Placental DNA methylation analysis of selective fetal growth restriction in monochorionic twins reveals aberrant methylated CYP11A1 gene for fetal growth restriction.

Fetal growth restriction (FGR) is associated with increased susceptibility to perinatal morbidity and mortality. Evidence suggests that epigenetic changes play critical roles in the regulation of fetal growth. We sought to present a comprehensive analysis of the associations between placental DNA methylation and selective fetal growth restriction (sFGR), which is a severe complication of monochorionic twin pregnancies, characterized by one fetus experiencing restricted growth. Genome-wide methylation analysis was performed on 24 placental samples obtained from 12 monochorionic twins with sFGR (Cohort 1) using Illumina Infinium MethylationEPIC BeadChip. Integrative analysis of our EPIC data and two previous placental methylation studies of sFGR (a total of 30 placental samples from 15 sFGR twins) was used to identify convincing differential promoter methylation. Validation analysis was performed on the placentas from 15 sFGR twins (30 placental samples), 15 FGR singletons, and 14 control singletons (Cohort 2) using pyrosequencing, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry (IHC). A globe shift toward hypomethylation was identified in the placentas of growth-restricted fetuses compared with the placentas of normal fetuses in monochorionic twins, including 5625 hypomethylated CpGs and 452 hypermethylated CpGs, especially in the regions of CpG islands, gene-body and promoters. The analysis of pathways revealed dysregulation primarily in steroid hormone biosynthesis, metabolism, cell adhesion, signaling transduction, and immune response. Integrative analysis revealed a differentially methylated promoter region in the CYP11A1 gene, encoding a rate-limiting enzyme of steroidogenesis converting cholesterol to pregnenolone. The CYP11A1 gene was validated to have hypomethylation and higher mRNA expression in sFGR twins and FGR singletons. In conclusion, our findings suggested that the changes in placental DNA methylation pattern in sFGR may have functional implications for differentially methylated genes and regulatory regions. The study provides reliable evidence for identifying abnormally methylated CYP11A1 gene in the placenta of sFGR.

Effect of acupuncture on regulating IL-17, TNF-ɑ and AQPs in Sjögren's syndrome.

AIM: The aim of the study was to observe the effect of acupuncture on regulating interleukin (IL)-17, tumor necrosis factor (TNF)-ɑ, and aquaporins (AQPs) in Sjögren's syndrome (SS) on patients and on non-obese diabetic (NOD) models. METHODS: Levels of anti-AQP 1, 5, 8, and 9 antibodies, IL-17, and TNF-ɑ in the serum of SS patients were compared prior and following 20 acupuncture treatment visits during 8 weeks. While in murine model, five groups were divided to receive interventions for 4 weeks, including control, model, acupuncture, isoflurane, and hydroxychloroquine. The submaxillofacial gland index, histology, immunohistochemistry of AQP1, 5, salivary flow, together with IL-17, and TNF-ɑ expression in peripheral blood were compared among the groups. RESULTS: Acupuncture reduced IL-17, TNF-ɑ, and immunoglobin A levels, and numeric analog scale of dryness in 14 patients with SS (p < 0.05). The salivary flow was increased, and the water intake decreased in NOD mice receiving acupuncture treatments. IL-17 and TNF-ɑ levels in peripheral serum were down-regulated (p < 0.05) and AQP1, 5 expression in the submandibular glands up-regulated in mice. CONCLUSION: The effect on relieving xerostomia with acupuncture may be achieved by up-regulating the expression of AQP1. AQP5, down-regulating levels of IL-17 and TNF-ɑ, and a decrease in inflammation of glands.

Low-molecular-weight organic acids inhibit the methane-dependent arsenate reduction process in paddy soils.

Anaerobic methane oxidation (AOM) can drive soil arsenate reduction, a process known as methane-dependent arsenate reduction (M-AsR), which is a critical driver of arsenic (As) release in soil. Low molecular weight organic acids (LMWOAs), an important component of rice root exudates, have an unclear influence and mechanism on the M-AsR process. To narrow this knowledge gap, three typical LMWOAs-citric acid, oxalic acid, and acetic acid-were selected and added to As-contaminated paddy soils, followed by the injection of 13CH4 and incubation under anaerobic conditions. The results showed that LMWOAs inhibited the M-AsR process and reduced the As(III) concentration in soil porewater by 35.1-65.7 % after 14 days of incubation. Among the LMWOAs, acetic acid exhibited the strongest inhibition, followed by oxalic and citric acid. Moreover, LMWOAs significantly altered the concentrations of ferrous iron and dissolved organic carbon in the soil porewater, consequently impacting the release of As in the soil. The results of qPCR and sequencing analysis indicated that LMWOAs inhibited the M-AsR process by simultaneously suppressing microbes associated with ANME-2d and arrA. Our findings provide a theoretical basis for modulating the M-AsR process and enhance our understanding of the biogeochemical cycling of As in paddy soils under rhizosphere conditions.

Dynamics of T follicular helper cells in patients with rheumatic diseases and subsequent antibody responses in a three-dose immunization regimen of CoronaVac.

Given increased acceptance of the CoronaVac, there is an unmet need to assess the safety and immunogenic changes of CoronaVac in patients with rheumatic diseases (RD). Here we comprehensively analysed humoral and cellular responses in patient with RD after a three-dose immunization regimen of CoronaVac. RD patients with stable condition and/or low disease activity (n = 40) or healthy controls (n = 40) were assigned in a 1:1 ratio to receive CoronaVac (Sinovac). The prevalence of anti-receptor binding domain (RBD) antibodies and neutralizing antibodies was similar between healthy control (HC) and RD patients after the second and the third vaccination. However, the titers of anti-RBD IgG and neutralizing antibodies were significantly lower in RD patients compared to HCs (p < 0.05), which was associated with an impaired T follicular helper (Tfh) cell response. Among RD patients, those who generated an antibody response displayed a significantly higher Tfh cells compared to those who failed after the first and the second vaccination (p < 0.05). Interestingly, subjects with a negative serological response displayed a similar Tfh memory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides as their anti-RBD IgG positive counterpart, and all (4/4) of the non-responders in HCs, and 62.5% (5/8) of the non-responders in patients with RD displayed a positive serological response following the third dose. No serious adverse events were observed. In conclusion, our findings support SARS-CoV-2 vaccination in patients with RD with stable and/or low disease activity. The impaired ability in generating vaccine-specific antibodies in patients with RD was associated with a reduction in Tfh cells induction. The window of vaccination times still needs to be explored in future studies. Clinical trial registration: This trial was registered with ChiCTR2100049138.

Chromosomal abnormalities in recurrent pregnancy loss and its association with clinical characteristics.

OBJECTIVE: To evaluate the distribution of chromosomal abnormalities in a recurrent pregnancy loss (RPL) cohort and explore the associations between chromosomal abnormalities and clinical characteristics. METHOD: Over a 5-year period, fresh products of conception (POC) from women with RPL were analyzed by single-nucleotide polymorphism (SNP) array at our hospital. After obtaining the information on clinical characteristics, we investigated the associations between the causative chromosomal abnormalities and clinical characteristics by the chi-squared test or Fisher's exact test and logistic regression. RESULTS: A total of 2383 cases were enrolled. Overall, 56.9% (1355/2383) were identified with causative chromosomal abnormalities, of which 92.1% (1248/1355) were numerical abnormalities, 7.5% (102/1355) were structural variants, and 0.4% (5/1355) were loss of heterozygosity (LOH). The risk of numerical abnormalities was increased in women with maternal age ≥ 35 years (OR, 1.71; 95% CI, 1.41-2.07), gestational age at pregnancy loss ≤ 12 weeks (OR, 2.78; 95% CI, 1.79-4.33), less number of previous pregnancy losses (twice: OR, 2.32; 95% CI, 1.84-2.94; 3 times: OR, 1.59; 95% CI, 1.23-2.05, respectively), and pregnancy with a female fetus (OR, 1.37; 95% CI, 1.15-1.62). The OR of pregnancy loss with recurrent abnormal CMA was 4.00 (95% CI: 1.87-8.58, P < 0.001) and the adjusted OR was 5.05 (95% CI: 2.00-12.72, P = 0.001). However, the mode of conception was not associated with the incidence of numerical abnormality. No association was noted between structural variants and clinical characteristics. CONCLUSION: Chromosomal abnormality was the leading cause of RPL. Numerical chromosome abnormality was more likely to occur in cases with advanced maternal age, an earlier gestational age, fewer previous pregnancy losses, and pregnancy with a female fetus.

Extraction of impacted mandibular third molars in close proximity to the inferior alveolar canal with coronectomy-miniscrew traction to avoid nerve injury.

OBJECTIVES: Extraction of impacted mandibular third molars (IMTMs) is the most common surgery performed in the Department of Oral and Maxillofacial Surgery. Inferior alveolar nerve (IAN) injury is a rare but severe complication, and the risk is significantly higher in cases of IMTM near the inferior alveolar canal (IAC). The existing surgical method to extract such IMTMs is either not safe enough or is time-consuming. A better surgical design is needed. MATERIALS AND METHODS: From August 2019 to June 2022, 23 patients underwent IMTM extraction by Dr. Zhao at Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, and were found to have IMTMs in close proximity to the IAC. Due to high IAN injury risk, these patients underwent coronectomy-miniscrew traction to extract their IMTMs. RESULTS: The time between coronectomy-miniscrew insertion and complete removal of the IMTM was 32.65 ± 2.110 days, which was significantly shorter than that of traditional orthodontic traction. Two-point discrimination testing revealed no IAN injury, and no injury was reported by patients during follow-up. Other complications, such as severe swelling, severe bleeding, dry socket, and limited mouth opening, were not observed. Postoperative pain levels were not significantly higher in the coronectomy-miniscrew traction group than in the traditional IMTM extraction group. CLINICAL RELEVANCE: For IMTMs that are in close proximity to the IAC and must be extracted, coronectomy-miniscrew traction is a novel approach to minimize the risk of IAN injury in a less time-consuming way with a lower possibility of complications.

The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study.

OBJECTIVE: We aimed to study the value of exome sequencing (ES) in severe pleural effusion with nonimmune hydrops fetalis (NIHF) that underwent thoracoamniotic shunt (TAS). METHODS: It was a retrospective study of NIHF that underwent TAS between 2012 and 2020 at Shanghai First Maternity and Infant Hospital. After a detailed assessment, NIHF cases with aneuploidies, infections, and structural anomalies were excluded, and TAS was offered to cases with severe pleural effusion. Quantitative fluorescence polymerase chain reaction (QF-PCR) was conducted to exclude Trisomy 21, 18, and 13 before fetal therapy, and chromosomal microarray analysis (CMA) was offered to all the cases. Before 2019, ES was retrospectively performed using stored fetal DNA extracted from prenatal samples; from 2019 onward, ES was discussed and offered before intrauterine therapies. RESULTS: A total of 18 NIHF cases underwent TAS with negative CMA and continuing pregnancy were included. Fetal hydrops was relieved in 16 cases (88.9%). The median gestational ages at intervention and at delivery were 31.2 (22.0-33.1) weeks and 34.3 (29.7-38.6) weeks, respectively. The neonatal survival rate was 72.2% (13/18), and no causative gene variants were identified from ES in any survivors. Pathogenic or likely pathogenic variants were detected in 3 out of 5 neonatal deaths. If rapid ES could have been available to guide fetal therapy, the neonatal survival rate after TAS would have increased from 72.2% to 86.7%. CONCLUSIONS: Single-gene disorders were one of the major causes of perinatal death in NIHF cases that underwent fetal therapy. Prenatal rapid ES may be of good promise in NIHF to explore precise etiology and guide fetal therapy.

The Future of Targeted Treatment of Primary Sjögren's Syndrome: A Focus on Extra-Glandular Pathology.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease defined by exocrine gland hypofunction resulting in dry eyes and dry mouth. Despite increasing interest in biological therapies for pSS, achieving FDA-approval has been challenging due to numerous complications in the trials. The current literature lacks insight into a molecular-target-based approach to the development of biological therapies. This review focuses on novel research in newly defined drug targets and the latest clinical trials for pSS treatment. A literature search was conducted on ClinicalTrials.gov using the search term "Primary Sjögren's syndrome". Articles published in English between 2000 and 2021 were included. Our findings revealed potential targets for pSS treatment in clinical trials and the most recent advances in understanding the molecular mechanisms underlying the pathogenesis of pSS. A prominent gap in current trials is in overlooking the treatment of extraglandular symptoms such as fatigue, depression, and anxiety, which are present in most patients with pSS. Based on dryness and these symptom-directed therapies, emerging biological agents targeting inflammatory cytokines, signal pathways, and immune reaction have been studied and their efficacy and safety have been proven. Novel therapies may complement existing non-pharmacological methods of alleviating symptoms of pSS. Better grading systems that add extraglandular symptoms to gauge disease activity and severity should be created. The future of pSS therapies may lie in gene, stem-cell, and tissue-engineering therapies.

Effect of HIF1α on the TRPC6 channel of glomerular podocytes under chronic hypoxia.

BACKGROUND: Chronic hypoxia plays an important role in the initiation and progression of chronic renal disease. The pathogenic role of chronic hypoxia in tubulointerstitial injury has been investigated widely, but little is known about acute hypoxia implications in glomerular damage. In this study, we investigated the effect of chronic hypoxia on transient receptor potential cation channel 6 (TRPC6) and the underlying mechanism in cultured human podocytes. METHODS: Fluo-3 was used as a calcium indicator of the OAG-induced receptor operated calcium entry (ROCE) and basal [Ca2+]i levels were monitored using laser scanning confocal microscope after exposure of cells to chronic hypoxia. 2-aminoethoxydiphenylborane (2-APB), a pharmacological blocker of TRPCs channels, was used to determine the role of TRPC6 in podocytes under chronic hypoxia. The mRNA expression and protein levels of TRPC6 were determined using Real-time RT-PCR and Western Blotting under normoxic and chronic hypoxic conditions. Actin arrangement was analyzed by confocal microscopy using phalloidin staining of F-actin in podocytes. RESULTS: Cytosolic free Ca2+ was increased by hypoxia or the treatment of TRPC6 agonist OAG under normoxic conditions. The increase of intracellular Ca2+ induced by hypoxia was time- and dose-dependent, which can be inhibited by 2-APB, demonstrating that the changes of intracellular Ca2+ induced by OAG depend on the activation of TRPC6. Further study showed that the TRPC6 expression levels were significantly increased by hypoxia, which were inhibited by the HIF1α inhibitor in podocytes. Similarly, the increase of intracellular Ca2+ induced by hypoxia was decreased when the podocytes were incubated with HIF1α inhibitor. We also found that F-actin was ruptured by hypoxia in podocytes, showing cytoskeleton reorganization. CONCLUSIONS: TRPC6 mRNA and protein expression levels were significantly increased in podocytes under hypoxia, which may result in the increase of intracellular Ca2+. This alternation of TRPC6 may be relevant to the modulation of HIF1α. Hypoxia in podocytes can result in cytoskeleton reorganization, which further leads to podocytes injury and disfunction.

Anticholinergics combined with alpha-blockers for treating lower urinary tract symptoms related to benign prostatic obstruction.

BACKGROUND: Lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) represent one of the most common clinical complaints in men. Alpha-blockers are widely used as first-line therapy for men with LUTS secondary to BPO, but up to one third of men report no improvement in their LUTS after taking alpha-blockers. Anticholinergics used in addition to alpha-blockers may help improve symptoms but it is uncertain how effective they are.  OBJECTIVES: To assess the effects of combination therapy with anticholinergics and alpha-blockers in men with LUTS related to BPO. SEARCH METHODS: We performed a comprehensive search of medical literature, including the Cochrane Library, MEDLINE, Embase, and trials registries, with no restrictions on the language of publication or publication status. The date of the latest search was 7 August 2020. SELECTION CRITERIA: We included randomized controlled trials. Inclusion criteria were men with LUTS secondary to BPO, ages 40 years or older, and a total International Prostate Symptom Score of 8 or greater. We excluded trials of men with a known neurogenic bladder due to spinal cord injury, multiple sclerosis, or central nervous system disease, and those examining medical therapy for men who were treated with surgery for BPO. We performed three comparisons: combination therapy versus placebo, combination therapy versus alpha-blockers monotherapy, and combination therapy versus anticholinergics monotherapy. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, extracted data, and assessed risk of bias. We performed statistical analyses using a random-effects model and interpreted data according to the Cochrane Handbook for Systematic Reviews of Interventions. We used the GRADE approach to rate the certainty of evidence. MAIN RESULTS: We included 23 studies with 6285 randomized men across three comparisons. The mean age of participants ranged from 54.4 years to 73.9 years (overall mean age 65.7 years). Of the included studies, 12 were conducted with a single-center setting, while 11 used a multi-center setting. We only found short-term effect (12 weeks to 12 months) of combination therapy based on available evidence. Combination therapy versus placebo: based on five studies with 2369 randomized participants, combination therapy may result in little or no difference in urologic symptom scores (mean difference (MD) -2.73, 95% confidence interval (CI) -5.55 to 0.08; low-certainty evidence). We are very uncertain about the effect of combination therapy on quality of life (QoL) (MD -0.97, 95% CI -2.11 to 0.16; very low-certainty evidence). Combination therapy likely increases adverse events (risk ratio (RR) 1.24, 95% CI 1.04 to 1.47; moderate-certainty evidence); based on 252 adverse events per 1000 participants in the placebo group, this corresponds to 61 more adverse events (95% CI 10 more  to 119 more) per 1000 participants treated with combination therapy. Combination therapy versus alpha-blockers alone: based on 22 studies with 4904 randomized participants, we are very uncertain about the effect of combination therapy on urologic symptom scores (MD -2.04, 95% CI -3.56 to -0.52; very low-certainty evidence) and QoL (MD -0.71, 95% CI -1.03 to -0.38; very low-certainty evidence). Combination therapy may result in little or no difference in adverse events rate (RR 1.10, 95% CI 0.90 to 1.34; low-certainty evidence); based on 228 adverse events per 1000 participants in the alpha-blocker group, this corresponds to 23 more adverse events (95% CI 23 fewer to 78 more) per 1000 participants treated with combination therapy. Combination therapy compared to anticholinergics alone: based on three studies with 1218 randomized participants, we are very uncertain about the effect of combination therapy on urologic symptom scores (MD -3.71, 95% CI -9.41 to 1.98; very low-certainty evidence). Combination therapy may result in an improvement in QoL (MD -1.49, 95% CI -1.88 to -1.11; low-certainty evidence). Combination therapy likely results in little to no difference in adverse events (RR 1.26, 95% CI 0.81 to 1.95; moderate-certainty evidence); based on 115 adverse events per 1000 participants in the anticholinergic alone group, this corresponds to 4 fewer adverse events (95% CI 7 fewer to 13 more) per 1000 participants treated with combination therapy. AUTHORS' CONCLUSIONS: Based on the findings of the review, combination therapy with anticholinergics and alpha-blockers are associated with little or uncertain effects on urologic symptom scores compared to placebo, alpha-blockers, or anticholinergics monotherapy. However, combination therapy may result in an improvement in quality of life compared to anticholinergics monotherapy, but an uncertain effect compared to placebo, or alpha-blockers. Combination therapy likely increases adverse events compared to placebo, but not compared to alpha-blockers or anticholinergics monotherapy. The findings of this review were limited by study limitations, inconsistency, and imprecision. We were unable to conduct any of the predefined subgroup analyses.

Emotional exhaustion in front-line healthcare workers during the COVID-19 pandemic in Wuhan, China: the effects of time pressure, social sharing and cognitive appraisal.

BACKGROUND: With the increasing spread of COVID-19, healthcare workers, especially front-line medical staff, have become more vulnerable to emotional exhaustion. OBJECTIVES: This study aimed to determine the influence of time pressure on the emotional exhaustion of front-line healthcare workers, and explore the effects of social sharing and cognitive reappraisal on this. METHODS: This cross-sectional study was conducted in March 2020. A total of 232 questionnaires were completed by front-line healthcare workers in Wuhan city, Hubei province, China. Hierarchical linear regression and conditional process analysis were performed to explore the relationships among time pressure, social sharing, cognitive reappraisal, and emotional exhaustion. RESULTS: Time pressure was positively associated with social sharing and emotional exhaustion. Social sharing presented the dark side, a negative effect that was always kept concealed, in terms of the impact on emotional exhaustion. Cognitive reappraisal negatively moderated the relationship between time pressure and social sharing, and it further indirectly influenced the relationship between time pressure and emotional exhaustion through social sharing. CONCLUSIONS: Our findings shed light on how time pressure influences the emotional exhaustion of healthcare workers during the COVID-19 period. Although social sharing is commonly regarded as a positive behavior, we identified a dark side in terms of its impact. We also identified that improving cognitive reappraisal may present a positive strategy toward alleviating emotional exhaustion.

Iguratimod treatment reduces disease activity in early primary Sjögren's syndrome: An open-label pilot study.

OBJECTIVES: To evaluate the efficacy and safety of iguratimod in patients with early primary Sjögren's syndrome (pSS). METHODS: Twenty-seven disease-modifying antirheumatic drug-naive female patients met the revised American-European Consensus Group criteria for pSS were enrolled in this open-label pilot study. Patients were treated with iguratimod 25 mg twice a day for 24 weeks. The disease activity was assessed with European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at 12 and 24 weeks. Salivary and lacrimal gland function, laboratory, and subjective variables were also assessed. Generalized estimating equations were used to analyze parameters over time. RESULTS: ESSDAI (median, 5 versus 2 versus 2, p < .01), IgG (median, 26.6 versus 22.4 versus 21.4 g/L, p < .01) and rheumatoid factor (median, 119.9 versus 94.1 versus 83.8 lU/mL, p < .01) levels decreased significantly during iguratimod treatment. ESSPRI, salivary and lacrimal gland function, fatigue and health-related quality of life did not change during treatment. One patient experienced thrombocytopenia, and no other serious adverse effects were observed. CONCLUSION: In this study, iguratimod treatment is safe and effective for improving disease activity and laboratory parameters in early pSS patients.

Bifid mandibular canals: CBCT assessment and macroscopic observation.

PURPOSE: The bifid mandibular canal is an anatomical variation, which causes anesthetic failure and surgical accidents occasionally. The purpose of this study is to observe the prevalence and anatomical location of bifid mandibular canals, providing clinical value in reducing the occurrence of surgical accidents and postoperative complications. METHODS: A total of 321 outpatients were selected in this study. Their CBCT images were observed, and the prevalence of bifid mandibular canals as well as the composition ratios of each branch type was evaluated according to the classification of Naitoh. The bifid mandibular canals and their branches' diameter, length, horizontal distance to the buccal/lingual wall of the mandible, and vertical distance to the mandibular alveolar ridge were measured. Furthermore, 194 dry adult mandibles from the Department of Oral Anatomy and Physiology of Tianjin Medical University were observed to evaluate the prevalence and the average diameter of retromolar foramina. RESULTS: Of all the 321 patients, 84 (26.17%) cases of bifid mandibular canals and 105 (16.36%) sides of unilateral bifurcation were observed. Based on Naitoh's classification, the retromolar canals were the most common types (46.67%), followed by the forward canals (40.00%), the dental canals (10.48%) and the buccolingual canals (2.86%). In 194 dry adult mandibles, 23 cases (11.86%) and 29 sides (7.47%) of retromolar foramina were found and the average diameter of retromolar foramina was 0.94 ± 0.30 mm. CONCLUSION: More than a quarter of the population has the bifid mandibular canal, which is a potential factor of the onset of surgery accidents. CBCT is an effective method to identify the branches of mandibular canals. Preoperative CBCT examination can help reduce various postoperative complications.

Maternal and umbilical cord serum-derived exosomes enhance endothelial cell proliferation and migration.

We investigated the role of exosomes derived from maternal and umbilical cord blood in the regulation of angiogenesis. We report here that both maternal exosomes (MEs) and umbilical exosomes (UEs) significantly enhance HUVEC proliferation, migration, and tube formation. Importantly, ME-treated HUVECs (MEXs) displayed significantly increased migration, but not proliferation or tube formation, compared with UE-treated HUVECs (UEXs). We found that the expression of a subset of migration-related microRNAs (miRNAs), including miR-210-3p, miR-376c-3p, miR-151a-5p, miR-296-5p, miR-122-5p, and miR-550a-5p, among others, were significantly increased or decreased in UEs, and this altered expression was likely correlated with the differential regulation of HUVEC migration. We also found that the mRNA expression of hepatocyte growth factor (HGF) was up-regulated in MEXs and UEXs and, moreover, that inhibiting HGF partially abolished the enhanced cell migration induced by UEs. Our results suggest that both MEs and UEs greatly enhanced endothelial cell (EC) functions and differentially regulated EC migration, which was mostly attributed to the different expression profiles of exosomal miRNA. These findings highlight the importance of exosomes in the regulation of angiogenesis during pregnancy. Exosomal miRNAs, in particular, may be of great significance for the regulation of angiogenesis in maintaining normal pregnancy.-Jia, L., Zhou, X., Huang, X., Xu, X., Jia, Y., Wu, Y., Yao, J., Wu, Y., Wang, K. Maternal and umbilical cord serum-derived exosomes enhance endothelial cell proliferation and migration.

Dental management of patient with dual antiplatelet therapy: a meta-analysis.

BACKGROUND: It is more common to need dual antiplatelet therapy (DAPT) for patients who had recently inserted coronary artery stent. However, the postoperative bleeding risk of patients in DAPT could significantly increase. The dental management of patients with antithrombotic therapy has always been a controversial problem. Focusing on this issue, this review discussed the available evidence to provide optimal strategy for patients taking dual antiplatelet agents in the dental setting. METHODS: We searched the PubMed, Embase, ScienceDirect, Web of Science (WOS), Cochrane Library, and China National Knowledge Infrastructure (CNKI) which was performed in May 2018. Relevant articles were included according to our inclusion and exclusion criteria. Meta-analysis was conducted with fixed effects models. Subgroup analysis was used due to different dental surgeries. RESULTS: Our meta-analysis included ten studies (continue DAPT vs. placebo, 535 patients vs.2907 patients). The quantitative results indicated that the risk of postoperative bleeding with continuing DAPT experienced significantly increase (RR = 1.95 95% CI [1.07, 3.54]; p = 0.03). There was no statistically significant difference between the postoperative bleeding rate and different dental surgeries (p = 0.72). CONCLUSION: On the current studies, postoperative hemorrhage is exacerbated with DAPT, but it could be controlled by enhancing hemostasis methods. We recommend continuing long-term DAPT before tooth extraction. CLINICAL RELEVANCE: In this work, we systematically evaluated and summarized the results of small clinical trials after reviewing the present literatures on this topic, so that we could propose more objective and more accurate evidence-based recommendations on dental management for patient with dual antiplatelet therapy.

Prenatal diagnosis of skeletal dysplasias using a targeted skeletal gene panel.

OBJECTIVE: This study aimed to perform an accurate and precise diagnosis for fetuses with suspected skeletal anomalies based on an incomplete and limited ultrasound phenotype. METHODS: Proband-only targeted skeletal gene panel sequencing was performed on 12 families who had fetuses with suspected skeletal anomalies based on ultrasound evaluations at a mean gestational age of 24 weeks and 3 days. The fetuses all had normal standard genetic testing yield (karyotyping and microarray). RESULTS: In 10 of 12 fetuses, panel sequencing provided a diagnosis or possible diagnosis with identification of variants in the following genes: FGFR3, COL1A2, IHH, COL2A1, and DYNC2H1. Two cases revealed novel variants in COL2A1 and DYNC2H1. CONCLUSIONS: Our study suggests that targeted skeletal gene panel sequencing is highly sensitive for prenatal diagnosis of fetuses presenting with unexpected ultrasound findings suggestive of a skeletal dysplasia.

Opioid Exposure is Associated with Aberrant DNA Methylation of OPRM1 Promoter Region in a Chinese Han Population.

The µ-opioid receptor (OPRM1) plays an important role in opiate addiction. The OPRM1 gene promoter showed hypermethylation in lymphocytes of opiate addicts as well as opioid medications users, while the methylation status displayed ethnic diversity. The purpose of the study was to investigate the methylation pattern of OPRM1 promoter in the Han Chinese population. We analyzed 22 CpG sites located in OPRM1 promoter in 186 former opiate addicts (94 males and 92 females) and 184 healthy controls (102 males and 82 females). The + 126 CpG site was significantly hypermethylated in the former heroin addicts compared with controls (13.67% versus 8.39%, [Formula: see text], corrected for 36 tests). Six CpG sites were significantly associated with opioid exposure, including the most significant +126 CpG site (opiate addicts 13.57%, control 8.39%, [Formula: see text], corrected for 36 tests), while the +23 GpG site was the only hypomethylated one in former opiate addicts compared with controls (P = 0.0023 after Bonferroni correction). Our results supported that opioid exposure was associated with methylation status of OPRM1 promoter and showed ethnic dependence.

Acupuncture for Primary Sjögren Syndrome (pSS) on symptomatic improvements: study protocol for a randomized controlled trial.

BACKGROUND: Currently, feasible medical treatments are hitherto not satisfying to relieve pSS symptoms, which concerns numbers of clinical doctors. Acupuncture seems to be an alternative to treat pSS and conduces to good symptomatic results. However further research is necessary. This trial is to investigate the efficacy of acupuncture on improving the key symptoms of pSS, which are dryness, pain and fatigue (DPF). METHODS & DESIGN: The study is designed as a randomized controlled trial of two arms with a single centre. We compare acupuncture with sham acupuncture on symptomatic improvements of pSS. A total of 120 pSS patients, aged at least 18, with DPF, will be randomly assigned to acupuncture or sham acupuncture groups, where they will have needle intervention for 8 weeks with 16 weeks of follow-up. Subjects will be assessed each time before interventions during the 8-week intervention, in week 8 after all interventions and in week 12, 16, 20 and 24 for follow-up with different measurements. The primary outcome are the proportions of subjects that have 30% or greater reduction in at least 2 out of 3 items of DPF in Numeric Analog Scale (NAS) scores (0 = the best, 10 = the severest), calculated between the baseline and the average scores of week 2 to 8. The secondary outcome are related to individual items of NAS scores, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Schirmer test score and unstimulated salivary flow, serum Immunoglobulin G, A and M levels, Medical Outcome Study Short Form 36 Short-Form Health Survey (SF-36), Salivary glands ultrasounds, Hospital Anxiety and Depression (HAD) scale score. The secondary outcome scores are to be collected at baseline, in week 8, 16, and 24. Besides, individual items of NAS will also be collected in week 12 and 20. Moreover, subjects' satisfaction and the proportion of the subjects who identified their allocation will also be measured and analyzed. DISCUSSION: This study will be the first randomized and controlled pilot trial of acupuncture on alleviating the symptoms of pSS with relatively long-term follow-up. The result of the study might offer a new option to treat pSS and might be a clinical proof that acupuncture has beneficial effects on pSS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02691377 (February 20, 2016).

Genetic variations in the 3'-untranslated region of SLC18A2 are associated with serum FSH concentration in polycystic ovary syndrome patients and regulate gene expression in vitro.

STUDY QUESTION: Are genetic variations at the human solute carrier family 18 member A2 (SLC18A2) locus associated with the etiology of polycystic ovary syndrome (PCOS) and/or with follicle stimulating hormone (FSH) levels and insulin secretion in PCOS? SUMMARY ANSWER: We found two common genetic variants in the 3'-untranslated region of SLC18A2 (rs363282 and rs363238) that are associated with serum FSH concentration in the PCOS group. WHAT IS KNOWN ALREADY: SLC18A2 is a vesicular monoamine transporter that is essential in dopamine regulation. Dopamine can negatively regulate FSH and insulin secretion through the D2 receptor. STUDY DESIGN, SIZE, DURATION: This study was a cross-sectional examination in women with PCOS (n = 319) and controls (n = 220) from China. PARTICIPANTS/MATERIALS, SETTING, METHODS: The PCOS patients were diagnosed based on the criteria of the Androgen Excess Society, including clinical and/or biochemical signs of hyperandrogenemia plus oligoamenorrhea or polycystic ovaries. Controls had regular menstrual cycles and no hyperandrogenism or other endocrine disorders related to PCOS. Tag single nucleotide polymorphisms (SNPs) were selected based on resequencing data in 48 PCOS patients and linkage disequilibrium analysis. Allele frequencies for variants (rs363282 and rs363238) were examined in PCOS cases and controls along with their relationship to quantitative traits. The samples were further divided into two subgroups for association analysis: AA + AG group and GG group (rs363282), CC + AC group and AA group (rs363238). The functional effects of SLC18A2 variants were measured by luciferase assay. The gene expression of SLC18A2 was compared with the NCBI's Gene Expression Omnibus datasets. MAIN RESULTS AND THE ROLE OF CHANCE: Two common genetic variants in the 3'-untranslated region (rs363282 and rs363238) are associated with serum FSH in the PCOS group (P= 0.005 and P= 0.001, respectively), while no associations were found in controls. Functional studies showed that minor alleles of the two variants (rs363282-G and rs363238-A) had significantly lower luciferase activities than rs363282-A (P= 0.009) and rs363238-C (P = 0.009). LIMITATIONS, REASONS FOR CAUTION: Results were not validated in another independent cohort, though we provided functional evidence of the two SNPs. Because of limited condition, more specific parameters, including ovarian follicle count and anti-Müllerian hormone were not included and relationship between SLC18A2 and these parameters cannot be evaluated. WIDER IMPLICATIONS OF THE FINDINGS: We found a novel association between two genetic variants in SLC18A2 and FSH levels in PCOS patients. These findings might indicate a novel regulatory mechanism in follicular development and maturation in PCOS. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Natural Science Foundation of China (grant numbers 81571501 and 81270747), National Basic Research Program of China (grant number 2015CB943300). No competing interests declared.

Differential DNA methylome profiling of nonfunctioning pituitary adenomas suggesting tumour invasion is correlated with cell adhesion.

Global and gene-specific changes to the epigenome are hallmarks of most tumours including those of pituitary origin, and this fact might offer important clues about diagnostic and therapeutic applications. We performed global DNA methylation screening with 6 invasive and 6 noninvasive nonfunctioning pituitary adenomas (PA) to investigate whether DNA methylation was associated with the invasion of nonfunctioning pituitary adenomas. An additional seven PAs were included as an independent cohort to validate the initial results. Five thousand nine hundred thirty-one CpGs were selected (△ߠ≥0.15 and p value ≤0.01) as differentially methylated sites (DMSs). The hypomethylated DMSs in the invasive PAs were significantly more than the hypermethylated sites. Cluster analysis of 339 CpGs (△ߠ≥0.25 and p value ≤0.001) demonstrated a complete distinction between the invasive and noninvasive nonfunctioning groups. GO analysis of the three hundred seven corresponding genes shown they were involved in homophilic cell adhesion, cell-cell adhesion, cell adhesion and biological adhesion. The mRNA expression of GALNT9 which contain a validated DMS was significantly downregulated in invasive group. Our findings indicate that the differential DNA methylome profiling of invasive and noninvasive nonfunctioning PAs suggesting tumour invasion is correlated with cell adhesion.