PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
Humans ; Cell Membrane ; Mutation, Missense ; Phosphates/metabolism* ; Sodium-Phosphate Cotransporter Proteins, Type III/genetics*

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.
Animals ; Brain Diseases/therapy* ; Xenotropic and Polytropic Retrovirus Receptor ; Brain/pathology*

Objective: To analyze the clinical epidemiological characteristics including composition of pathogens , clinical characteristics, and disease prognosis acute bacterial meningitis (ABM) in Chinese children. Methods: A retrospective analysis was performed on the clinical and laboratory data of 1 610 children <15 years of age with ABM in 33 tertiary hospitals in China from January 2019 to December 2020. Patients were divided into different groups according to age,<28 days group, 28 days to <3 months group, 3 months to <1 year group, 1-<5 years of age group, 5-<15 years of age group; etiology confirmed group and clinically diagnosed group according to etiology diagnosis. Non-numeric variables were analyzed with the Chi-square test or Fisher's exact test, while non-normal distrituction numeric variables were compared with nonparametric test. Results: Among 1 610 children with ABM, 955 were male and 650 were female (5 cases were not provided with gender information), and the age of onset was 1.5 (0.5, 5.5) months. There were 588 cases age from <28 days, 462 cases age from 28 days to <3 months, 302 cases age from 3 months to <1 year of age group, 156 cases in the 1-<5 years of age and 101 cases in the 5-<15 years of age. The detection rates were 38.8% (95/245) and 31.5% (70/222) of Escherichia coli and 27.8% (68/245) and 35.1% (78/222) of Streptococcus agalactiae in infants younger than 28 days of age and 28 days to 3 months of age; the detection rates of Streptococcus pneumonia, Escherichia coli, and Streptococcus agalactiae were 34.3% (61/178), 14.0% (25/178) and 13.5% (24/178) in the 3 months of age to <1 year of age group; the dominant pathogens were Streptococcus pneumoniae and the detection rate were 67.9% (74/109) and 44.4% (16/36) in the 1-<5 years of age and 5-<15 years of age . There were 9.7% (19/195) strains of Escherichia coli producing ultra-broad-spectrum β-lactamases. The positive rates of cerebrospinal fluid (CSF) culture and blood culture were 32.2% (515/1 598) and 25.0% (400/1 598), while 38.2% (126/330)and 25.3% (21/83) in CSF metagenomics next generation sequencing and Streptococcus pneumoniae antigen detection. There were 4.3% (32/790) cases of which CSF white blood cell counts were normal in etiology confirmed group. Among 1 610 children with ABM, main intracranial imaging complications were subdural effusion and (or) empyema in 349 cases (21.7%), hydrocephalus in 233 cases (14.5%), brain abscess in 178 cases (11.1%), and other cerebrovascular diseases, including encephalomalacia, cerebral infarction, and encephalatrophy, in 174 cases (10.8%). Among the 166 cases (10.3%) with unfavorable outcome, 32 cases (2.0%) died among whom 24 cases died before 1 year of age, and 37 cases (2.3%) had recurrence among whom 25 cases had recurrence within 3 weeks. The incidences of subdural effusion and (or) empyema, brain abscess and ependymitis in the etiology confirmed group were significantly higher than those in the clinically diagnosed group (26.2% (207/790) vs. 17.3% (142/820), 13.0% (103/790) vs. 9.1% (75/820), 4.6% (36/790) vs. 2.7% (22/820), χ²=18.71, 6.20, 4.07, all P<0.05), but there was no significant difference in the unfavorable outcomes, mortility, and recurrence between these 2 groups (all P>0.05). Conclusions: The onset age of ABM in children is usually within 1 year of age, especially <3 months. The common pathogens in infants <3 months of age are Escherichia coli and Streptococcus agalactiae, and the dominant pathogen in infant ≥3 months is Streptococcus pneumoniae. Subdural effusion and (or) empyema and hydrocephalus are common complications. ABM should not be excluded even if CSF white blood cell counts is within normal range. Standardized bacteriological examination should be paid more attention to increase the pathogenic detection rate. Non-culture CSF detection methods may facilitate the pathogenic diagnosis.
Adolescent ; Brain Abscess ; Child ; Child, Preschool ; Escherichia coli ; Female ; Humans ; Hydrocephalus ; Infant ; Infant, Newborn ; Male ; Meningitis, Bacterial/epidemiology* ; Retrospective Studies ; Streptococcus agalactiae ; Streptococcus pneumoniae ; Subdural Effusion ; beta-Lactamases

OBJECTIVE：To evaluate the efficacy and safety of atomization inhalation of polymyxin combined in the adjunctive treatment for ventilator-associated pneumonia ，and to provide evidence-based reference for clinical treatment. METHODS ： Retrieved from Cochrane Library ，Embase，PubMed，Web of Science ，CNKI，CBM，VIP and Wanfang database （from their inception to March 2021），randomized controlled trials （RCTs）about efficacy and safety of atomization inhalation of polymyxin combined with conventional treatment （trial group ） versus conventional treatment （control group ） for ventilator- associated pneumonia were collected. After data extraction and quality evaluation of included literatures met inclusion and exclusion criteria ， Meta-analysis was performed by using Rev Man 5.4 software. RESULTS ：A total of 13 clinical studies were included ，involving 2 RCTs and 11 cohort studies with a total of 1 066 patients. The results of Meta-analysis showed that clinical response rate [OR ＝ 1.53，95％CI（1.17，2.00），P＝0.002]，microbial clearance rate [OR ＝1.46，95％CI（1.11，1.91），P＝0.007] of trial group were significantly higher than those of control group ，with statistical significance. There was no statistical significance in the mortality rate [OR ＝0.88，95％CI（0.68，1.14），P＝0.32] and the incidence of renal impairment [OR ＝1.04，95％CI（0.72，1.49），P＝0.85] between 2 groups. CONCLUSIONS ：Based on current evidence ，atomization inhalation of polymyxin combined with conventional treatment can significantly improve clinical response rate and microbial clearance rate of patients with ventilator- associated pneumonia. However ， more strictly-designed ， long-term follow-up and large-scale RCTs are needed.

Objective To establish an artificial intelligence model based on B-mode thyroid ultrasound images to predict central compartment lymph node metastasis(CLNM)in patients with papillary thyroid carcinoma(PTC). Methods We retrieved the clinical manifestations and ultrasound images of the tumors in 309 patients with surgical histologically confirmed PTC and treated in the First Medical Center of PLA General Hospital from January to December in 2018.The datasets were split into the training set and the test set.We established a deep learning-based computer-aided model for the diagnosis of CLNM in patients with PTC and then evaluated the diagnosis performance of this model with the test set. Result The accuracy,sensitivity,specificity,and area under receiver operating characteristic curve of our model for predicting CLNM were 80%,76%,83%,and 0.794,respectively. Conclusion Deep learning-based radiomics can be applied in predicting CLNM in patients with PTC and provide a basis for therapeutic regimen selection in clinical practice.
Artificial Intelligence ; Humans ; Lymph Nodes/diagnostic imaging* ; Lymphatic Metastasis ; Retrospective Studies ; Risk Factors ; Thyroid Cancer, Papillary/diagnostic imaging* ; Thyroid Neoplasms/diagnostic imaging*

As a common tonic traditional Chinese medical herb,Polygoni Multiflori Radix has been extensively applied in clinic. In recent years,there have been many literatures related to Polygoni Multiflori Radix. By reviewing the literatures in domestic and foreign,the latest progress on chemical components and pharmacology of Polygoni Multiflori Radix have been summarized and analyzed. At present,more than 133 kinds of compounds have been isolated from Polygoni Multiflori Radix, such as stilbene glycosides,terpenoids,flavonoids,phospholipids and phenylpropanoids. Among them, stilbene dimer and dianthrone glycosides are two kind of new compounds recently isolated from it. The current researches about the pharmacological effect of Polygoni Multiflori Radix focus on anti-oxidative,anti-tumor,anti-atherosclerosis and neuro-protective effects,with potentials in treating neurodegenerative diseases, preventing and treating arterial and reducing blood sugar. Its medicinal ingredients mainly include stilbene glycosides,terpenoids and flavonoids,in which 2,3,5,4'-tetrahydroxysilbene 2-O-glucopyranoside shows a variety of biological activities. However,there are a few studies on the pharmacological activities of other compounds. Therefore,to ensure the further development and utilization of Polygoni Multiflori Radix,it is suggested to conduct a more in-depth and comprehensive research on the material basis of its efficacy.

OBJECTIVE: To investigate the effects of aminooxyacetic acid (AOAA) on learning and memory ability and possible mechanisms in rats with chronic alcoholism. METHODS: Sixty SD male rats were randomly divided into three groups on average.The model group rats and the remedy group rats were fed with the water containing (v/v) 6% alcohol for 28 days.After 14 days, the remedy group rats were treated with AOAA (5 mg/kg·d) by intraperitoneal injection once a day for 14 days and the other two group rats were treated with the equal amount of saline by intraperitoneal injection every day.Five days before the end of the experiment, the water maze test was carried out to test the learning and memory ability of rats for 5 days.Subsequently, the content of HS, the activity of ATP enzyme and the expression of 5-HT in hippocampus were measured. RESULTS: Compared with the rats in the control group, the latency and the swimming distance of the 2nd to the 4th day, the content of HS in hippocampus of rats in the model group were all increased, the mitochondrial ATP enzyme activity in hippocampus and the positive expression of 5-HT in hippocampus CA1 and CA3 of rats in the model group were decreased (<0.01).Compared with the rats in the model group, the latency and the swimming distance of the 2nd to the 4th day, the content of HS in hippocampus of the rats in the remedy group were decreased, the mitochondrial ATP enzyme activity in hippocampus and the positive expression of 5-HT in hippocampus CA1 and CA3 of rats in the model group were increased (<0.01). CONCLUSIONS AOAA could alleviate the symptoms of chronic alcoholism rats, which may be related to the effects of AOAA on the content of HS, the mitochondrial enzyme activity and the expression of 5-HT in hippocampus.
Alcoholism ; Aminooxyacetic Acid ; Animals ; Hippocampus ; Learning ; Male ; Maze Learning ; Memory ; Rats ; Rats, Sprague-Dawley

Objective To investigate the value of corneal laser confocal microscope in the diagnosis of corneal subepithelial plexus,corneal cell density and morphological changes of patients with diabetic retinopathy (DR).Methods Together 94 cases of confirmed DR (114 eyes),including 41 cases of non-proliferative diabetic retinopathy (NPDR group,52 eyes) and 53 cases of proliferative diabetic retinopathy (PDR group,62 eyes) were selected from January 2016 to April 2017,and meanwhile,40 diabetic patients (40 eyes) with no fundus abnormality were grouped as control group.Corneal laser confocal microscopy was used to compare the corneal subepithelial plexus,corneal cell density and morphological changes in the three groups,Results The cell densities of the basal layer,the superficial stromal layer,the medium stromal layer and the deep stromal layer of the cornea in NPDR and PDR were significantly lower than those of the control group (all P ＜ 0.05),and the PDR group was significantly lower than the NPDR group (all P ＜ 0.05).The corneal endothelial cell density,hexagonal cell ratio,nerve fiber density,and nerve fiber length in the NPDR and PDR group were significantly lower than those in the control group (all P ＜ 0.05);and the variability of endothelial cell and nerve branch density in NPDR and PDR patients were significantly higher than those in the control group (all P ＜ 0.05).The corneal endothelial cell density,hexagonal cell ratio,nerve fiber density,and nerve fiber length in the PDR group was (1962.0-± 117.3) · mm-2,46.1％ ± 5.5％,(15.4 ± 3.3) · mm-2,(6.2 ± 2.7) mm · mm-2,respectively,which were significantly lower than those in the NPDR group [(2381.4 ± 144.0) · mm-2,58.2％ ±7.0％,(20.6 ±3.8) ·mm-2,(8.6 ± 2.4)mm · mm-2,respectively] (all P ＜ 0.05),but the variability of endothelial cell and nerve branch density in PDR group were significantly higher than those in the NPDR group (all P ＜ 0.05).Conclusion Corneal confocal microscopy can effectively observe the density and morphological changes in corneal subepithelial plexus and corneal cell in DR patients so as to provide guidance for clinical diagnosis and treatment.

AIM:To observe the expression of calreticulin(CRT)in nasopharyngeal carcinoma tissues,ana-lyze the significance of clinical pathology and the influence on epithelial -mesencymal transition(EMT)of CNE2 cells. METHODS:The expression of calreticulin was detected by immunohistochemistry in 52 nasopharyngeal carcinoma and 57 nasopharyngeal benign tissues,and the significance of clinical pathology was evaluated.The calreticulin gene-specific small interfering RNA was constructed,and then was transfected into the NPC cell line CNE 2 using the cationic liposome meth-od.The effect of CRT on the morphological changes of the CNE 2 cells was observed under light microscope.The effect of CRT on the cell migration and invasion abilities of the CNE 2 cells was detected by Transwell migration and invasion assays. The expression of EMT-related proteins E-cadherin,vimentin,transforming growth factor(TGF)-βand matrix metallopro-teinase(MMP)-9 in the CNE2 cells was determined by Western blot.RESULTS:The positive expression rate of CRT in the benign lesion tissues was 19.29%(11/57),which was significantly increased in the nasopharyngeal carcinoma tissues as 82.69%(43/52).The expression rate of CRT was positively correlated with the stage of nasopharyngeal carcinoma and lymph node metastasis(P<0.05).Knockdown of CRT expression made the CNE 2 cells showing a spindle shape to a flat, cobblestone-like epithelial state change,arranged more compact,and the migration and invasion abilities were significantly decreased(P<0.05).Knockdown of CRT expression resulted in significant increase in the protein expression of E -cadhe-rin,and the decreases in the protein expression of vimentin, TGF-βand MMP-9 in the CNE2 cells(P<0.05).CON-CLUSION:Calreticulin expression in nasopharyngeal carcinoma is significantly higher and positively correlated with naso -pharyngeal carcinoma stage and lymph node metastasis.Calreticulin promotes cell migration and invasion of nasopharyngeal carcinoma CNE2 cells by inducing EMT.