Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial.

OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).

A novel long noncoding RNA-lncRNA-AABR07066529.3 alleviates inflammation, apoptosis, and pyroptosis by inhibiting MyD88 in lipopolysaccharide-induced myocardial depression.

Sepsis-induced myocardial depression (SIMD) is common in pediatric intensive care units and seriously threatens children's health. Recently, long noncoding RNAs (lncRNAs) have been showed to play important roles in various diseases; however, its role in SIMD is unclear. In this study, we used lipopolysaccharide (LPS)-treated rats and H9c2 cardiomyocytes to mimic SIMD in vivo and in vitro. We found that the expression of a novel lncRNA, we named lncRNA-AABR07066529.3, was elevated in LPS-induced rat heart tissue and H9c2 cardiomyocytes. In addition, LPS-induced inflammation, apoptosis, and pyroptosis were significantly exacerbated after lncRNA-AABR07066529.3 knockdown. Moreover, we found that myeloid differentiation factor 88 (MyD88) was upregulated in LPS-treated groups and was inhibited by lncRNA-AABR07066529.3. Besides, MyD88 knockdown abolished lncRNA-AABR07066529.3 silencing effects on inflammation, apoptosis, and pyroptosis induced by LPS in H9c2 cardiomyocytes. In our study, we found lncRNA-AABR07066529.3 exerted protective effects on LPS-induced cardiomyocytes by regulating MyD88 and might serve as a potential treatment target for SIMD.

Kcnma1 is involved in mitochondrial homeostasis in diabetes-related skeletal muscle atrophy.

Uncontrolled diabetes causes a catabolic state with multi-organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore-forming α-subunit of Ca2+ - and voltage-gated K+ channels of large conductance (BK channels), and loss-of-function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time-course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor-deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle-specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno-associated virus-9 (AAV9)-encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9-shKcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9-shKcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis-related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate-treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes.

Correlation between the changes of brain amplitude of low-frequency fluctuation and cognitive impairment in patients with neuropsychiatric lupus.

PURPOSE: To explore the relationship between brain function changes and clinical serological indicators and behavioral cognitive assessment in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), and understand the pathogenesis of NPSLE from the perspective of imaging. METHODS: The resting-state functional imaging data, clinical serological, and behavioral cognitive assessment scores of 28 patients with NPSLE and 22 healthy controls (HC) were prospectively collected. The resting-state amplitude of low-frequency fluctuation (ALFF) values obtained from the analysis and processing were correlated with the serological data and behavioral cognitive assessment scores to determine the relationship between these data. RESULTS: The average age of the patients of the NPSLE group was older than that of the HC group; significant differences in education level, Auditory Verbal Learning Test Hua Shan Version (AVLT-H), and Trail Making Test scores were observed between the two groups. The NPSLE group demonstrated increased brain activity in the insula, precentral gyrus, and superior temporal gyrus, and decreased brain activity in the superior parietal gyrus. The ALFF value of the insula positively correlated with the Anti-ß2gp1 antibody and negatively correlated with the anti-nucleosome antibody and the AVL-recall (RC) score. The ALFF of the precentral gyrus negatively correlated with the AVL-immediate recall (I). The ALFF value of the superior temporal gyrus negatively correlated with the AVL-RC score. The left superior parietal gyrus positively correlated with the c-reactive protein. The right superior parietal gyrus positively correlated with the System Lupus Erythematosus Disease Activity Index and negatively correlated with the AVL-I score. CONCLUSION: Patients with NPSLE show different brain activity changes in different brain regions, and the abnormal brain regions are correlated with certain lupus antibodies, inflammatory factors, and cognitive assessment, thereby suggesting that the correlation between the three could provide novel insights into the pathogenesis of NPSLE.

Targeting epigenetic and post-translational modifications regulating pyroptosis for the treatment of inflammatory diseases.

Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases.

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Sepsis-induced myocardial depression (SIMD), a common complication of sepsis, is one of the main causes of death in patients with sepsis. The pathogenesis of SIMD is complicated, and the process of SIMD remains incompletely understood, with no single or definitive mechanism fully elucidated. Notably, pyroptosis, as a pro-inflammatory programmed cell death, is characterized by Gasdermin-mediated formation of pores on the cell membrane, cell swelling, and cell rupture accompanied by the release of large amounts of inflammatory factors and other cellular contents. Mechanistically, pyroptosis is mainly divided into the canonical pathway mediated by caspase-1 and the non-canonical pathway mediated by caspase-4/5/11. Pyroptosis has been confirmed to participate in various inflammation-associated diseases. In recent years, more and more studies have shown that pyroptosis is also involved in the occurrence and development of SIMD. This article reviews the molecular mechanisms of pyroptosis and its research progress in SIMD, aiming to provide novel strategies and targets for the treatment of SIMD.

Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives.

The metabolism of glucose and lipids is essential for energy production in the body, and dysregulation of the metabolic pathways of these molecules is implicated in various acute and chronic diseases, such as type 2 diabetes, Alzheimer's disease, atherosclerosis (AS), obesity, tumor, and sepsis. Post-translational modifications (PTMs) of proteins, which involve the addition or removal of covalent functional groups, play a crucial role in regulating protein structure, localization function, and activity. Common PTMs include phosphorylation, acetylation, ubiquitination, methylation, and glycosylation. Emerging evidence indicates that PTMs are significant in modulating glucose and lipid metabolism by modifying key enzymes or proteins. In this review, we summarize the current understanding of the role and regulatory mechanisms of PTMs in glucose and lipid metabolism, with a focus on their involvement in disease progression associated with aberrant metabolism. Furthermore, we discuss the future prospects of PTMs, highlighting their potential for gaining deeper insights into glucose and lipid metabolism and related diseases.

Risks of specific congenital anomalies in offspring of women with diabetes: A systematic review and meta-analysis of population-based studies including over 80 million births.

BACKGROUND: Pre-gestational diabetes mellitus (PGDM) has been known to be a risk factor for congenital heart defects (CHDs) for decades. However, the associations between maternal PGDM and gestational diabetes mellitus (GDM) and the risk of specific types of CHDs and congenital anomalies (CAs) in other systems remain under debate. We aimed to investigate type-specific CAs in offspring of women with diabetes and to examine the extent to which types of maternal diabetes are associated with increased risk of CAs in offspring. METHODS AND FINDINGS: We searched PubMed and Embase from database inception to 15 October 2021 for population-based studies reporting on type-specific CAs in offspring born to women with PGDM (combined type 1 and 2) or GDM, with no limitation on language. Reviewers extracted data for relevant outcomes and performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. Risk of bias appraisal was performed using the Cochrane Risk of Bias Tool. This study was registered in PROSPERO (CRD42021229217). Primary outcomes were overall CAs and CHDs. Secondary outcomes were type-specific CAs. Overall, 59 population-based studies published from 1990 to 2021 with 80,437,056 participants met the inclusion criteria. Of the participants, 2,407,862 (3.0%) women had PGDM and 2,353,205 (2.9%) women had GDM. The meta-analyses showed increased risks of overall CAs/CHDs in offspring born to women with PGDM (for overall CAs, relative risk [RR] = 1.99, 95% CI 1.82 to 2.17, P < 0.001; for CHDs, RR = 3.46, 95% CI 2.77 to 4.32, P < 0.001) or GDM (for overall CAs, RR = 1.18, 95% CI 1.13 to 1.23, P < 0.001; for CHDs, RR = 1.50, 95% CI 1.38 to 1.64, P < 0.001). The results of the meta-regression analyses showed significant differences in RRs of CAs/CHDs in PGDM versus GDM (all P < 0.001). Of the 23 CA categories, excluding CHD-related categories, in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories; the corresponding RRs ranged from 1.57 (for hypospadias, 95% CI 1.22 to 2.02) to 18.18 (for holoprosencephaly, 95% CI 4.03 to 82.06). Maternal GDM was associated with a small but significant increase in the risk of CAs in 9 categories; the corresponding RRs ranged from 1.14 (for limb reduction, 95% CI 1.06 to 1.23) to 5.70 (for heterotaxia, 95% CI 1.09 to 29.92). The main limitation of our analysis is that some high significant heterogeneity still persisted in both subgroup and sensitivity analyses. CONCLUSIONS: In this study, we observed an increased rate of CAs in offspring of women with diabetes and noted the differences for PGDM versus GDM. The RRs of overall CAs and CHDs in offspring of women with PGDM were higher than those in offspring of women with GDM. Screening for diabetes in pregnant women may enable better glycemic control, and may enable identification of offspring at risk for CAs.

Comparative transcriptome analysis of transcripts of uncertain coding potential in septic myocardial depression.

BACKGROUND: Septic shock with myocardial depression is very common in intensive care units. However, the exact molecular mechanisms underlying sepsis-induced myocardial depression remain unclear. Whether the profiles of transcripts of uncertain coding potential (TUCPs) differ between patients with and without myocardial depression is also unknown. Our study aimed to find expression differences between groups of TUCPs and determine their potential functions in a preclinical model. METHODS: We generated rat models of hypodynamic septic shock induced by lipopolysaccharide. A total of 12 rats were established and left ventricular tissue from each was collected. We performed RNA-seq to identify TUCPs in each sample. Transcripts with an corrected P value of < 0.05 were defined as differentially expressed (DE). We also performed GO terms and KEGG analysis to identify the potential functions of DE TUCPs. RESULTS: A total of 4,851 TUCPs were identified in heart samples, 85 of which were expressed differently between the sepsis and control groups. Further bioinformatic analyses suggested that TUCPs play important roles in myocardial contraction, energy regulation, and metabolic processes, and are also involved in the regulation of several pathways. CONCLUSION: Our results demonstrate that TUCPs both participate in and mediate the pathological process of myocardial depression. Our study improves the understanding of the basic molecular mechanisms underlying myocardial depression from a novel perspective.

Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation, migration, and invasion.

Fibronectin 1 (FN1) is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, metastasis, and implicated in various biochemical processes. However, its effects on the development and progression of human cancer, especially colorectal cancer (CRC), are unclear. To evaluate the relationship between the expression of FN1 and the histopathologic parameters of patients with CRC or the proliferation, migration, and invasion of colorectal cancer cell lines, we screened FN1 as a new candidate gene which promotes development of CRC, in an independent dataset (The Human Protein Atlas website). Here, we reported that FN1 was elevated in CRC tissues compared with normal colon tissues. Further, FN1 expression level was correlated with age, lymph vascular invasion, and survival rate. Knockdown of FN1 in two CRC cell lines, LOVO, and SW1116, significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Western blot analysis showed that down-regulation of FN1 significantly decreased the expression of Bcl-2, MMP-9, Twist, and increased the expression of Bax, Caspase-3, and E-cadherin in LOVO and SW1116 cells. Then, we found that the protein ITGA5 was identified as a binding partner of FN1 and ITGA5 overexpression reversed FN1-induced tumorigenesis of CRC in vitro. Taken together, FN1 suppressed apoptosis and promoted viability, invasion, and migration in CRC through interacting with ITGA5. FN1 may be a prognostic factor and potential target for CRC treatment.

Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort studies of more than 9 million births.

BACKGROUND: In 2005, the FDA cautioned that exposure to paroxetine, a selective serotonin reuptake inhibitor (SSRI), during the first trimester of pregnancy may increase the risk of cardiac malformations. Since then, the association between maternal use of SSRIs during pregnancy and congenital malformations in infants has been the subject of much discussion and controversy. The aim of this study is to systematically review the associations between SSRIs use during early pregnancy and the risk of congenital malformations, with particular attention to the potential confounding by indication. METHODS: The study protocol was registered with PROSPERO (CRD42018088358). Cohort studies on congenital malformations in infants born to mothers with first-trimester exposure to SSRIs were identified via PubMed, Embase, Web of Science, and the Cochrane Library databases through 17 January 2018. Random-effects models were used to calculate summary relative risks (RRs). RESULTS: Twenty-nine cohort studies including 9,085,954 births were identified. Overall, use of SSRIs was associated with an increased risk of overall major congenital anomalies (MCAs, RR 1.11, 95% CI 1.03 to 1.19) and congenital heart defects (CHD, RR 1.24, 95% CI 1.11 to 1.37). No significantly increased risk was observed when restricted to women with a psychiatric diagnosis (MCAs, RR 1.04, 95% CI 0.95 to 1.13; CHD, RR 1.06, 95% CI 0.90 to 1.26). Similar significant associations were observed using maternal citalopram exposure (MCAs, RR 1.20, 95% CI 1.09 to 1.31; CHD, RR 1.24, 95% CI 1.02 to 1.51), fluoxetine (MCAs, RR 1.17, 95% CI 1.07 to 1.28; CHD, 1.30, 95% CI 1.12 to 1.53), and paroxetine (MCAs, RR 1.18, 95% CI 1.05 to 1.32; CHD, RR 1.17, 95% CI 0.97 to 1.41) and analyses restricted to using women with a psychiatric diagnosis were not statistically significant. Sertraline was associated with septal defects (RR 2.69, 95% CI 1.76 to 4.10), atrial septal defects (RR 2.07, 95% CI 1.26 to 3.39), and respiratory system defects (RR 2.65, 95% CI 1.32 to 5.32). CONCLUSIONS: The evidence suggests a generally small risk of congenital malformations and argues against a substantial teratogenic effect of SSRIs. Caution is advisable in making decisions about whether to continue or stop treatment with SSRIs during pregnancy.

Autophagy is activated in the ovarian tissue of polycystic ovary syndrome.

The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on EGFR, ERBB2, FOXO1, MAPK1, NFKB1, IGF1,TP53 and MAPK9 may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.

The Trend of ß3-Adrenergic Receptor in the Development of Septic Myocardial Depression: A Lipopolysaccharide-Induced Rat Septic Shock Model.

Septic shock with low cardiac output is very common in children. However, the mechanism underlying myocardial depression is unclear. The role of ß3-AR in the development of myocardial depression in sepsis is unknown. In the present study, we generated an adolescent rat model of hypodynamic septic shock induced by lipopolysaccharide (LPS). Neonatal cardiomyocytes were also treated with LPS to mimic myocardial depression in sepsis, which was confirmed via an in vivo left ventricular hemodynamic study, and measurements of contractility and the Ca2+ transient in isolated adolescent and neonatal cardiomyocytes. After 16 h of LPS treatment, cultured neonatal cardiomyocytes showed a diminished Ca2+ transient amplitude associated with an increase in the ß3-AR level. With the addition of a ß3-AR agonist, the Ca2+ transient in LPS-treated neonatal rat cardiomyocytes gradually decreased over time; such a change was absent in cells treated with nitric oxide synthase (NOS) inhibitors prior to treatment with a ß3-AR agonist. In adolescent rats with septic myocardial depression, cardiac function declined as indicated by decreased MAP, dP/dtmax, and dP/dtmix for 6 h after LPS injection; however, the ß3-AR level first increased 2 h after LPS treatment and then decreased 6 h after LPS treatment in the absence of exogenous catecholamines. The results indicate that, in vitro, at the cellular level ß3-AR may be involved in the development of myocardial depression (Ca2+ transient depression) in sepsis through NOS signaling pathways; however, in vivo, a complicated mechanism for modulating ß3-AR may exist.

Assessment of the development of assisted reproductive technology in Liaoning province of China, from 2012 to 2016.

BACKGROUND: The development of assisted reproduction techniques (ART) has resulted in rapid advances in the treatment of infertility. However, a systematic assessment of ART and its processes and outcomes in China has never been carried out. The goal of this study was to assess the features of ART status from 2012 to 2016 in clinics and in vitro fertilization (IVF) laboratories in Liaoning, the largest IVF province in the northeast of China. METHODS: Data from Jan 1, 2012 to Dec 31, 2016 was retrieved from the assisted reproductive certificate registry of Liaoning province. We extracted data from: i) fresh and thawed cycles; ii) donor sperm and donor egg cycles; iii) intrauterine insemination with husband semen and donor semen (AIH and AID). RESULTS: We showed that: (i) there has been a significant increase in the number of IVF fresh and thawed cycles, and the proportion of cases of primary infertility and secondary infertility has decreased and increased, respectively; (ii) standard long GnRH agonist was the major ovarian stimulation protocol. During the observation period, increasing trends in the use of GnRH antagonists, mild stimulation, and natural cycles were observed; (iii) significant differences in the number of cycles, number of retrieved oocytes, fertilization rates, implantation rates, and sex ratio were noticed between conventional IVF and intracytoplasmic sperm injection; (iv) significant differences in age at treatment for infertility, number of cycles, and ectopic pregnancy rates were noticed between donor sperm cycles and donor egg cycles; (v) significant differences in number of thawed cycles, number of thawed embryos, embryo recovery rates, implantation rates, and clinical pregnancy rates were noticed between day 3 and day 5 embryos; (vi) significant differences in age at treatment for infertility, number of cycles, clinical pregnancy rates, ectopic pregnancy rates, and live birth ratio were noticed between AIH and AID. CONCLUSIONS: ART in Liaoning province has undergone substantial development from 2012 to 2016 in clinics and IVF laboratories. This presentation of detailed ART data will provide researchers, policy makers, and potential ART users a rich source of information about IVF characteristics in the northeast of China.

Fluoxetine and congenital malformations: a systematic review and meta-analysis of cohort studies.

AIMS: To investigate the safety of fluoxetine use during pregnancy, and to better understand the relationship between maternal fluoxetine use during the first trimester and congenital malformations in infants. METHODS: PubMed and Web of Science databases were systematically searched from inception to 21 March 2016. Additional studies were identified in a manual search of the reference lists. Two reviewers independently extracted data. A third reviewer checked the data. Estimates were pooled using a random-effects model to calculate the summarized relative ratios (RR) and 95% confidence intervals (CI). RESULTS: Among 1918 initially identified articles, 16 cohort studies were included. The offspring of pregnant women exposed to fluoxetine during the first trimester had a statistically increased risk of major malformations (RR = 1.18, 95% CI = 1.08-1.29), cardiovascular malformations (RR = 1.36, 95% CI = 1.17-1.59), septal defects (RR = 1.38, 95% CI = 1.19-1.61), and non-septal defects (RR = 1.39, 95% CI = 1.12-1.73) with low heterogeneity in infants. There were no significant observations of other system-specific malformations in the nervous system, eye, urogenital system, digestive system, respiratory system, or musculoskeletal system, respectively. There was no indication of publication bias. CONCLUSIONS: The results of this meta-analysis indicate maternal fluoxetine use is associated with a slightly increased risk of cardiovascular malformations in infants. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with fluoxetine during pregnancy.

Sertraline use in the first trimester and risk of congenital anomalies: a systemic review and meta-analysis of cohort studies.

AIM: To perform a meta-analysis of available cohort studies on the association between sertraline use by pregnant women in the first trimester and the findings of congenital anomalies in infants. METHODS: A comprehensive search of articles published from the index date up to 31st December 2015 investigating the aforementioned associations was conducted on PubMed and Web of Science. Mesh headings used included the terms "serotonin reuptake inhibitor," "sertraline," "congenital anomalies" and "obstetrical outcome." RESULTS: Twelve cohort studies that involved 6 468 241 pregnant women were identified. We summarized odds ratios (ORs) and 95% confidence intervals (CIs) of congenital anomalies using the random-effects model. Pregnant women who used sertraline in the first trimester had a statistically significant increased risk of infant cardiovascular-related malformations (OR = 1.36; 95% CI = 1.06-1.74; I2  = 64.4%; n = 12) as well as atrial and/or ventricular septal defects (OR = 1.36, 95% CI = 1.06-1.76; I2  = 62.2%; n = 8). Additionally, positive but nonsignificant associations between sertraline use and congenital anomalies of the nervous system (OR = 1.39; 95% CI = 0.83-2.32; I2  = 0%; n = 5), digestive system (OR = 1.23; 95% CI = 0.76-1.98; I2  = 0%; n = 5), eye, ear, face and neck (OR = 1.08; 95% CI = 0.33-3.55; I2  = 32.1%; n = 3), urogenital system (OR = 1.03; 95% CI = 0.73-1.46; I2  = 0%; n = 5), and musculoskeletal system (OR = 0.97; 95% CI = 0.69-1.36; I2  = 0%; n = 5) were observed. CONCLUSION: This meta-analysis suggested that the use of sertraline use by pregnant women in the first trimester had an increased risk of cardiovascular-related malformations as well as atrial and/or ventricular septal defects in infants. Meanwhile, nonsignificant associations between sertraline use and other congenital anomalies were found. More cohort studies are warranted to provide detailed results of other congenital anomalies.

[Investigation of the risk of hepatitis B virus reactivation in arthritis patients undergoing anti-tumour necrosis factor alpha therapy].

OBJECTIVE: To investigate the prevalence of HBV infection and the risk of hepatitis B virus (HBV) reactivation in patients with inflammatory arthritis receiving tumour hecrosis factor alpha (TNFα) inhibitors. METHODS: The liver function, serology of HBV and viral loads (HBV DNA) were tested before using TNFα inhibitors, at 3 months and 6 months. Patients with chronic hepatitis B (CHB) infection (HBV DNA > 1×10(3) copies/ml) were eliminated. RESULTS: A total of 162 patients were investigated including 156 patients who finished the study. Eleven (7.05%) patients were HBsAg-positive. Two patients with HBV DNA > 1×10(3) copies/ml were eliminated before starting anti-TNFα therapy. Among HBsAg-positive patients, HBV reactivation was documented in only one of the 11 patients. This patient with rheumatoid arthritis developed elevation of glutamic-pyruvic transaminase (ALT) and HBV DNA copies three months after infliximab therapy. Therefore lamivudine was given for three months, which translated into the fall of ALT and HBV DNA copies back to normal level. After follow-up for six months, the virology and serology remained stable. In contrast, none of the other 155 patients had demonstrated evidence of HBV infection or HBV reactivation. CONCLUSION: The kinetics of HBV viral loads should be carefully monitored in patients with inflammatory arthritis and HBsAg-positive during anti-TNFα therapy. HBV reactivation should be treated with antiviral medicine through out the period of anti-TNFα therapy.

Serum Levels of MDC and MMP-9 and the Relationship Between Serum Levels and Disease Activity in the Patients with Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVE: Systemic lupus erythematosus (SLE) is a complicated autoimmune disease. Although its pathogenesis is not clear, cytokine may be involved in it. So we investigated serum levels of macrophage-derived chemokine (MDC), and matrix metalloproteinase-9 (MMP-9), and to determine the relationship between serum levels and the disease activity of SLE. METHODS: Serum levels of MDC and MMP-9 were measured by enzyme-linked immuno sorbent assay (ELISA). RESULTS: Significantly decreased serum levels of MDC and MMP-9 were found in SLE as compared to those in controls (P<0.001 P<0.001), but serum levels of MDC and MMP-9 increased after treatment (P<0.001 P<0.05). Serum levels of MDC and MMP-9 were lower in patients with active disease than those with inactive disease (P<0.001 P<0.05). Significantly decreased serum levels of MDC and MMP-9 were found in patients with renal damage than those without the damage (P<0.001 P<0.05). Serum level of MDC was lower in patients with arthritis than those without the damage (P<0.001), but serum level of MMP-9 has no significant difference in two groups (P>0.05). CONCLUSION: The present data suggest that MDC and MMP-9 may be involved in the pathogenesis of SLE, and serum levels of MDC and MMP-9 could be markers of monitoring disease activity, renal damage, disease progression and improvement in SLE.

Dietary fructose regulates hepatic manganese homeostasis in female mice.

Arginase, an enzyme dependent on manganese (Mn), plays a crucial role in the production of urea and processing of ammonia in the liver. Previous studies have shown that overconsumption of fructose disrupts Mn homeostasis in the liver of male mice. However, the potential sex-specific differences in the impact of fructose on hepatic Mn homeostasis remain uncertain. In this study, we provide evidence that heightened fructose intake disrupts liver Mn homeostasis in female mice. Elevated fructose exposure led to a reduction in liver Mn levels, resulting in decreased arginase and manganese superoxide dismutase (Mn-SOD) activity in the liver of female mice. The underlying mechanism involves the upregulation of carbohydrate-responsive element binding protein (ChREBP) expression and the Mn exporting gene Slc30a10 in the liver in response to fructose consumption. In summary, our findings support the involvement of fructose in liver Mn metabolism via the ChREBP/Slc30a10 pathway in female mice, and indicate that there is no disparity in the impact of fructose on hepatic Mn homeostasis between sexes.

KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2.

Potassium Channel Tetramerization Domain Containing 15 (KCTD15) participates in the carcinogenesis of several solid malignancies; however, its role in colorectal cancer (CRC) remains unclear. Here we find that KCTD15 exhibits lower expression in CRC tissues as compared to para-carcinoma tissues. Tetracycline (tet)-induced overexpression and knockdown of KCTD15 confirms KCTD15 as an anti-proliferative and pro-apoptotic factor in CRC both in vitro and in xenografted tumors. N6-methyladenosine (m6A) is known to affect the expression, stabilization, and degradation of RNAs with this modification. We demonstrate that upregulation of fat mass and obesity-associated protein (FTO), a classical m6A eraser, prevents KCTD15 mRNA degradation in CRC cells. Less KCTD15 RNA is recognized by m6A 'reader' YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) in FTO-overexpressed cells. Moreover, KCTD15 overexpression decreases protein expression of histone deacetylase 1 (HDAC1) but increases acetylation of critical tumor suppressor p53 at Lys373 and Lys382. Degradation of p53 is delayed in CRC cells post-KCTD15 overexpression. We further show that the regulatory effects of KCTD15 on p53 are HDAC1-dependent. Collectively, we conclude that KCTD15 functions as an anti-growth factor in CRC cells, and its expression is orchestrated by the FTO-YTHDF2 axis. Enhanced p53 protein stabilization may contribute to KCTD15's actions in CRC cells.