Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

Image 1.

Objective:To investigate the relationship between positive asthma prediction index (API) and single nucleotide polymorphisms (SNPs) of interleukin (IL-13), IL-4, β 2 adrenergic receptor (ADRB2), and type I Fc ε receptor β (FcER1B) genes in asthmatic children.Methods:A prospective study was conducted on 102 asthmatic children under 5 years old admitted to Zhongshan Boai Hospital and Foshan First People′s Hospital (51 cases were API positive and 51 cases were API negative) from January 2020 to August 2023. Oral and buccal mucosal exfoliated cells were collected from the children, and genomic DNA was extracted using magnetic bead method. Four gene loci (IL-13 rs20541, IL-4 rs2243250, ADRB2 rs1042713, FcER1B rs569108) were genotyped using a matrix assisted laser desorption ionization time-of-flight mass spectrometer. Logistic regression analysis was used to evaluate the correlation between SNP typing at these four gene loci and API positivity in asthmatic children.Results:There was a statistically significant difference in the SNP typing and allele distribution frequency of IL-13 rs20541, IL-4 rs2243250, ADRB2 rs1042713, FcER1B rs569108 between the API positive and API negative groups of wheezing children (all P<0.05). Among API positive children, the proportion of IL-13 rs20541 site was higher in GG type, the proportion of IL-4 rs2243250 site was higher in TT type, the proportion of ADRB2 rs1042713 site was higher in AG type, and the proportion of FcER1B rs569108 site was higher in AA type; The results of logistic regression analysis showed that IL-13 rs20541 GG type, IL-4 rs2243250 TT type, FcER1B rs569108 AA type were associated with the risk of API positivity in asthmatic children (all P<0.05). Conclusions:IL-13, IL-4, and FcER1B genes are risk genes for the development of API positive wheezing in children under 5 years old. SNP typing of these genes can be used to evaluate the risk of API positivity in clinical practice.

Objective:To investigate the satisfaction levels of the rural elderly in Dafeng district of Yancheng, Jiangsu province with the contracted family doctor services, and to identify the factors that influence their satisfaction.The findings of this study will provide valuable insights for improving the quality of the contracted family doctor services offered to the rural elderly population.Methods:The study utilized the stratified cluster sampling method to select elderly individuals aged 60 years and above from Dafeng district, Yancheng city for a questionnaire survey.Specifically, the study focused on elderly individuals who had participated in contracted family doctor services for more than six months.The survey aimed to gather information on the elderly population's general situation, as well as their understanding, utilization, and satisfaction with contracted family doctor services.The satisfaction of contracted family doctor services was analyzed using the chi square test and multivariate Logistic regression to identify the influencing factors.Results:The study surveyed 385 elderly individuals from rural areas who had contracted family doctor services.The results showed that 88.3%(340/385)of respondents were satisfied with the services they received.Additionally, 99.2%(382/385)of those surveyed were aware of the contracted family doctor services, and 81.8%(315/385)had received basic medical services from their signed-up doctors.The results of a multifactor analysis that examined the factors influencing the overall satisfaction of elderly patients with their contracted family doctor services revealed several significant factors.Specifically, being female( OR=2.557, 95% CI: 1.122-5.830, P=0.026)and unmarried( OR=7.355, 95% CI: 1.850-29.237, P=0.005), supporting the contracted family doctor services system( OR=18.442, 95% CI: 1.732-195.973, P=0.016), believing that the contracted medical institutions had excellent hardware facilities( OR=9.918, 95% CI: 2.313-42.526, P=0.002)and providing high-quality health services for the elderly( OR=8.723, 95% CI: 1.556-48.908, P=0.014), as well as experiencing improved health status after signing the contract( OR=5.006, 95% CI: 1.764-14.201, P=0.002)were all significant factors influencing their satisfaction.These findings suggest that these factors are important considerations for improving the satisfaction of elderly patients with their contracted family doctor services. Conclusions:The contracted family doctor services provided in Dafeng district, Yancheng city have been well received by the rural elderly population.Factors such as gender, marital status, attitude towards the contracted family doctor services system, improvements in health status after contracting the service, quality of the hardware facilities at the contracted medical institution, and availability of health services specifically tailored for the elderly all play a role in determining the level of satisfaction among the contracted elderly population.To better serve the elderly population, it is crucial that we prioritize their needs.This can be achieved by improving the level of "suitable aging" in the contracted services and enhancing the satisfaction of family doctors who provide these services.

Objective:To investigate the clinical and electrophysiological characteristics of patients with amyotrophic lateral sclerosis (ALS) with positive repetitive nerve stimulation (RNS) test results on the accessory nerve and negative needle electromyography (EMG) test results on the sternocleidomastoid with the goal to enrich the knowledge of disease progression in patients with ALS.Methods:The clinical data of 612 patients diagnosed with ALS at the Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to August 2022 were collected. In total, 267 cases had undergone EMG tests on the sternocleidomastoid following a positive 3 Hz RNS test result on the accessory nerve, who were selected as the study subjects. The differences in clinical indicators were compared between RNS (+)/EMG (-) group and RNS (+)/EMG (+) group. A binomial distribution model with multiple variables was built to quantitatively analyze the major factors and their effects.Results:At the initial visit, 15.8% of patients with ALS were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid, accounting for 36.3% of RNS (+) patients. The decremental range of the 3 Hz RNS test delivered to the accessory nerve in these patients [-14% (-19%, -12%)] was lower than that in patients with RNS (+)/EMG (+) [-17% (-23%, -13%)] ( P<0.05), while the ratio of upper limb onset (64.9%) and non-definite diagnosis (28.9%) were higher [54.7% and 13.5% for patients with RNS (+)/EMG (+), P<0.05]. Furthermore, the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score [40 (37, 42)], body mass index (BMI) [23.8 (22.0, 25.4) kg/m 2] and forced vital capacity (FVC) [92.8% (76.6%, 103.8%)] were higher in patients with RNS(+)/EMG(+) ( P<0.05). The multivariate model suggested that, in patients with RNS (+)/EMG (-), the ratio of upper limb onset to lower limb onset was 1.04, while that of upper limb onset to bulbar onset was 2.02, and that of lower limb onset to bulbar onset was 1.94. The ratio of non-definite ALS to definite ALS was 1.13. The ALSFRS-R score, BMI, and FVC had a protective contribution to the electrophysiological function of the motor neurons. The ratio of the effect size of the ALSFRS-R or BMI to that of FVC was 3.37 and 1.14, respectively. Conclusions:Patients with ALS that were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid had a smaller decremental range of the compound muscle action potential amplitude, and a higher proportion of upper limb onset and non-definite ALS. A higher ALSFRS-R score, BMI, and FVC have a protective effect to the electrophysiological function of motor neurons. The effect size of the ALSFRS-R score is the largest, followed by BMI and FVC.

Objective:To investigate the intention to stay on among primary health care workers (PHWs) during the COVID-19 epidemics and its influencing factors.Methods:An online questionnaire survey was conducted among PHWs from 62 primary health institutions in 31 provinces, autonomous regions and municipalities across China selected by multi-stage whole cluster random sampling method between May and October 2022. According to the job position, the PHWs were divided into 5 categories: general practitioners (GPs), nurses, public health doctors, managers and support staff. Intention to stay was measured using the Chinese version of the Intention to Stay Questionnaire. Multiple linear regression model was used to analyze the influencing factors of the intention to stay in PHWs of different occupational categories, including personal factors, work factors, factors related to the COVID-19 and psychological reactions.Results:A total of 3 769 PHWs from 44 community health service centers, 18 township hospitals of 27 provinces/autonomous regions and 4 municipalities participated in this survey. The mean age of participants was (37.4±9.2) years, including 2 971(78.8%) women. The mean score of intention to stay of participants was 21.7±4.1. Compared with GPs, managers had lower intention to stay ( P=0.004). Age, female, in marriage, monthly income, years of primary care service, self-evaluation of unit support function, MSQ-SF score, and PA score were positively correlated with the score of intention to stay (all P<0.05), while PHQ-9 score, EE score, and DP score were negatively correlated with the score of intention to stay (all P<0.05). The MSQ-SF scores of all occupational categories were positively correlated with the scores of intention to stay (all P<0.01). In addition, among GPs, monthly income, years of service in primary care, self-evaluation of unit support function, and PA scores were positively correlated with the score of intention to stay (all P<0.05), while PHQ-9 scores and EE scores were negatively correlated with the score of intention to stay (all P<0.05). Among nurses, age, female gender, monthly income, self-evaluation of unit support function, and PA score were positively correlated with the score of intention to stay (all P<0.05), while EE scores and retention will score were negatively associated with ( P<0.001). Among public health doctors, in marriage was positively correlated with the score of intention to stay ( P=0.018). Among managers, DP score was negatively correlated with the score of intention to stay ( P=0.001). Among support staff, female gender, monthly income, years of primary care service, self-evaluation of unit support function, and PA scores were positively correlated with the score of intention to stay (all P<0.05), while EE score and DP score were negatively correlated with intention to stay (all P<0.05). Conclusions:The intention to stay of PHWs in China during the COVID-19 was at an intermediate level, which was affected by many factors. Among them, job satisfaction was positively correlated with the intention to stay of all occupational categories, and the influencing factors of different occupational categories have some variations.

Objective:To investigate the value of soluble interleukin-6 (IL-6) receptor (sIL-6R) level in predicting ultrafiltration insufficiency in peritoneal dialysis (PD) patients.Methods:It was a prospective cohort study. The patients who received continuous ambulatory PD and regular follow-up between November 2016 and July 2018 in the PD Center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University were enrolled. Enzyme-linked immunosorbent assay was used to determine dialysate sIL-6R and its appearance rate (AR) was calculated. Patients were divided into high sIL-6R AR group and low sIL-6R AR group according to median value of sIL-6R AR and prospectively followed up until death, PD cessation, or the end of the study (December 31, 2022). Multiple linear regression was used to analyze the related factors of sIL-6R AR. Kaplan-Meier method and log-rank test were used to compare the survival rate difference of ultrafiltration insufficiency between high sIL-6R AR group and low sIL-6R AR group. Multivariate Cox regression and multivariate competing risk models were used to assess the risk factors associated with occurrence of ultrafiltration insufficiency.Results:A total of 198 PD patients were enrolled, including 115 (58.1%) males, with age of (54.9±13.7) years old and PD duration of 22.5 (6.6, 65.0) months. The sIL-6R AR of the cohort was 2 094.7 (1 672.4, 2 920.9) pg/min. Compared with low sIL-6R AR（<2 094.7 pg/min）group, high sIL-6R AR（>2 094.7 pg/min）group had older age ( t=-3.269, P=0.001), higher body mass index ( t=-3.248, P=0.001), proportion of combined diabetes mellitus ( χ2=8.890, P=0.003), 24 h glucose exposure ( Z=-2.257, P=0.024), 24 h ultrafiltration capacity ( Z=-2.515, P=0.012), 4 h dialysate creatinine to serum creatinine ratio ( t=-2.609, P=0.010), mass transfer area coefficient of creatinine ( Z=-2.308, P=0.021), IL-6 AR ( Z=-3.533, P<0.001) and solute glycoprotein 130 AR ( Z=-8.670, P<0.001), and lower serum albumin ( t=2.595, P=0.010) and residual renal function ( t=2.133, P=0.033). Multiple linear regression analysis showed that body mass index ( β=0.194, P=0.005), serum albumin ( β=-0.215, P=0.002) and dialysate lg[IL-6 AR] ( β=0.197, P=0.011) were independently correlated with sIL-6R AR. By the end of the study, 57 (28.8%) patients developed ultrafiltration insufficiency. Kaplan-Meier analysis showed that high sIL-6R AR group had a significantly inferior ultrafiltration insufficiency-free survival rate than that in low sIL-6R AR group (log-rank χ 2=5.375, P=0.020). Multivariate Cox regression analysis and multivariate competing risk models showed that high dialysate sIL-6R AR (>2 094.7 pg/min) was an independent influencing factor of ultrafiltration insufficiency ( HR=2.286 , 95% CI 1.254-4.165 , P=0.007 ; SHR=2.074, 95% CI 1.124-3.828, P=0.020) in PD patients. Conclusions:Dialysate sIL-6R level was associated with body mass index, serum albumin and dialysate IL-6 level. Dialysate sIL-6R may be a predictive factor of ultrafiltration insufficiency in PD patients.

Objective:To analyze the clinical characteristics of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.Methods:Three patients with IPEX syndrome diagnosed at the Children′s Hospital of Fudan University from January 24, 2013 to July 29, 2019 were selected as the study subjects. Their clinical features, laboratory investigations and results of genetic testing were summarized. Treatment and prognosis were also explored.Results:All of the three children had developed the disorder during infancy. One child had initial features including diabetes and diabetic ketoacidosis, whilst the other two had initiated by diarrhea. All patients had gastrointestinal involvement, and one was diagnosed as very early onset inflammatory bowel disease by colonoscopy and biopsy. Two children also had endocrine glands involvement. One child had manifested type 1 diabetes and positivity for thyroglobulin and thyroid peroxidase antibodies, though his thyroid function had remained normal. Another one had hypothyroidism and was treated by levothyroxine. Genetic testing revealed that all children had harbored missense variants of the FOXP3 gene, including c. 1222G>A (p.V408M), c. 767T>C (p.M256T) and c. 1021A>G (p.T341A). The clinical symptoms of one patient were alleviated following allogeneic hematopoietic stem cell transplantation. One patient was stable after treatment with infliximab plus insulin, and one child had died of refractory septic shock and multiple organ dysfunction syndrome at 3 months old. Conclusion:FOXP3 gene variant-associated IPEX syndrome may have very early onset and diverse clinical manifestations. For male patients with infantile onset chronic diarrhea, multiple endocrine or multiple system involvement, genetic testing is recommended, which may facilitate early diagnosis, treatment and genetic counseling.