Objective:To analyze the clinical features of pachydermoperiostosis (PDP) and improve its diagnostic level.Methods:A retrospective analysis was conducted on the clinical data of four patients with PDP treated at Sun Yat-sen Memorial Hospital, Sun Yat-sen University from 2015 to 2023, including clinical manifestations, laboratory tests, imaging examinations, and genetic testing results.Results:All four patients were male with an average onset age of 15 years old (ranging from 9 to 18 years old). One patient′s uncle had PDP, and another patient′s parents were consanguineous, though neither parent showed signs of PDP. All four patients exhibited clubbing, skin thickening, and acne; three had frontal bossing and deepened nasolabial folds; two showed scalp sulci changes on head MRI, and all had periosteal thickening of the phalanges visible on X-ray. One patient accompanied with hypokalemic nephropathy, and another had gastric ulcer. One patient underwent whole exome sequencing test which revealed a homozygous mutation, SLCO2A1 gene c.1406C>T, leading to a protein change p.Pro469Leu. Computational tools REVEL, SIFT, and Polyphen2 predicted this variant as deleterious.Conclusion:In addition to skin thickening, frontal bossing, scalp sulci changes, clubbing, and periosteal proliferation, patients with PDP may also present with hypokalemic nephropathy and gastric ulcer. The SLCO2A1 gene c.1406C>T mutation may be pathogenic.

Objective:To analyze the clinical features of pachydermoperiostosis (PDP) and improve its diagnostic level.Methods:A retrospective analysis was conducted on the clinical data of four patients with PDP treated at Sun Yat-sen Memorial Hospital, Sun Yat-sen University from 2015 to 2023, including clinical manifestations, laboratory tests, imaging examinations, and genetic testing results.Results:All four patients were male with an average onset age of 15 years old (ranging from 9 to 18 years old). One patient′s uncle had PDP, and another patient′s parents were consanguineous, though neither parent showed signs of PDP. All four patients exhibited clubbing, skin thickening, and acne; three had frontal bossing and deepened nasolabial folds; two showed scalp sulci changes on head MRI, and all had periosteal thickening of the phalanges visible on X-ray. One patient accompanied with hypokalemic nephropathy, and another had gastric ulcer. One patient underwent whole exome sequencing test which revealed a homozygous mutation, SLCO2A1 gene c.1406C>T, leading to a protein change p.Pro469Leu. Computational tools REVEL, SIFT, and Polyphen2 predicted this variant as deleterious.Conclusion:In addition to skin thickening, frontal bossing, scalp sulci changes, clubbing, and periosteal proliferation, patients with PDP may also present with hypokalemic nephropathy and gastric ulcer. The SLCO2A1 gene c.1406C>T mutation may be pathogenic.

Objective To employ next-generation sequencing(NGS)to analyze differentially expressed mRNAs in the gingival tissue of hypertensive rats with or without periodontitis to provide a theoretical basis for the prevention and treatment of hypertension with periodontitis.Methods After obtaining approval from the Animal Experiment Ethics Committee,a hypertensive rat model was established by administering high-salt feed containing 8％(w/w)NaCl,and a periodontitis rat model was established by ligating the first molar of the mandibular region using 3-0 sterile silk thread.Rat models of the normal control(N),hypertension(H),and hypertension with periodontitis(PH)groups were estab-lished.The blood pressure,heart rate,alveolar bone resorption,and number of osteoclasts in the alveolar bone were measured,before harvesting the gingival tissues from the three groups for NGS to analyze the expression of significantly different genes.Gene ontology(GO)enrichment analysis was performed for all significantly differentially expressed genes between the H and PH groups.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis was per-formed.Key genes were screened by protein-protein interaction(PPI)networks,and the key gene expression in each group was verified using immunohistochemistry(IHC).The expression of key genes in the systemic circulation of each group was analyzed using enzyme-linked immunosorbent assay(ELISA).Results At the end of the experiment(11th week),the blood pressure was higher in both the H and PH groups than that in the N group(P<0.001),but there was no statistically significant difference in blood pressure between the H and PH groups.There was no statistical difference in heart rate among the 3 groups.Micro-CT showed that the distance from the cemento-enamel junction to the alveolar bone crest(CEJ-ABC)of the mandibular first molar in the PH group was significantly higher than that in the N and H groups(P<0.016 7).The number of osteoclasts in the alveolar bone of the PH group was significantly higher than that of the N and H groups(P<0.0167).No common differentially expressed genes were found among the 3 groups.There were 235 significantly differentially expressed genes in the gingival tissue between the H and PH groups,and 137 upreg-ulated genes(e.g.,P-selectin,keratin 16,and S100 calcium binding protein A)and 98 downregulated genes(e.g.,FK506 binding protein 5,mediator complex subunit 22,zinc finger and BTB domain containing 16)in the PH group compared to the H group.GO analysis showed that the major enriched biological processes(BP)were leukocyte migra-tion,the major cellular component(CC)was complex of collagen trimers,and the significant molecular function(MF)was extracellular matrix structural constituent in the H and PH groups.KEGG pathway analysis showed that signaling pathways such as cytokine-cytokine receptor interaction,IL-17 signaling pathway,and TNF-α signaling pathway were significantly enriched in the H and PH groups.PPI analysis identified four key genes affecting periodontitis in hyperten-sive conditions,including interleukin-1β(IL-1β),matrix metalloproteinase-9(MMP-9),collagen type Ⅰ alpha1(COL1α 1),and chemokine ligand 1(CXCL1).Compared to the N and H groups,the expressions of IL-1β and TNF-α were all upregulated in the gingival tissue and systemic serum in the PH group(P<0.016 7).Conclusion The differentially expressed mRNAs in hypertension with or without periodontitis included IL-1β and MMP-9,while the differentially ex-pressed signaling pathways were IL-17 and TNF-α.These results provide a theoretical reference for further investigation of the molecular regulatory mechanism of hypertension with periodontitis in the future.

Objective To explore the effects of HPV16 E6 on genes and signaling pathways in cervical epithelial cells and to screen genes associated with oncogenic transformation.Methods HUCEC models infected with HPV16 E6 were constructed,and transcriptome sequencing was performed to screen for differentially expressed genes(DEGs),which were subjected to Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment to analyze the differential signaling pathways.RT-qPCR was used to validate major differentially down-regulated expressed genes.After predicting the major differentially expressed proteins by molecular docking analysis,the expression of major differential genes in HUCEC cell model was verified by RT-qPCR and Western blotting.In addition,RT-qPCR and Western blotting were used to further verify the expression of major differential genes in cervical cancer cell lines,SiHa and CaSki.Results A total of 55 genes with more than two-fold differential expression were screened.The results centering on down-regulated genes showed that the negatively regulated differential gene was mainly enriched in redox processes;KEGG enrichment analysis revealed that it was mainly associated with carbohydrate metabolism and cancer.RT-qPCR results showed that the down-regulated differential expression trends of the selected 10 genes were basically consistent with the sequencing results.Molecular docking analysis predicted an interaction between DHRS2 and HPV16 E6,and RT-qPCR and Western blotting confirmed that HPV16 E6 down-regulated DHRS2 mRNA(P＜0.01)and protein(P＜0.05)and ETV5 protein expression(P＜0.01).In SiHa and CaSki cells,compared with the control group,the mRNA and protein expression of DHRS2 was downregulated and positively correlated with the trend of P53 protein expression(P＜0.05).Conclusion HPV16 E6 can mediate oncogenic transformation of cervical cells and promote cervical carcinogenesis through downregulating DHRS2 expression.

Biapenem is a carbapenem antibiotic， and can be used for the treatment of sepsis， pneumonia， lung abscess， chronic respiratory lesions secondary infection， complex urinary tract infection and pyelonephritis， etc. This article reviewed the studies on the pharmacokinetics， pharmacodynamics and therapeutic drug monitoring （TDM） of biapenem. The pharmacokinetic parameters of biapenem are not significantly different in healthy subjects， and there is no accumulation after multiple doses of biapenem. However， there are large differences in pharmacokinetic parameters in patients with severe disease and patients with abnormal renal function compared with healthy subjects， which leads to conventional treatment regimens not achieving the desired outcome. In terms of pharmacodynamics， biapenem can improve the rate of reaching the target value by increasing the frequency of administration and prolonging the infusion time. For patients with anuria in end-stage renal disease， dosing intervals can be extended to avoid drug accumulation. However, for patients with severe infection, a daily dose of 1.2 g still can not control infections caused by Acinetobacter baumannii or Pseudomonas aeruginosa, which limits its use in patients with severe disease. It is recommended to implement TDM in severe patients and patients with abnormal renal function， and explore the best dosing regimen for biapenem in combination with pharmacokinetic models to ensure that the time that the free blood concentration of biapenem remains above minimum inhibitory concentration as a percentage of the time between doses （%fT＞MIC） is within the effective range，so that biapenem can exert a greater efficacy in severe patients and patients with abnormal renal function. For medical institutions that cannot carry out TDM， the efficacy of biapenem can be maximized by increasing the frequency of administration and prolonging the infusion time. For infections caused by P. aeruginosa， A. baumannii and Serratia marcescens with high drug resistance rates， it is recommended to combine or replace other antibiotics.

Objective:To investigate the clinical characteristics of choledocholithiasis com-bined with periampullary diverticulum and influencing factor for difficult cannulation of endoscopic retrograde cholangiopancreatography (ERCP).Methods:The retrospective case-control study was conducted. The clinical data of 1 920 patients who underwent ERCP for choledocholithiasis in 15 medical centers, including the First Hospital of Lanzhou University, et al, from July 2015 to December 2017 were collected. There were 915 males and 1 005 females, aged (63±16)years. Of 1 920 patients, there were 228 cases with periampullary diverticulum and 1 692 cases without periampullary diverticulum. Observation indicators: (1) clinical characteristics of patients with choledocholithiasis; (2) intraoperative and postoperative situations of patients undergoing ERCP for choledocholithiasis; (3) influencing factor analysis for difficult cannulation in patients undergoing ERCP for choledocholithiasis. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range) or M( Q1, Q3), and com-parison between groups was conducted using the Wilcoxon rank sum test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test or Fisher exact probability. The Logistic regression model was used for univariate and multivariate analyses. Results:(1) Clinical characteristics of patients with choledocholithiasis. Age, body mass index, cases with complications as chronic obstructive pulmonary disease, diameter of common bile duct, cases with diameter of common bile duct as <8 mm, 8?12 mm, >12 mm, diameter of stone, cases with number of stones as single and multiple were (69±12)years, (23.3±3.0)kg/m 2, 16, (14±4)mm, 11, 95, 122, (12±4)mm, 89, 139 in patients with choledocholithiasis combined with periampullary diverticulum, versus (62±16)years, (23.8±2.8)kg/m 2, 67, (12±4)mm, 159, 892, 641, (10±4)mm, 817, 875 in patients with choledocholithiasis not combined with periampullary diver-ticulum, showing significant differences in the above indicators between the two groups ( t=?7.55, 2.45, χ2=4.54, t=?4.92, Z=4.66, t=?7.31, χ2=6.90, P<0.05). (2) Intraoperative and postoperative situations of patients undergoing ERCP for choledocholithiasis. The balloon expansion diameter, cases with intraoperative bleeding, cases with hemorrhage management of submucosal injection, hemostatic clip, spray hemostasis, electrocoagulation hemostasis and other treatment, cases with endoscopic plastic stent placement, cases with endoscopic nasal bile duct drainage, cases with mechanical lithotripsy, cases with stone complete clearing, cases with difficult cannulation, cases with delayed intubation, cases undergoing >5 times of cannulation attempts, cannulation time, X-ray exposure time, operation time were 10.0(range, 8.5?12.0)mm, 56, 6, 5, 43, 1, 1, 52, 177, 67, 201, 74, 38, 74, (7.4±3.1)minutes, (6±3)minutes, (46±19)minutes in patients with choledocholithiasis combined with periampullary diverticulum, versus 9.0(range, 8.0?11.0)mm, 243, 35, 14, 109, 73, 12, 230, 1 457, 167, 1 565, 395, 171, 395, (6.6±2.9)minutes, (6±5)minutes, (41±17)minutes in patients with choledocholithiasis not combined with periampullary diverticulum, showing significant differences in the above indicators between the two groups ( Z=6.31, χ2=15.90, 26.02, 13.61, 11.40, 71.51, 5.12, 9.04, 8.92, 9.04, t=?3.89, 2.67, ?3.61, P<0.05). (3) Influencing factor analysis for difficult cannulation in patients undergoing ERCP for choledocholithiasis. Results of multivariate analysis showed total bilirubin >30 umol/L, number of stones >1, combined with periampullary diverticulum were indepen-dent risk factors for difficult cannulation in patients with periampullary diverticulum who underwent ERCP for choledocholithiasis ( odds ratio=1.31, 1.48, 1.44, 95% confidence interval as 1.06?1.61, 1.20?1.84, 1.06?1.95, P<0.05). Results of further analysis showed that, of 1 920 patients undergoing ERCP for choledocholithiasis, the incidence of postoperative pancreatitis was 17.271%(81/469) and 8.132%(118/1 451) in the 469 cases with difficult cannulation and 1 451 cases without difficult cannula-tion, respectively, showing a significant difference between them ( χ2=31.86, P<0.05). In the 1 692 patients with choledocholithiasis not combined with periampullary diverticulum, the incidence of postopera-tive pancreatitis was 17.722%(70/395) and 8.250%(107/1 297) in 395 cases with difficult cannula-tion and 1 297 cases without difficult cannulation, respectively, showing a significant difference between them ( χ2=29.00, P<0.05). In the 228 patients with choledocholithiasis combined with peri-ampullary diverticulum, the incidence of postoperative pancreatitis was 14.865%(11/74) and 7.143%(11/154) in 74 cases with difficult cannulation and 154 cases without difficult cannulation, respectively, showing no significant difference between them ( χ2=3.42, P>0.05). Conclusions:Compared with patients with choledocholithiasis not combined with periampullary divertioulum, periampullary divertioulum often occurs in choledocholithiasis patients of elderly and low body mass index. The proportion of chronic obstructive pulmonary disease is high in choledocholithiasis patients with periampullary diverticulum, and the diameter of stone is large, the number of stone is more in these patients. Combined with periampullary diverticulum will increase the difficult of cannulation and the ratio of patient with mechanical lithotripsy, and reduce the ratio of patient with stone complete clearing without increasing postoperative complications of choledocholithiasis patients undergoing ERCP. Total bilirubin >30 μmol/L, number of stones >1, combined with periampullary diverticulum are independent risk factors for difficult cannulation in patients of periampullary diverticulum who underwent ERCP for choledocholithiasis.

Depressive disorder ranks as a major bur-den of disease worldwide,yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects.The lateral septum(LS)is thought to control of depression,however,the cellular and circuit substrates are largely unknown.Here,we identified a subpopulation of LS GABAergic adenosine A2A receptors(A2AR)-positive neurons mediating depres-sive symptoms via direct projects to the lateral habenula(LHb)and the dorsomedial hypothalamus(DMH).Activa-tion of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipula-tion of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive pheno-types.Thus,the optogenetic modulation(stimulation or inhibition)of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH,phenocopied depressive behaviors.Moreover,A2AR are upregulated in the LS in two male mouse mod-els of repeated stress-induced depression.This identifica-tion that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant poten-tial of A2AR antagonists,prompting their clinical transla-tion.

Bile acids(BAs)are synthesized by the liver from cholesterol through several complementary pathways and aberrant cholesterol metabolism plays pivotal roles in the pathogeneses of cholesterol gallbladder polyps(CGP)and cholesterol gallstones(CGS).To date,there is neither systematic study on BAs profile of CGP or CGS,nor the relationship between them.To explore the metabolomics profile of plasma BAs in healthy volunteers,CGP and CGS patients,an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method was developed and validated for simultaneous determination of 42 free and conjugated BAs in human plasma.The developed method was sensitive and reproducible to be applied for the quantification of BAs in the investigation of plasma samples.The results show that,compared to healthy volunteers,CGP and CGS were both characterized by the significant decrease in plasma BAs pool size,furthermore CGP and CGS shared aberrant BAs metabolic characteristics.Cheno-deoxycholic acid,glycochenodeoxycholic acid,λ-muricholic acid,deoxycholic acid,and 7-ketolithocholic acid were shared potential markers of these two cholesterol gallbladder diseases.Subsequent analysis showed that clinical characteristics including cysteine,ornithine and body mass index might be closely related to metabolisms of certain BA modules.This work provides metabolomic information for the study of gallbladder diseases and analytical methodologies for clinical target analysis and efficacy evaluation related to BAs in medical institutions.

Neurofibromatosis type 1 is a progressive autosomal dominant inherited disease caused by a mutation in neurofibromin 1(NF1)gene located on chromosome 1 7q1 1.2.NF1 can cause systemic peripheral neuropathy,but the clinical manifestations are varied due to the different onset times and lesion sites in different patients.The treatment of NF1 involves multiple disciplines due to different lesion sites.Clinical monitoring and symptomatic treatment are the main methods for NF1 management,while radical treatment is difficult.New drugs targeted at the pathogenic gene-related signaling pathways are expected to improve the therapeutic effect for NF1.This review summarizes the progress in the basic research and clinical diagnosis and treatment of NF1.

Objective To investigate the expression of oxytocin ( OXT ) and oxytocin receptor (OXTR) in the prefrontal cortex of postpartum depression (PPD) rats induced by restraint stress during pregnancy and to observe the antidepressant effect of oxytocin and its analogue capitoxin and its mechanism. Methods Twenty-four adult female SD rats of SPF grade were randomly divided into control group,PPD +saline group,PPD + oxytocin group and PPD + captopril group with 6 rats in each group. Rats were subjec-ted to restraint stress for 2 hours every day on the 8th to 21st day of pregnancy to establish PPD model. While the rats in control group were not given any treatment. Rats in PPD + saline,PPD + oxytocin and PPD +captopril were injected bilaterally into prefrontal cortex (PFC) at 10 days postpartum (1 μl/side),oxytocin (30 ng/side) and captopril (45 ng/side) respectively once a day for 5 days. The depressive behaviors of rats were detected by sugar-water preference experiment. Rats were sacrificed 18 days after delivery. The ex-pression of OXT was detected by ELISA method,OXTR by Western blot,Iba-1 by immunofluorescence,and IL-1β,IL-6 and TNF-α by qRT-PCR. Results (1) The sucrose consumption of the PPD + saline group ((67. 1±10. 4)%) was significantly lower than that of the control group((92. 6± 3. 9)%,t=-5. 31,P<0. 01). (2) The expression of oxytocin in prefrontal cortex in PPD group was significantly lower than that in control group ((0. 03±0. 01) ng/mg) vs (0. 08 +0. 05) ng/mg,t=-2. 67,P<0. 05). However,there was no significant difference in the expression of oxytocin receptor between PPD group and control group ((0. 90 ±0. 06) vs (0. 90±0. 05),t=0. 709,P=0. 517). (3) The sucrose consumption of PPD+saline group de-creased than that of control group((65. 6±16. 9)% vs (91. 5±3. 5)%,t=3. 35,P<0. 001). Compared with PPD+saline group,the sucrose consumption of PPD+oxytocin group ((81. 8±8. 4)%) and PPD+carbetocin group ((78. 4±9. 4)%) increased(t=1. 98,1. 68,both P<0. 05). (4) The expression of Iba-1 in the pre-frontal lobe of PPD + saline group was higher than that of control group ((1. 15±0. 05) vs (1. 04 +0. 06), t=3. 50,P<0. 01). Compared with PPD + saline group,the expression of Iba-1 in PPD + oxytocin group (1. 03±0. 06) and in PPD + captopril group (1. 00±0. 02) were lower (t=-3. 50,-6. 55,both P<0. 01). (5) The expression of inflammatory factors IL-1β mRNA (1. 0±0. 1),IL-6 mRNA (1. 1±0. 1) and TNF-α mRNA (1. 7±0. 4) in the prefrontal cortex of rats in the PPD group were higher than that in the control group (IL-1β mRNA (0. 7± 0. 3),IL-6 mRNA (0. 9± 0. 1),TNF-α mRNA ( 1. 1± 0. 3),t=1. 92,3. 19, 2. 43 respectively,all P<0. 05). The expression of inflammatory factors IL-1β,IL-6 and TNF-α mRNA of the PPD+oxytocin group(IL-1β mRNA (0. 6±0. 1),IL-6 mRNA (0. 9±0. 1),TNF-α mRNA (1. 2±0. 4) )and the PPD+carbetocin group ( IL-1β mRNA ( 0. 7± 0. 1),IL-6 mRNA ( 0. 9 ± 0. 1),TNF-α mRNA ( 1. 0 ± 0. 2))in the prefrontal cortex were lower than that in the PPD group(t=-3. 17,-2. 78,-1. 84,t=-2. 76,-2. 40,-2. 94 respectively,all P<0. 05). Conclusion Oxytocin and capitoxin injected into prefrontal cortex can effectively improve depression-like behaviors in PPD model rats. Activation of microglia and decrease of inflammatory factors in prefrontal cortex may be the potential antidepressant mechanism.