Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Nodal marginal zone B-cell lymphoma(NMZL),the least common subtype of marginal zone lymphoma,represents a low-grade malignancy arising from the marginal zone of lymph node follicles,composed of small B-cells with an inert non-Hodgkin lymphoma nature.It accounts for 1.5% to 1.8% of all non-Hodgkin lymphomas and 10% of all marginal zone lymphomas.The low incidence and lack of typical clinical and pathological features pose a challenge to the diagnosis and clinical management of NMZL.In this article,we reported the diagnosis and treatment of a case of NMZL located in the parapharyngeal space of the left neck and reviewed the relevant literature from both domestic and international sources.We summarized the clinical manifestations,histopathological features,immunohistochemical characteristics,imaging features,diagnosis and treatment modalities,and prognosis of NMZL.
Humans ; Lymphoma, B-Cell, Marginal Zone/pathology* ; Lymph Nodes/pathology* ; Neck/pathology* ; Male

Objective To analyze the predictive value of fecal form for the quality of bowel preparation in patients scheduled for colonoscopy,identify risk factors for bowel preparation failure,and develop and validate a risk prediction model.Methods This was a prospective cohort study using convenience sampling.Patients scheduled for colonoscopy in the Digestive Department of a tertiary A hospital in Jiangsu Province from June to December 2022 were included in the modeling cohort.General information sheet and the Bristol Stool Form Scale(BSFS)were used for data collection.Patients were categorized into a successful bowel preparation group and a bowel preparation failure group based on the quality of bowel preparation.The optimal cutoff value for BSFS was determined using the best cutoff value method.Logistic regression analysis was employed to identify risk factors for bowel preparation failure,and a nomogram risk prediction model was constructed.Patients undergoing colonoscopy in the same hospital from January to February 2023 were served as the validation cohort.Results The modeling cohort included 569 patients,and the validation cohort included 212 patients,with bowel preparation failure rates of 19.0％and 19.8％,respectively.The risk prediction model formula derived from logistic regression analysis was P=-2.209+0.619 × hospitalized patients+0.635 × age≥65 years-0.710 × previous colonoscopy history+2.031 × BSFS type 1～2.The area under the receiver operating characteristic curve for the model was 0.751,with a sensitivity of 54.6％,a specificity of 85.9％,and the optimal cutoff value was 0.225,corresponding to a risk score of 80 for bowel preparation failure.The Hosmer-Lemeshow test showed x2=4.429,P=0.351.External validation demonstrated an area under the receiver operating characteristic curve of 0.775,indicating good model fit and high predictive value.Conclusion The incidence of bowel preparation failure in colonoscopy patients is relatively high.Patients aged 65 years,hospitalized patients,those with no history of colonoscopy,and those with BSFS type 1～2 are more likely to experience bowel preparation failure.The risk prediction model developed in this study has good predictive performance and can provide a basis for clinical nurses to quickly assess the risk of bowel preparation failure in patients.

OBJECTIVES: To study the efficacy and safety of repeated application of rituximab (RTX) at a low dose (200 mg/m²) versus the recommended dose (375 mg/m²) for remission maintenance in frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). METHODS: A randomized controlled trial was conducted for 29 children with FRNS/SDNS who received systemic treatment in the Department of Nephrology, Anhui Provincial Children's Hospital, from September 2020 to December 2021. These children were divided into a recommended dose group (n=14) and a low dose group (n=15) using a random number table. The two groups were compared in terms of general characteristics, changes in CD19 expression after RTX treatment, number of relapses, glucocorticoid dose, adverse reactions of RTX, and hospital costs. RESULTS: After RTX treatment, both the low dose group and the recommended dose group achieved B-lymphocyte depletion and had significant reductions in the number of relapses and glucocorticoid dose (P<0.05). The low dose group had a comparable clinical effect to the recommended dose group after RTX treatment (P>0.05), and the low dose group had a significant reduction in hospital costs for the second, third, and fourth times of hospitalization (P<0.05). There were no serious adverse reactions in either group during RTX treatment and late follow-up, and there was no significant difference in adverse reactions between the two groups (P>0.05). CONCLUSIONS Repeated RTX treatment at a low dose has comparable clinical efficacy and safety to that at the recommended dose and can significantly reduce the number of FRNS/SDNS relapses and the amount of glucocorticoids used, with little adverse effect throughout the treatment cycle. Therefore, it holds promise for clinical application.
Humans ; Child ; Nephrotic Syndrome/drug therapy* ; Rituximab/adverse effects* ; Glucocorticoids/adverse effects* ; Prospective Studies ; Adaptor Proteins, Signal Transducing

OBJECTIVES: To study the risk factors for food sensitization and the influence of food sensitization on quality of life and clinical signs in children with atopic dermatitis (AD). METHODS: A retrospective analysis was performed on the medical data of 241 children with AD, including demographic features, age of onset, severity of AD, quality of life, physical examination results, skin prick test (SPT) results, serum total IgE levels, and eosinophil count. According to the results of SPT, the children were divided into a food sensitization group (n=127) and a non-food sensitization group (n=114). The multivariate logistic regression analysis was used to identify the risk factors for food sensitization in children with AD. RESULTS: The prevalence rate of food sensitization was 52.7% (127/241) in the children with AD. The multivariate logistic regression analysis showed that birth in autumn or winter, age of onset of AD<12 months, severe AD, and total IgE>150 IU/mL were risk factors for food sensitization (P<0.05). Compared with the non-food sensitization group, the food sensitization group had a significantly poorer quality of life (P=0.008) and significantly higher prevalence rates of non-specific hand/foot dermatitis and palmar hyperlinearity (P<0.05). Compared with the single food sensitization group, the multiple food sensitization group had more severe AD and a significantly higher proportion of children with exclusive breastfeeding or total IgE>150 IU/mL (P<0.05). CONCLUSIONS The AD children born in autumn or winter, or those with early onset (<12 months), severe AD or total IgE>150 IU/mL have a higher risk of food sensitization. The AD children with food sensitization have a poorer quality of life and are more likely to develop non-specific hand/foot dermatitis and palmar hyperlinearity.
Allergens ; Child ; Cross-Sectional Studies ; Dermatitis, Atopic ; Food Hypersensitivity ; Humans ; Immunoglobulin E ; Infant ; Quality of Life ; Retrospective Studies ; Risk Factors

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC₅₀ = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

Metformin, as a first-line drug in the treatment of type 2 diabetes, is widely used in clinic with definite efficacy and few adverse reactions. In recent years, other effects besides hypoglycemia have been found, such as a possible therapeutic effect on mental disorders (e.g., anxiety disorder, Alzheimer's disease), cancer, and cardiovascular disease. It also has regulatory effects on intestinal microbiota. The purpose of this review is to summarize the recent investigations of metformin on mental disorders, cardiovascular diseases, cancer, and intestinal microbiota.

Objective:To meet the individualized needs of residents in standardized residency training of cardiac intervention specialty for cardiac ultrasound teaching, to construct a bionic 3D printing model of ultrasound source, and to discuss its application value in ultrasound teaching and simulation exercises.Methods:Sixty residents majored in cardiovascular medicine receiving standardized residency training of ultrasound in ultrasound imaging department of Renmin Hospital of Wuhan University were randomized into experimental group and control group in average. The experimental group adopted ultrasound bionic 3D printing heart model combined with problem-based learning (PBL) teaching method, and the control group adopted traditional multimedia PPT combined with PBL teaching method. At the end of teaching activities, theoretical examination, operation assessment and questionnaire survey were conducted to evaluate and compare the teaching effect between the two groups. SPSS 21.0 software was performed for t test. Results:The theoretical examination scores of the experimental group and the control group were (81.4±8.2) points and (74.8±9.4) points, respectively, P=0.002, and the operation assessment scores were (89.1±5.6) points and (71.5±8.8) points, respectively, P<0.001. The questionnaire survey showed that the experimental group had better feedbacks than the control group in the aspects of mastery of heart anatomy knowledge, learning experience, learning interest, learning efficiency, understanding of interventional heart disease, clinical skills of interventional operation and overall satisfaction (all P<0.05). Conclusions:Ultrasound bionic 3D printing combined with PBL teaching method can help strengthen the mastery of cardiac anatomy knowledge, promote the learning experience of cardiac ultrasound and improve the skills of interventional operation. The teaching effect is significant and the students' satisfaction is high.

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPAR agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC values <5 nmol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound , the most effective one, gave the IC of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure-activity relationships and provide evidence for further structural modifications.

OBJECTIVETo assess the value of blood glucose at different time points in oral glucose tolerance test (OGTT), particularly one?hour post load plasma glucose (1 hPG), in evaluating glucose metabolism in adult patients with obstructive sleep apnea (OSA).

METHODSEighty nine adultswith newly diagnosed OSA were analyzed retrospectively for sleep architecture assessed using polysomnography and glucose metabolism assessed by OGTT at different time points (0, 30, 60, 120, and 180 min). Pearson's correlatives and multiple linear regression models were established to investigate the correlations between glucose metabolism and other indices including sleep architecture, apnea hypopnea index (AHI), mean and lowest oxygen saturation (MSOand LSO) and obesity measurements.

RESULTSThe majority (67.4%) of the patients had abnormal 1 hPG, and 41.6% had abnormal 2 hPG. 1 hPG was positively correlated with neck circumference (r=0.245), abdomen circumference (r=0.231), systolic blood pressure (r=0.213), diastolic blood pressure (r=0.276) and AHI (r=0.324), and was negatively associated with MSO(r=-0.341) and LSO(r=-0.387) (all P<0.05). After controlling for age, BMI, neck and abdomen circumferences, 1 hPG was found to inversely correlated with MSO(r=-0.253, P=0.032) and LSO(r=-0.311, P=0.008). In non-obese OSA subgroup, 1 hPG was significantly associated with OSA-related indices, and regression models showed that LSOand N2 were the two most important contributors to 1 hPG (adjusted R=0.349, P<0.001); plasma glucose at other time points did not show such correlations.

CONCLUSIONS1 hPG abnormality occurs earlier than 2 hPG in OSA patients. 1 hPG is significantly associated with OSA independent of obesity and may serve as a better index for measuring OSA-related glucose disorder.