67 proliferation index can predict poor prognosis of patients with moderate-risk and high-risk small intestinal primary GIST. Postoperative adjuvant therapy can significantly improve the prognosis of patients with small intestinal intermediate-risk and high-risk primary GIST.

Pathogenesis, prenatal diagnosis and clinical features of fetal cardiomyopathies / 中华超声影像学杂志

Objective:To summarize the etiological mechanism, echocardiographic and clinical features of fetal cardiomyopathies (FCMs).Methods:According to the data of echocardiography in Maternal-Fetal Medicine Center in Fetal Heart Disease of Beijing Anzhen Hospital during 2015 January to 2020 December, 70 cases with FCMs were retrospectively reviewed, and the clinical, ultrasonic, pathological and clinical outcome data were collected. Whole exome sequencing and whole genome sequencing were used to identify the genetic changes.Results:Primary FCMs were diagnosed in 55 cases (78.6%, 55/70), including 39 fetuses with non-compaction of the ventricular myocardium (NVM), 10 with dilated cardiomyopathy (DCM), 5 with hypertrophic cardiomyopathy (HCM), and 1 with restricted cardiomyopathy (RCM). Secondary FCMs were diagnosed in 15 cases (21.4%, 15/70), including 7 fetuses with maternal anti-Ro/La antibodies (presenting with DCM), 4 with twin-twin transfusion syndrome (2 with DCM and 2 with HCM), 2 with fetal anemia (presenting with DCM), 1 with maternal diabetes (presenting with HCM) and 1 with chorioangioma of the placenta (presenting with DCM). In all cases, 9 cases were born, 3 cases died in perinatal period, and 58 pregnancies were terminated due to ineffective treatment or the decisions of pregnant women. Thirty cases with primary FCMs were performed with genetic tests, and 13 of them were identified with positive genetic changes related to FCMs, including 12 cases with NVM and 1 with HCM.Conclusions:Primary FCMs are more common than secondary FCMs in fetal period. The genetic disorders have a high proportion in fetal NVM. Fetal DCM and HCM have a large spectrum of intrinsic and extrinsic causes.

Serum levels of complement B and D in patients with diabetic peripheral neuropathy and their correlation / 中国医师杂志

Objective:To investigate the serum level and significance of complement factor B (CFB) and complement factor D (CFD) in patients with type 2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN).Methods:From October 2019 to October 2020, 110 patients with T2DM in the endocrinology department of Affiliated Hospital of Jining Medical College were divided into DPN group ( n=60) and simple T2DM group ( n=50) according to whether or not DPN was combined. In addition, 52 cases of physical examination population in the physical examination center in the same period were selected as the normal control group ( n=52). The serum levels of CFB, CFD and tumor necrosis factor-α (TNF-α) were measured by enzyme linked immunosorbent assay (ELISA). The correlation between CFB, CFD and clinical indexes was analyzed, and the influencing factors of DPN were analyzed by logistic regression. Results:The serum levels of CFB and CFD in DPN group were higher than those in T2DM group and normal control group [CFB: (845.43±101.10)μg/ml vs (792.19±116.59)μg/ml, (739.20±123.43)μg/ml, P<0.05], [CFD: (491.71±41.03)mg/L vs (467.58±45.16)mg/L, (445.16±50.47)mg/L, P<0. 05]. Pearson correlation analysis showed that the serum level of CFB was positively correlated with glycosylated hemoglobin (HbA 1c), fasting plasma glucose (FPG) and TNF-α (all P<0.05) and negatively correlated with triiodothyronine (FT3) and total bilirubin (TBIL) (all P<0.05). Serum CFD level was positively correlated with systolic blood pressure, HbA 1c, FPG and TNF-α (all P<0.05), but negatively correlated with FT3 and TBIL (all P<0.05). Logistic regression analysis showed that CFB and CFD were still influential factors for the occurrence and development of DPN after excluding confounding factors such as systolic blood pressure, HbA 1c, FPG, FT3, DBIL, TBIL and TNF-α. Conclusions:(1) Serum CFB and CFD levels were significantly increased in DPN patients, suggesting that CFB and CFD may be involved in the occurrence and development of DPN. (2) Serum TNF-α level was significantly increased in DPN patients, confirming the role of TNF-α in the pathogenesis of DPN.

Robotic arm-assisted arthroplasty: The latest developments / 中华创伤杂志(英文版)

Joint arthroplasty is an effective method for treating end-stage joint lesions and damages. Robotic arm-assisted arthroplasty, a rapidly developing technology that combines navigation technology, minimally invasive technology, and precise control technology of the robotic arm, can achieve accurate preoperative planning, optimal selection of implants, minimally invasive surgery, precise osteotomy, and accurate placement of the artificial joint. It has the characteristics of high accuracy and stability, and thus is more and more widely used in the field of joint surgery. In this paper, we systematically reviewed the application and clinical efficacy of robotic arm-assisted technology in hip and knee arthroplasty to provide reference for its future promotion.

Adult linear scleroderma with ptosis: a case report and literature review / 中华神经科杂志

Objective:To discuss the clinical features, diagnosis and treatment of linear scleroderma (LS).Methods:A case of LS diagnosed in the Second Hospital of Shandong University in October 20, 2020, was reported and the clinical features and pathological documentation of the disease reported in the literature were reviewed.Results:A 24-year-old woman presented cicatricial alopecia on the left frontoparietal area and facial atrophy for about 10 years. Two years before, she began to suffer ptosis and neurological complaints. Clinical features of different stages of the disease are presented. All 15 patients reported in the literature were analyzed, with a median of 22 years and a male to female ratio of 9∶6. There were 4 cases of linear scleroderma with ipsilateral drooping eyelids and lateral contraction, 3 cases of linear scleroderma with demyelinating lesions, combined with lateral contraction, 3 cases of linear scleroderma combined with lateral atrophy, and 1 case of linear scleroderma with ipsilateral facial spasm. Two cases were with the chest sclerosing spot. Two cases of linear scleroderma were with epileptic seizure and white matter demyelination lesion. Six cases were treated with hormone, 2 cases were treated with methotrexate. One case was treated with both hormone and methotrexate. One case was treated with botulinum toxin. Three cases were treated with surgical correction of eyelid ptosis. One case was treated with ultraviolet A1 radiation phototherapy and 1 case was treated with vitamin therapy.Conclusions:Patients with scleroderma may have ipsilateral facial atrophy, blepharoptosis and facial spasm. Some patients involving the nervous system may have epilepsy and myelitis. And demyelinating lesions can be seen in magnetic resonance imaging. Localized scleroderma may develop into systemic scleroderma. Therefore, it is recommended to combine immunosuppressants as soon as possible to control the development of the disease if necessary.

Clinical characteristics of 272 437 patients with different histopathological subtypes of primary esophageal malignant tumors / 中华内科杂志

Objective:To characterize the histopathological subtypes and their clinicopathological parameters of gender and onset age by common, rare and sparse primary esophageal malignant tumors (PEMT).Methods:A total of 272 437 patients with PEMT were enrolled in this study, and all of the patients were received radical surgery. The clinicopathological information of the patients was obtained from the database established by the State Key Laboratory of Esophageal Cancer Prevention & Treatment from September 1973 to December 2020, which included the clinical treatment, pathological diagnosis and follow-up information of esophagus and gastric cardia cancers. All patients were diagnosed and classified by the criteria of esophageal tumor histopathological diagnosis and classification (2019) of the World Health Organization (WHO). The esophageal tumors, which were not included in the WHO classification, were analyzed separately according to the postoperative pathological diagnosis. The χ 2 test was performed by the SPSS 25.0 software on count data, and the test standard α=0.05. Results:A total of 32 histopathological types were identified in the enrolled PEMT patients, of which 10 subtypes were not included in the WHO classification. According to the frequency, PEMT were divided into common (esophageal squamous cell carcinoma, ESCC, accounting for 97.1%), rare (esophageal adenocarcinoma, EAC, accounting for 2.3%) and sparse (mainly esophageal small cell carcinoma, malignant melanoma, etc., accounting for 0.6%). All the common, rare, and sparse types occurred predominantly in male patients, and the gender difference of rare type was most significant (EAC, male∶ female, 2.67∶1), followed with common type (ESCC, male∶ female, 1.78∶1) and sparse type (male∶ female, 1.71∶1). The common type (ESCC) mainly occurred in the middle thoracic segment (65.2%), while the rare type (EAC) mainly occurred in the lower thoracic segment (56.8%). Among the sparse type, malignant melanoma and malignant fibrous histiocytoma were both predominantly located in the lower thoracic segment (51.7%, 66.7%), and the others were mainly in the middle thoracic segment.Conclusion:ESCC is the most common type among the 32 histopathological types of PEMT, followed by EAC as the rare type, and esophageal small cell carcinoma and malignant melanoma as the major sparse type, and all of which are mainly occur in male patients. The common type of ESCC mainly occur in the middle thoracic segment, while the rare type of EAC mainly in the lower thoracic segment. The mainly sparse type of malignant melanoma and malignant fibrous histiocytoma predominately occur in the lower thoracic segment, and the remaining sparse types mainly occur in the middle thoracic segment.

Medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

GKK1032B from endophytic Penicillium citrinum induces the apoptosis of human osteosarcoma MG63 cells through caspase pathway activation / 中国天然药物

Chemical investigation of the culture extract of an endophytic Penicillium citrinum from Dendrobium officinale, afforded nine citrinin derivatives (1-9) and one peptide-polyketide hybrid GKK1032B (10). The structures of these compounds were determined by spectroscopic methods. The absolute configurations of 1 and 2 were determined for the first time by calculation of electronic circular dichroism (ECD) data. Among them, GKK1032B (10) showed significant cytotoxicity against human osteosarcoma cell line MG63 with an IC50 value of 3.49 μmol·L-1, and a primary mechanistic study revealed that it induced the apoptosis of MG63 cellsvia caspase pathway activation.

Association of status of mismatch repair protein expression and EB virus infection with clinicopathological parameters in 886 gastric adenocarcinoma patients / 中华胃肠外科杂志

Objective: To analyze the expression of mismatch repair (MMR) protein and the EB virus infection in gastric adenocarcinoma, and to examine the association of MMR expression and EB virus infection with clinicopathological parameters. Methods: A case-control study was performed. Clinicopathological data of patients who was pathologically diagnosed as gastric adenocarcinoma, received radical gastrectomy and had complete clinicopathological data from August 2017 to April 2020 in Tianjin Medical University Cancer Institute and Hospital were retrospectively collected and analyzed. The immunohistochemistry (IHC) of MMR proteins and in situ hybridization (ISH) of Epstein-Barr virus encoded RNA (EBER) were reviewed. The associations of MMR and EBER results with clinicopathological parameters were analyzed. The main observations of the study were MMR and EBER expression, and association of MMR and EBER results with clinicopathological parameters. Results: Eight hundred and eighty-six patients were enrolled, including 98 patients who received preoperative neoadjuvant chemoradiotherapy. Of 886 patients, 613 (69.2%) were males and the median age was 60 (22-83) years; 831 (93.8%) were mismatch repair proficiency (pMMR), and 55 (6.2%) were mismatch repair deficiency (dMMR). In dMMR group, 47 cases (85.5%) had the deficiency of both MLH1 and PMS2, 1 case (1.8%) had the deficiency of both MSH2 and MSH6, 4 cases (7.3%) had the deficiency only in PMS2, 2 cases (3.6%) had the deficiency only in MSH6, and 1 case (1.8%) had the deficiency only in MSH2. The deficiency rates of PMS2, MLH1, MSH6 and MSH2 were 5.8% (51/886), 5.3% (47/886), 0.3% (3/886) and 0.2% (2/886), respectively. Among the 871 cases with EBER results, 4.9% (43/871) were positive EBER. Univariate analysis showed that dMMR was more frequently detected in female patients (χ(2)=10.962, P=0.001), cancer locating in the antrum (χ(2)=9.336,P=0.020), Lauren intestinal type (χ(2)=9.718, P=0.018), stage T3 (χ(2)=25.866, P<0.001) and TNM stage II (χ(2)=15.470, P=0.002). The ratio of dMMR was not significantly associated with age, tumor differentiation, histological type, lymph node metastasis, distant metastasis or Her-2 immunohistochemical score (all P>0.05). Compared with negative EBER, positive EBER was more frequent in male patients (χ(2)=9.701, P=0.002), cancer locating in gastric fundus and corpus (χ(2)=17.964, P<0.001), gastric cancer with lymphoid stroma (χ(2)=744.073, P<0.001) and poorly differentiated cancer (χ(2)=13.739, P=0.010). Positive EBER was not significantly associated with age, depth of invasion, lymph node metastasis, distant metastasis, TNM stage or Her-2 immunohistochemical score (all P>0.05). In addition, all dMMR cases were EBER negative, and all cases of positive EBER were pMMR. Conclusions: The positive EB virus status is mutually exclusive with dMMR, indicating that different molecular subtypes of gastric adenocarcinoma are involved in different molecular pathways in tumorigenesis and progression. The overlapping of dMMR or positive EBER status and positive Her-2 expression is found in some cases of gastric adenocarcinoma. Patients with gastric adenocarcinoma after radical surgery should be tested for MMR status if they are female, the tumor locates in gastric antrum, the TNM staging is stage II or T3, or if the Lauren classification is intestinal type. And if patients are male, the tumor locates in the gastric fundus and corpus, the cancer is lymphoid stroma, or poor differentiated, the expression of EBER should be detected. Results of our study may provide evidence for further decision-making of clinical treatment.