OBJECTIVES: To investigate the role and mechanism of copper overload-mediated endoplasmic reticulum stress (ERS) in vascular endothelial injury in Kawasaki disease (KD). METHODS: Four-week-old male C57BL/6 mice were randomly divided into four groups: control, KD, KD plus copper chelator tetrathiomolybdate (TTM), and KD plus ERS inhibitor AMG PERK 44 (AMG) (n=20 per group). A KD mouse model was established using Candida albicans extract. Human umbilical vein endothelial cells (HUVECs) were divided into control (intervention with healthy children's serum), KD (intervention with KD patients' serum), and KD+TTM (intervention with KD patients' serum plus 20 µmol/L TTM). Copper deposition in mouse heart tissue was assessed using rubeanic acid staining. Vascular pathological changes were observed using hematoxylin-eosin staining and measurement of abdominal aortic diameter and area. ERS activation was detected by transmission electron microscopy and immunofluorescence. HUVEC viability, apoptosis, and functional changes were evaluated using CCK8, flow cytometry, cell scratch assay, and angiogenesis experiments. ERS marker protein expression levels were measured by Western blot. RESULTS: Compared to the KD group, the KD+TTM and KD+AMG groups showed reduced copper deposition in the vascular wall, decreased swelling of coronary endothelial cells and endoplasmic reticulum, reduced inflammatory cell infiltration, and less abdominal aortic lesion expansion. The abdominal aortic diameter and area, and the fluorescence intensity of ERS marker proteins (GRP78 and CHOP) were significantly lower (P<0.05). Compared to the KD group, the KD+TTM group exhibited increased cell viability, tube number, and scratch healing rate, along with decreased apoptosis rate and expression of ERS marker proteins (GRP78, CHOP, ATF6, and p-PERK) (P<0.05). CONCLUSIONS Copper overload aggravates vascular endothelial injury in KD by activating the ERS pathway. TTM can exert protective effects on the endothelium by regulating copper metabolism and inhibiting the ERS pathway.
Endoplasmic Reticulum Stress ; Copper/toxicity* ; Male ; Mucocutaneous Lymph Node Syndrome/metabolism* ; Animals ; Humans ; Endoplasmic Reticulum Chaperone BiP ; Mice, Inbred C57BL ; Mice ; Human Umbilical Vein Endothelial Cells ; Apoptosis ; Endothelium, Vascular/injuries*

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5^492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
Animals ; Disease Models, Animal ; Mice ; Protein Serine-Threonine Kinases/deficiency* ; Mutation/genetics* ; Epileptic Syndromes/genetics* ; Humans ; Dendritic Spines/pathology* ; Spasms, Infantile/genetics* ; Male ; Seizures/genetics* ; Mice, Inbred C57BL

AIM To determine the contents of aspartic acid,glutamic acid,serine,glycine,threonine,citrulline,arginine,alanine,γ-amino-butyric acid,tyrosine,valine,phenlalanine,isoleucine,ornithine,leucine,lysine and proline in Gualoupi Injection and its intermediates,and to analyze their change laws.METHODS The OPA-FMOC online derivatization analysis was performed on a 45℃ thermostatic Waters XBridge C18 column(4.6 mm×100 mm,3.5 μm),with the mobile phase comprising of phosphate buffer solution-[methanol-acetonitrile-water(45 : 45 : 10)]flowing at 1 mL/min in a gradient elution manner,and the detection wavelengths were set at 262,338 nm.Principal component analysis and heatmap analysis were adopted in chemical pattern recognition for the corresponding intermediates in ten processes of six batches of samples.RESULTS Seventeen amino acids showed good linear relationships within their own ranges(R2>0.998 0),whose average recoveries were 83.4％-119.5％with the RSDs of 0.91％-7.94％.Different batches of samples in the same process were clustered,and the corresponding intermediates in different processed were clustered into three groups.Alcohol precipitation and cation exchange column demonstrated the biggest influences on amino acid composition.CONCLUSION This experiment can provide important references for the critical factors on quality control of Gualoupi Injection,thus ensure the stability and uniformity of final product.

BACKGROUND: Butylphthalide (NBP) and edaravone (EDV) injection are common acute ischemic stroke medications in China, but there is a lack of large real-world safety studies on them. This study aimed to determine the incidence of adverse events, detect relevant safety signals, and assess the risk factors associated with these medications in real-world populations. METHODS: In this study, data of acute ischemic stroke patients were extracted from the electronic medical record database of six tertiary hospitals between January 2019 and August 2021. Baseline confounders were eliminated using propensity score matching. The drugs' safety was estimated by comparing the results of 24 laboratory tests standards on liver function, kidney function, lipid level, and coagulation function. The drugs' relative risk was estimated by logistic regression. A third group with patients who did not receive NBP or EDV was constructed as a reference. Prescription sequence symmetry analysis was used to evaluate the associations between adverse events and NBP and EDV, respectively. RESULTS: 81,292 patients were included in this study. After propensity score matching, the NBP, EDV, and third groups with 727 patients in each group. Among the 15 test items, the incidence of adverse events was lower in the NBP group than in the EDV group, and the differences were statistically significant. The multivariate logistic regression equation revealed that NBP injection was not a promoting factor for abnormal laboratory test results, whereas EDV had statistically significant effects on aspartate transaminase, low-density lipoprotein cholesterol and total cholesterol. Prescription sequence symmetry analysis showed that NBP had a weak correlation with abnormal platelet count. EDV had a positive signal associated with abnormal results in gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and platelet count. CONCLUSIONS In a large real-world population, NBP has a lower incidence of adverse events and a better safety profile than EDV or other usual medications.

Pediatric acute hyperextension spinal cord injury (SCI) named as PAHSCI by us, is a special type of thoracolumbar SCI without radiographic abnormality and highly related to back-bend in dance training, which has been increasingly reported. At present, it has become the leading cause of SCI in children, and brings a heavy social and economic burden. Both domestic and foreign academic institutions and dance education organizations lack a correct understanding of PAHSCI and relevant standards, specifications or guidelines. In order to provide standardized guidance, the expert team formulated this guideline based on the principles of science and practicability, starting from the diagnosis, differential diagnosis, etiology, admission evaluation, treatment, complications and prevention. This guideline puts forward 23 recommendations for 14 related issues.
Child ; Humans ; Spinal Cord Injuries/complications* ; Spinal Cord

A hydrophilic interaction chromatography tandem mass spectrometry method was developed for simultaneous quantification of 35 components in gualoupi injection. The analytes were separated with an ACQUITY XBridge Amide column using 20 mmol·L^-1 ammonium formate aqueous solution (pH 3.0) as mobile phase A and 20 mmol·L^-1 ammonium formate (pH 3.0)∶acetonitrile (1∶9) as mobile phase B for gradient elution. Mass spectrometry with dynamic multiple reaction monitoring and external standard method were used for quantitative analysis. A total of 35 components were determined in 10 batches of gualoupi injection. The results showed that the 35 compounds had a good linear relationship within their respective concentration ranges with the correlation coefficients (R² > 0.998 0), the recoveries ranged from 76.6% to 118.5%. The results showed that γ-aminobutyric acid, trigonelline, alanine, threonine, homoserine, citrulline, and leucine were abundant in gualoupi injection, while nicotinamide, methylsuccinic acid, cytosine and choline account for a low percentege. The present study provides an important reference for elucidation of the effective material basis and the improvement of quality standard of gualoupi injection.

Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses

Current treatments for cancer and the central nervous system diseases are limited,partly due to the difficulties posed by the insolubility,poor distribution of drugs among cells and lack of selectivity of drugs,the inability of drugs to cross cellular barriers and blood brain barrier (BBB).Carbon nanotubes (CNTs) possess many distinct properties including good electronic properiies,remarkably penetrating capability on the cell membrane,high drug-loading and pH-dependent therapeutic unloading capacities,thermal properties,large surface area and easy modification with molecules,which render them as a suitable candidate to deliver drugs to cancer and brain.CNTs as a drug delivery could achieve a high efficacy,enhance specificity and diminish side effects.Whereas CNTs have been primarily employed in cancer treatment,a few studies have focused on the treatment and diagnosis of the central nervous system diseases using CNTs.Here,we review the current progress of in vitro and in vivo researches of CNTs-based drug delivery to cancer involving CNTs-based tumor-targeted drug delivery systems (DDS),photodynamic therapy (PDT) and photothermal therapy (PTT).Meanwhile,we also review the current progress of in vitro and in vivo researches of CNTs-based drug delivery to brain.

BACKGROUNDOptimizing treatment outcomes for depression requires understanding of how evidence-based treatments are utilized in clinical practice. Antipsychotic medications concurrent with antidepressant treatment are frequently used in major depression, but few studies have investigated trends and patterns of their use over time. This study aimed to examine the prescription patterns of antipsychotic medications for major depression in China from 2002 to 2012 and their association with treatment satisfaction and quality of life (QOL).

METHODSA total of 3655 subjects with major depression treated in 45 Chinese psychiatric hospitals/centers nationwide were interviewed between 2002 and 2012. Patients' socio-demographic and clinical characteristics including psychopathology, medication side effects, satisfaction with treatment and QOL were recorded using a standardized protocol and data collection.

RESULTSThe frequency of antipsychotic use was 24.9% in the whole sample; the corresponding figures were 17.1%, 20.3%, and 32.8% in 2002, 2006, and 2012, respectively (χ2 = 90.3, df = 2, P < 0.001). Multiple logistic regression analyses revealed that patients on concurrent antipsychotics had significantly more delusions or hallucinations, longer illness duration, greater side effects, and more likely to be treated as inpatients and in major hospitals (i.e., Level-III hospital). Antipsychotic use was associated with lower treatment satisfaction while there was no significant difference with respect to physical and mental QOL between the antipsychotic and nonantipsychotic groups.

CONCLUSIONSConcurrent antipsychotic use was found in about one in four treated depressed patients in China, which has increased over a 10-year period. Considering the association of drug-induced side effects and the lack of patients' and relatives' satisfaction with antipsychotic treatment, further examination of the rationale and appropriateness of the use of antipsychotics in depression is needed.

Adult ; Antipsychotic Agents ; therapeutic use ; Depressive Disorder, Major ; drug therapy ; Female ; Humans ; Male ; Middle Aged ; Personal Satisfaction ; Psychotropic Drugs ; therapeutic use ; Quality of Life

BACKGROUNDThe continual and rapid development of techniques which are used for diagnosis and treatment makes management of colorectal cancer more difficult depending on single discipline. Colorectal cancer multidisciplinary team (MDT) working model is recommended by UK and other countries, but there is little information on the impact of MDT working on management of colorectal cancer in China. The aim of this study was to assess the effect on management of colorectal cancer after the inception of an MDT.

METHODSA total of 595 consecutive colorectal cancer patients were referred to the Department of Gastroenterological Surgery, the pre-MDT cohort include 297 patients, recruited from January 1999 to November 2002, and the MDT cohort had 298 patients enrolled from December 2002 to September 2006. Information recorded included: TNM stage from histological reports, degree of differentiation, the number of examined lymph nodes and CT TNM staging performed or not, and its accuracy, including local and distant recurrence.

RESULTSThe number of examined lymph nodes and the accuracy of TNM staging by CT in the MDT group were significantly more than those in pre-MDT group. CT TNM staging was more accurate in the MDT group compared to the pre-MDT group (P = 0.044). The rate of tumor recurrence in the MDT group was lower than pre-MDT group (log-rank test, P < 0.001). Multivariate analysis revealed that age (P = 0.001), management after inception of the MDT (P = 0.002), degree of differentiation (P = 0.003), number of examined lymph nodes (P = 0.002), and TNM stage (P = 0.000) were important factors that independently influence overall survival.

CONCLUSIONSThe inception of MDT working improved the diagnostic accuracy and overall survival of colorectal cancer patients. MDT working promoted communication and cooperation between disciplines and ensured high-quality diagnosis, evidence-based decision making, and optimal treatment planning.

Aged ; Colorectal Neoplasms ; diagnostic imaging ; pathology ; surgery ; Disease Management ; Female ; Humans ; Interdisciplinary Communication ; Male ; Middle Aged ; Neoplasm Staging ; Radiography ; Treatment Outcome