Objective : To investigate the changes of lipid biomarkers and lipid metabolic pathways related to liver injury in BTBR ob/ob mice with type 2 diabetes mellitus by biochemical and metabolomics methods． Methods : 16 BTBR wild-type (WT) mice (WT group) and 14 BTBR ob/ob obese mice (ob / ob group) at 7 weeks of age were selected and fed in SPF environment until 20 weeks of age．Liver injury was compared between the two groups : The activities of mitochondrial respiratory enzyme complex in liver tissue were detected by high-resolution respirators，and the lipid metabolomic analysis of liver tissue samples in the two groups of mice was performed by ultra-perform- ance liquid chromatography-quadrupole time-of-flight mass spectrometry，mainly detecting endogenous metabolites. Principal component analysis (PCA) ，orthogonal partial least squares discriminant analysis ( OPLS-DA) and other models were used to screen potential biomarkers，and the metabolic pathway analysis of the identified metabolites was performed by MetaboAnalyst 5. 0 . Results : Compared with the WT group，the ob / ob group had significantly increased body weight，fasting blood glucose ，serum levels of aspartate aminotransferase ( AST) ，alanine amin- otransferase (ALT) ，low-density lipoprotein (LDL-C) and cholesterol ( CHO) (P＜0. 01) ．Liver hematoxylin-eo- sin staining (HE) staining showed that the mice in ob / ob group had structural disorder of liver lobules，swelling of liver cells ，a large number of fat vacuoles in cells ，diffuse distribution and loose cytoplasm． Oil red O staining showed that there was a large amount of lipid deposition in the hepatocytes ofob/ob mice．The high resolution spi- rometer showed that the ob/ob mice had mitochondrial oxidative phosphorylation disorder and the activity of complex Ⅳ decreased．Lipid metabolomic analysis showed that the lipid metabolic profile of ob/ob mice changed，and the metabolic pathways involved mainly included glycerophospholipid metabolism，glycosylphosphatidylinositol ( GPI) anchor biosynthesis，triglyceride metabolism，linoleic acid metabolism，α-linolenic acid metabolism and arachidon- ic acid metabolism． Conclusion The liver injury of ob / ob group mice may be related to the disorder of lipid me- tabolism，in which the disorder of glycerophospholipid metabolism is the most critical metabolic pathway.

Objective:To obtain skin-derived induced pluripotent stem cells (iPSCs) from an Osteogenesis imperfecta (OI) patient carrying WNT1c.677C>T mutation in order to provide a new cell model for investigating the underlying molecular mechanism and stem cell therapy for OI. Methods:The pathogenic variant of the patient was identified by Sanger sequencing. With informed consent from the patient, skin tissue was biopsied, and primary skin fibroblasts were cultured. Skin fibroblasts were induced into iPSCs using Sendai virus-mediated non-genomic integration reprogramming method. The iPSC cell lines were characterized for pluripotency, differentiation capacity, and karyotyping assay.Results:The patient was found to carry homozygous missense c. 677C>T (p.Ser226Leu) mutation of the WNT1 gene. The established iPSC lines possessed self-renewal and capacity for in vitro differentiation. It also has a diploid karyotype (46, XX). Conclusion:A patient-specific WNT1 gene mutation ( WNT1c.677C>T) iPSC line was established, which can provide a cell model for the study of OI caused by the mutation.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective To investigate the effect of laparoscopic Roux-en-Y gastric bypass surgery(LRYGB)in the treatment of obese diabetes.Methods The clinical data of 20 obese diabetic patients who received LRYGB from 2012 to 2018 in the Minimally Invasive and Herniac Abdominal Surgery Center of Xinjiang People's Hospital were retrospectively analyzed.Result The all 20 surgeries were successfully completed,and 1 case was converted to open surgery.The surgical time ranged from 60 to 420 minutes,with an average of(150±105.64)minutes,the intraoperative blood loss ranged from 20 to 100,with an average of(37.5±20.99)ml,and the postoperative hospital stay ranged from 5 to 15,with an average of(8.25±2.51)days.Complications occurred in 7 cases(35.00％)within 5 years after surgery,all of which were Clavien Dindo grade Ⅱ.The body weight,BMI,glycosylated blood glucose,fasting blood glucose,and the percentage of total weight loss(TWL％)at 1,3,and 5 postoperatively improved compared with those before surgery(P＜0.05).15 cases(75.00％)of type 2 diabetes were completely relieved by LRYGB 5 years after operation.Conclusion Laparoscopic gastric bypass surgery is an effective way to reduce weight and blood sugar in obese patients with type 2 diabetes.

Objective:To evaluate the effect of esketamine on extremity ischemia-reperfusion-induced lung injury in elderly patients undergoing total knee replacement.Methods:Sixty elderly patients of both sexes, aged 65-80 yr, with body mass index <35 kg/m 2, of American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ, scheduled for elective unilateral total knee replacement under neuraxial anesthesia, were divided into 2 groups according to the random number table method: control group (C group) and esketamine group (S group), with 30 cases in each group. Esketamine 0.3 mg/kg was intravenously infused before tourniquet inflation in group S. Immediately after the end of operation, the two groups received adductor block with 0.5% ropivacaine 15 ml under ultrasound guidance. And then patient-controlled intravenous analgesia was performed, patient-controlled intravenous analgesia solution included sufentanil 1.5 μg/kg in 100 ml of normal saline in group C and sufentanil 1.5 μg/kg and esketamine 0.75 mg/kg in 100 ml of normal saline in group S. The background infusion rate was 1.5 ml/h, the patient-controlled analgesia dose was 1.5 ml, and the lockout interval was 15 min in the two groups. When the visual analogue scale score at rest≥ 4 points within 3 days after surgery, ketorolac tromethamine 30 mg was intravenously injected for rescue analgesia. Blood samples from the radial artery were collected for blood gas analysis at 30 min before tourniquet inflation(T 0), 30 min after tourniquet inflation(T 1), and 3 min, 30 min and 24 h (T 4) after tourniquet release (T 2-4), and PaO 2 and PaCO 2 were recorded. The alveola-arterial oxygen partial pressure difference, oxygenation index and respiratory index were calculated. Peripheral venous blood samples were collected at T 0, T 3 and T 4 for determination of serum endothelin-1 and malondialdehyde by enzyme-linked immunosorbent assay. The requirement for rescue analgesia and occurrence of dizziness, hallucinations and pulmonary complications within 3 days after surgery were recorded. Results:Compared with group C, alveola-arterial oxygen partial pressure difference was significantly decreased at T 1-3, respiratory index was decreased, oxygenation index was increased at T 2, 3, and serum endothelin-1 and malondialdehyde concentrations were decreased at T 3, 4, and the rate of postoperative rescue analgesia was decreased in group S( P<0.05). There was no significant difference in the incidence of postoperative dizziness, hallucinations, and pulmonary complications between the two groups ( P>0.05). Conclusions:Esketamine can reduce extremity ischemia-reperfusion-induced lung injury in elderly patients undergoing total knee replacement, and the mechanism may be related to regulating vascular endothelial function and reducing lipid peroxidation.

Objective:To evaluate the relationship between postoperative delirium(POD) and preoperative frailty in elderly patients undergoing spinal surgery.Methods:Two hundred and twenty patients of both sexes, aged ≥65 yr, of American Society of Anesthesiologists Physical Status classification Ⅱ-Ⅳ, undergoing elective posterior lumbar decompression, bone grafting and internal fixation under general anesthesia, were selected. Frailty was measured using the FRAIL (fatigue, resistance, ambulation, illness, and loss of weight) scale on 1 day before surgery. POD was assessed twice a day within 3 days by Confusion Assessment Method. Patients were divided into POD group and non-POD group according to whether POD occurred within 3 days after surgery. Multivariate logistic regression analysis was used to identify the risk factors for POD in elderly patients undergoing spinal surgery, and the value of preoperative frailty in predicting POD was analyzed using the receiver operating characteristic curve.Results:A total of 190 patients were finally enrolled, among which 55 patients presented with frailty before surgery, and the incidence was 29.0%. Forty-six patients developed POD, and the incidence was 24.2%. Multivariate logistic regression analysis showed that aging ( OR=1.15, 95% confidence interval [ CI] 1.03-1.29, P=0.017), preoperative frailty ( OR=2.35, 95% CI 1.24-4.43, P=0.009), increase in surgical segments ( OR=4.14, 95% CI 1.71-10.05, P=0.002) and increase in postoperative 24-h pain VAS score ( OR=1.38, 95% CI 1.07-1.78, P=0.013) were independent risk factors for POD in elderly patients undergoing spinal surgery. The area under receiver operating characteristic curve of preoperative frailty in predicting POD was 0.702 (95% CI 0.608-0.796, P<0.001). Conclusions:Preoperative frailty is an independent risk factor for POD in elderly patients undergoing spinal surgery. Preoperative frailty can predict the occurrence of POD in elderly patients undergoing spinal surgery to some extent.

OBJECTIVE: To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS). METHODS: Three children who had respectively presented at Shandong Provincial Hospital in April 2019 and Peking Union Medical College Hospital in August 2020 and May 2021 were selected as the research subjects. Peripheral blood samples of the probands and their family members were taken for the extraction of genomic DNA. Potential variants were screened by whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing of the patients and their family members. RESULTS: The proband from family 1 was found to harbor a heterozygous c.601C>T (p.R201C) missense variant in exon 8 of the GNAS gene, whilst the probands from families 2 and 3 were both found to harbor a heterozygous c.602G>A (p.R201H) missense variant in exon 8 of the GNAS gene. Both variants were known to be pathogenic, and all probands were found to be mosaics for the corresponding variants but with various degrees. CONSLUSION WES can effectively diagnose MAS and other somatic genetic disorders. In this study, the combined WES and Sanger sequencing have verified the degree of mosaicisms of pathogenic variants in the three MAS patients, albeit no apparent correlation was found between the degree of mosaicisms and the phenotype of patients. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the affected families.
Humans ; Mutation ; Fibrous Dysplasia, Polyostotic/genetics* ; East Asian People ; Exons ; Phenotype ; Pedigree

OBJECTIVE: To explore the pathogenic variants and clinical classification of two fetuses with Short-rib thoracic dysplasia with or without polydactyly (SRTD). METHODS: With informed consent obtained, the phenotypic characteristics of the fetuses were comprehensively examined, and genomic DNA was extracted from fetal skin tissue and peripheral blood samples of the parents with conventional phenol-chloroform method. Whole exome sequencing (WES) was carried out on both fetuses, and the candidate variants were validated by Sanger sequencing. The pathogenicity of the candidate variants was analyzed using bioinformatic software VarCards, and the impact of the variants on the protein structure was predicted with Swiss-Pdb-viewer. RESULTS: Both fetuses were found to harbor compound heterozygous variants of the DYNC2H1 gene, including c.515C>A (p.Pro172Gln) and c.5983G>A (p.Ala1995Thr) in fetus 1, and c.5920G>T (pGly1974) and c.9908T>C (p.He3303Thr) in fetus 2. The parents of both fetuses were heterozygous carriers. CONCLUSION The compound heterozygous variants of the DYNC2H1 gene probably underlay the SRTD3 in the two fetuses.
Humans ; Fetus ; Chloroform ; Computational Biology ; Ethnicity ; Ribs

Objective To investigate the clinicopathological characteristics and prognosis of well-differentiated rectal neuroendocrine tumor(RNET).Methods A retrospective analysis was conducted using the clinical data from 83 patients with well-differentiated RNET from August 2017 to December 2021,including clinical manifestations,endoscopy,endoscopic treatment,postoperative complications,postoperative pathology,follow-up and prognosis.Pathological results according to the 2019 World Health Organization(WHO)Classification of digestive system tumors,83 patients were divided into G1 stage group(72 cases)and G2 stage group(11 cases);Based on the number of tumors in the patient,83 patients were divided into two groups:single RNET group(77 cases)and multiple RNET group(6 cases),the expressions of chromogranin A(CgA),synapsin(Syn)and CD56 were compared among different groups.Results Based on pathological findings in the group,G1 stage group CgA positive rate was significantly higher than that of G2 stage group,the difference was statistically significant(χ2 = 4.23,P = 0.040);Based on the number of tumors,multiple RNET group CgA positive rate was significantly higher than that of single RNET group,the difference was statistically significant(χ2 = 5.74,P = 0.017).It was no significant difference in Syn and CD56 between the two groups(P＞0.050).Conclusion Well-differentiated RNET has no specific clinical manifestations.It is mostly isolated in G1 stage and single RNET.ESD is safe and has a good prognosis,the positive rate of CgA is higher in G1 stage patients,and the positive rate of CgA is higher in patients with multiple RNET.

ObjectiveTo explore the correlation between dryness and energy metabolism of Atractylodis Rhizoma， and to analyze the difference of medicinal properties between Atractylodes lancea and A. chinensis. MethodA total of 110 healthy SD rats were randomly divided into 11 groups， including normal group， volatile oil of A. lancea 1-5 group （S1-S5 group， doses of 447， 473， 442， 489， 496 mg·kg^-1） and volatile oil of A. chinensis 1-5 group （N1-N5 group， doses of 197， 118， 281， 222， 185 mg·kg^-1）， the administration volume was 0.01 mL·g^-1 with intragastric administration for 21 days. Dryness effect of A. lancea and A. chinensis on rats was evaluated by comparing the body weight， drinking water volume， urine volume， whole blood viscosity and pathological sections of submandibular gland stained with hematoxylin-eosin （HE）. The expression of aquaporin 2 （AQP2） in rat kidney was measured by immunohistochemistry， the mRNA expressions of cytochrome C oxidase subunit 7A2 （COX7A2） and succinate dehydrogenase （SDH） complex subunit D （SDHD） in liver tissue were detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The contents of SDH， lactate dehydrogenase （LDH） and sodium ion-potassium ion-adenosine triphosphatase （Na⁺-K⁺-ATPase） in rat plasma were determined by colorimetry. The quality of A. lancea and A. chinensis was evaluated by coefficient of variation method， and Pearson correlation coefficient was used to analyze the correlation between dryness and energy metabolism. ResultCompared with the normal group， the amounts of drinking water and urine in volatile oil of A. lancea group and volatile oil of A. chinensis group increased， and the submandibular gland acini atrophied， the whole blood viscosity of rats in the volatile oil of A. lancea group increased significantly （P<0.01）， the expression levels of COX7A2 and SDHD mRNA， the activities of SDH， LDH and Na⁺-K⁺-ATPase increased significantly （P<0.01）， and the expression of AQP2 in kidney decreased significantly （P<0.01）. Compared with the normal group， the expression level of COX7A2 mRNA， SDH activity and whole blood viscosity in the volatile oil of A. chinensis group increased （P<0.05， P<0.01）， the AQP2 and SDH mRNA expression levels， LDH and Na⁺-K⁺-ATPase activities had no significant difference. The comprehensive score analysis of each index showed that the effect of volatile oil of A. lancea on dryness and energy metabolism was stronger than that of volatile oil of A. chinensis， and there was a positive correlation between dryness index and energy metabolism index. ConclusionThe two indexes show that medicinal properties of A. lancea is stronger than that of A. chinensis， and energy metabolism is closely related to the dryness of Atractylodis Rhizoma. It is suggested that it is reasonable to evaluate the dryness effect of Atractylodis Rhizoma from the perspective of energy metabolism， which can further enrich the evaluation indexes of medicinal properties.