OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a Chinese Han pedigree with Darier's disease (DD). METHODS: A DD pedigree, who visited Tongji Hospital of Tongji University on October 22, 2023, was selected as the study subject. Clinical data of the pedigree were collected, and whole exome sequencing was performed on the proband. Suspected variant loci were screened, and Sanger sequencing was used to validate the variant in pedigree members. Bioinformatics analysis was performed on the variant loci. This study was approved by the Medical Ethics Committee of Tongji Hospital of Tongji University Ethics No.K-W-2024-004). RESULTS: The proband is a 67-year-old female with clinical features of DD, such as keratotic papules in sebaceous areas. whole exome sequencing revealed a missense variant, c.68G>A (p.Gly23Glu), in the exon 1 of ATP2A2 gene of the proband. Sanger sequencing showed that the proband's eldest daughter also carried this variant. This variant was not detected in other pedigree members, indicating a co-segregation of the variant with the disease phenotype in the pedigree. According to the interpretation principles of gene variants by the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic (PS1+PM1+PM2_Supporting+PP1+PP3+PP4). CONCLUSION The c.68G>A (p.Gly23Glu) variant in the ATP2A2 gene may be the genetic cause of the disease in this pedigree. This finding further enriches the genetic variant spectrum in DD patients and provides a basis for clinical diagnosis and genetic counseling for patients.
Aged ; Female ; Humans ; Male ; China ; Darier Disease/genetics* ; Exome Sequencing ; Mutation, Missense ; Pedigree ; Phenotype ; East Asian People ; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Objective To investigate the effects of penehyclidine hydrochloride(PHC)admin-istered at different time points on neurological function and the blood-brain barrier(BBB)in rat model of severe intracerebral hemorrhage(ICH),and to preliminarily explore its potential mechanism of action based on the growth arrest-specific protein 6(GAS6)/receptor tyrosine kinase(Axl)signaling pathway.Methods ICH model rats were established via intracerebral injection of a collagenase type Ⅳ solu-tion.The model rats were randomly divided into sham operation group(intracerebral injection of an equal volume of saline),model group(intracerebral injection of 0.4 μL of collagenase type Ⅳ solu-tion),24 h drug administration group(intracerebral injection of 0.4 μL of collagenase type Ⅳ solu-tion combined with intraperitoneal injection of 2 mg/kg PHC 24 h after successful model establish-ment),6 h drug administration group(intracerebral injection of 0.4 μL of collagenase type Ⅳ solu-tion combined with intraperitoneal injection of 2 mg/kg PHC 6 h after successful model establish-ment),pre-drug administration group(intraperitoneal injection of 2 mg/kg PHC before modeling combined with intracerebral injection of 0.4 μL of collagenase type Ⅳ solution),and pathway in-hibitor group(intraperitoneal injection of 2 mg/kg PHC before modeling combined with intracerebral injection of 0.4 μL of collagenase type Ⅳ solution and intraperitoneal injection of 75 mg/kg R428,a GAS6/Axl signaling pathway inhibitor,after successful model establishment).The degree of neu-rological impairment in rats was assessed after successful model establishment and at the end of treat-ment;brain tissue water content in rats was calculated;brain tissue damage and Evans blue(EB)content in rats were evaluated using hematoxylin-eosin(HE)and EB staining methods;western blot was used to detect the expression levels of Claudin-5,zonula occludens-1(ZO-1),Occludin,ma-trix metalloproteinase-9(MMP-9),and proteins related to the GAS6/Axl signaling pathway in brain tissue.Results HE staining revealed that compared with the sham operation group,the model group exhibited irregular arrangement of brain tissue cells,a large number of necrotic cells,and sig-nificant infiltration of inflammatory cells;compared with the model group,the 24 h drug administra-tion,6 h drug administration,pre-drug administration,and pathway inhibitor groups showed more orderly brain tissue cells,reduced cell gaps,and decreased infiltration of inflammatory cells;com-pared with the 24 h drug administration group,the 6 h drug administration,pre-drug administration,and pathway inhibitor groups exhibited more intact brain tissue cell structures,reduced cell gaps,and decreased infiltration of inflammatory cells;compared with the pre-drug administration group,the 6 h drug administration and pathway inhibitor groups showed slight swelling of brain tissue cells and a small amount of inflammatory cell infiltration.Compared with the sham operation group,the model group had increased neurological function scores,brain tissue water content,EB content in brain tissue,and MMP-9 protein levels,along with decreased levels of ZO-1,Occludin,Claudin-5 proteins,and GAS6 and p-Axl protein expression;compared with the model group,the 24 h drug administration,6 h drug administration,pre-drugadministration,and pathway inhibitor groups had decreased neurological function scores,brain tissue water content,EB content in brain tissue,and MMP-9 protein levels,along with increased levels of ZO-1,Occludin,Claudin-5 proteins,and GAS6 and p-Axl protein levels in brain tissue;compared with the 24 h drug administration group,the 6 h drug administration,pre-drug administration,and pathway inhibitor groups had decreased neurological function scores,brain tissue water content,EB content in brain tissue,and MMP-9 protein levels,along with increased levels of ZO-1,Occludin,Claudin-5 proteins,and GAS6 and p-Axl protein expression;compared with the pre-drug administration group,the 6 h drug administra-tion and pathway inhibitor groups had increased neurological function scores,brain tissue water con-tent,EB content in brain tissue,and MMP-9 protein levels,along with decreased levels of ZO-1,Occludin,Claudin-5 proteins,and GAS6 and p-Axl protein expression in brain tissue;the between-group differences mentioned above were statistically significant(P＜0.05).Conclusion Early ad-ministration of PHC can improve neurological function and the BBB in ICH rats by reducing brain tissue damage and brain edema,and its mechanism may be related to the activation of the GAS6/Axl signaling pathway.

Objective:To explore the clinical phenotype and genetic characteristics of a Chinese Han pedigree with Darier′s disease(DD).Methods:A DD pedigree, who visited Tongji Hospital of Tongji University on October 22, 2023, was selected as the study subject. Clinical data of the pedigree were collected, and whole-genome exom sequencing was performed on the proband. Suspected variant loci were screened, and Sanger sequencing was used to validate the variant in pedigree members. Bioinformatics analysis was performed on the variant loci. This study was approved by the Medical Ethics Committee of Tongji Hospital of Tongji University(Ethics No.K-W-2024-004).Results:① The proband is a 67-year-old female with clinical features of DD, such as keratotic papules in sebaceous areas. ② Whole-genome exom sequencing revealed a missense variant, c. 68G>A (p.Gly23Glu), in the exon 1 of ATP2A2 gene of the proband. Sanger sequencing showed that the proband′s eldest daughter also carried this variant. This variant was not detected in other pedigree members, indicating a co-segregation of the variant with the disease phenotype in the pedigree. ③ According to the interpretation principles of gene variants by the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic (PS1+ PM1+ PM2_Supporting+ PP1+ PP3+ PP4). Conclusions:The c. 68G>A (p.Gly23Glu) variant in the ATP2A2 gene may be the genetic cause of the disease in this pedigree. This finding further enriches the genetic variant spectrum in DD patients and provides a basis for clinical diagnosis and genetic counseling for patients.

Objective:To explore the clinical phenotype and genetic characteristics of a Chinese Han pedigree with Darier′s disease(DD).Methods:A DD pedigree, who visited Tongji Hospital of Tongji University on October 22, 2023, was selected as the study subject. Clinical data of the pedigree were collected, and whole-genome exom sequencing was performed on the proband. Suspected variant loci were screened, and Sanger sequencing was used to validate the variant in pedigree members. Bioinformatics analysis was performed on the variant loci. This study was approved by the Medical Ethics Committee of Tongji Hospital of Tongji University(Ethics No.K-W-2024-004).Results:① The proband is a 67-year-old female with clinical features of DD, such as keratotic papules in sebaceous areas. ② Whole-genome exom sequencing revealed a missense variant, c. 68G>A (p.Gly23Glu), in the exon 1 of ATP2A2 gene of the proband. Sanger sequencing showed that the proband′s eldest daughter also carried this variant. This variant was not detected in other pedigree members, indicating a co-segregation of the variant with the disease phenotype in the pedigree. ③ According to the interpretation principles of gene variants by the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic (PS1+ PM1+ PM2_Supporting+ PP1+ PP3+ PP4). Conclusions:The c. 68G>A (p.Gly23Glu) variant in the ATP2A2 gene may be the genetic cause of the disease in this pedigree. This finding further enriches the genetic variant spectrum in DD patients and provides a basis for clinical diagnosis and genetic counseling for patients.

Immune response occurs in a variety of cellular stresses that severely disrupt function of endoplasmic reticulum(ER),leading to accumulation of misfolded or unfolded protein in ER lumen,resulting in endoplasmic reticulum stress(ERS).ERS triggers unfolded protein response to restore ER homeostasis,but its duration is too long and can lead to cell apoptosis.Although sus-tained ERS can lead to an increase in pro-inflammatory cytokines that induce inflammatory responses and activate immune responses,causal relationship between ERS and immune responses has not been established.This review summarizes role of ERS in inducing im-mune cell differentiation,cytokine expression and immune function,and further illustrates regulatory role of ERS in pathogenesis of immune disorders,which is helpful to explore new therapies for ERS-related diseases.

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results:593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores.Conclusion:After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects that previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks. Safety profiles of kidney, bone, metabolism, body weight, and others were evaluated.Results:666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144. The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144. In subjects switching from TDF to TMF, the non-indexed estimated glomerular filtration rate (by non-indexed CKD-EPI formula) and creatinine clearance (by Cockcroft-Gault formula) were both increased, which were (2.31±8.33) ml/min and (4.24±13.94) ml/min, respectively. These changes were also higher than those in subjects with extending TMF treatment [(0.91±8.06) ml/min and (1.30±13.94) ml/min]. Meanwhile, switching to TMF also led to an increase of the bone mineral density (BMD) by 0.75% in hip and 1.41% in spine. On the other side, a slight change in TC/HDL ratio by 0.16 (IQR: 0.00, 0.43) and an increase in body mass index (BMI) by (0.54±0.98) kg/m 2 were oberved with patients switched to TMF, which were significantly higher than that in TMF group. Conclusion:CHB patients receiving 144 weeks of TMF treatment showed favorable safety profile. After switching to TMF, the bone and renal safety was significantly improved in TDF group, though experienceing change in metabolic parameters and weight gain (NCT03903796).

Hepatogenous diabetes (HD) is a common complication of end-stage liver disease, and many studies have confirmed its adverse effect on prognosis. In recent ten years, a great number of studies have been conducted on the pathogenesis of HD and some progress has been made. This article reviews the research advances in the pathogenesis of HD, in order to provide a reference for the diagnosis and treatment of HD by clinicians.

Both diabetes mellitus and liver cirrhosis have high incidence rate and mortality rate around the world, and in recent ten years, scholars in China and globally have conducted many studies on the association between diabetes mellitus and liver cirrhosis. This article systematically reviews the advances in the basic and clinical research on the influence of diabetes mellitus on liver cirrhosis and its complications and summarizes possible mechanisms. The results show that diabetes mellitus can accelerate the process of liver fibrosis, increase the risk of complications and progression to liver cancer in patients with liver cirrhosis, and reduce their survival rate.

Objective To investigate the prognostic risk factors of patients with acute inferior myocardial infarction and intra-operative occurrence of ventricular fibrillation (VF) when undergoing emergency percutaneous coronary intervention (PCI). Methods The data of 52 patients with acute inferior myocardial infarction treated in Cangzhou City People's Hospital from May 2016 to May 2018 were retrospectively analyzed, and they were divided into poor prognosis group (19 cases) and good prognosis group (33 cases) according to whether cardiovascular events occurred during 1 year of follow-up. The patients' gender, age, smoking or not, histories of diabetes, hypertension, hyperlipidemia, and the results of well performed color echocardiography within recent 3 days, such as left ventricular ejection fraction (LVEF), cardiac infarction size (IS), and coronary Gensini score were recorded in the two groups; the indicators with statistical significance in univariate analysis were included in the multivariate logistic regression analysis to screen out the prognostic risk factors of patients with acute inferior wall myocardial infarction undergoing emergency PCI and occurrence of intra-operative VF; Receiver operating characteristic (ROC) curve was drawn to evaluate the values of coronary Gensini score and IS in predicting intraoperative occurrence of VF in patients with acute inferior wall myocardial infarction undergoing emergency PCI. Results During 1-year follow-up, 19 of 52 patients with acute inferior myocardial infarction occurred VF, the incidence being 36.5%. The univariate analysis showed that the IS and Gensini score in poor prognosis group were significantly higher than those in the good prognosis group [IS: (3.2±0.2)% vs. (2.5±0.4)%, Gensini score: 98.8±12.5 vs. 85.7±8.4, both P < 0.05], the LVEF level was significantly lower in the poor prognosis group than that in the good prognosis group (0.37±0.08 vs. 0.46±0.11, P < 0.05). The multivariate Logistic regression analysis showed that IS [odds ratio (OR) = 5.016] and coronary Gensini score (OR = 2.415) were the risk factors of occurrence of cardiovascular events after surgery in patients with acute inferior myocardial infarction and intra-operative VF when undergoing PCI (P < 0.05). The ROC curve analysis showed that IS and coronary Gensini scores had certain predictive values for the prognosis of patients with acute inferior myocardial infarction and occurrence of intra-operative VF when undergoing emergency PCI, the area under the ROC curve (AUC) was 0.863 and 0.597, respectively, indicating that IS had a medium predictive value, while the value of coronary Gensini score was lower, when the IS optimal cut off value was 3.0, the sensitivity was 89.4% and the specificity was 88.0%. Conclusion High IS and Gensini score are the risk factors of prognosis of patients with acute inferior myocardial infarction and intra-operative occurrence of VF when undergoing emergency PCI.