Approximately 70% epilepsy may be associated with genetic etiology. To date, more than 2 900 genes related to epilepsy have been reported, and genotype-phenotype association in epilepsy has received increasing attention. Explaining how mutations in the same gene can lead to different diseases or phenotypes remains challenging. Sub-molecular mechanisms, including functional structural domains, amino acid substitutions, isoforms, and monoallelic/biallelic mutations, provide new perspectives for deciphering genotype-phenotype association in epilepsy. This review summarizes the role of sub-molecular mechanisms in genotype-phenotype association in epilepsy, to provide new strategies for clinical diagnosis and precise treatment of epilepsy.

Approximately 70% epilepsy may be associated with genetic etiology. To date, more than 2 900 genes related to epilepsy have been reported, and genotype-phenotype association in epilepsy has received increasing attention. Explaining how mutations in the same gene can lead to different diseases or phenotypes remains challenging. Sub-molecular mechanisms, including functional structural domains, amino acid substitutions, isoforms, and monoallelic/biallelic mutations, provide new perspectives for deciphering genotype-phenotype association in epilepsy. This review summarizes the role of sub-molecular mechanisms in genotype-phenotype association in epilepsy, to provide new strategies for clinical diagnosis and precise treatment of epilepsy.

Objective By screening and passaging G0 generation Wistar rats,we obtained hypoxia-sensitive and hypoxia-tolerant G1 generation rats,and then the differences in hypoxia sensitivity among these rats were preliminarily explored.Methods 200 Wistar rats(half male and half female)were selected as G0 generation and placed in a controlled oxygen concentration system.The hypoxia tolerance time,which refers to the time from placement to near death,was recorded for the G0 generation rats at an oxygen volume fraction of 3％.30 rats(half male and half female)with the shortest hypoxia tolerance time were selected for mating and passage to obtain G1 generation hypoxia-sensitive rats.Similarly,30 rats(half male and half female)with the longest hypoxia tolerance time were selected for mating and passage to obtain G1 generation hypoxia-tolerant rats.An additional 24 standard Wistar rats were randomly divided into two groups:a control group and a model group,with 12 rats in each group(half male and half female).The control group was kept in a normoxic environment,while the model group,along with the G1 generation hypoxia-sensitive rats(G1 sensitive group)and G1 generation hypoxia-tolerant rats(G1 tolerant group),were placed in a hypobaric hypoxia chamber(simulating an altitude of 5 000 m).After 12 hours,various indicators,including blood gas,complete blood count,blood biochemistry,pathological sections,and hypoxia-related genes were detected or observed to compare the differences in hypoxia sensitivity among the 4 groups.Results Compared with the G0 generation standard rats,the hypoxia tolerance time of G1 generation rats was significantly prolonged(P＜0.01).Compared with the model group,the oxygen saturation(SatO2)in G1 tolerant group was significantly higher(P＜0.05).In the G1 sensitive group,the levels of white blood cell(WBC)count,neutrophil(NEUT)count,hemoglobin(HGB)concentration,hematocrit(HCT),red blood cell distribution width(RDW),platelet(PLT),and creatinine(Cr)significantly increased(P＜0.05 or P＜0.01),while actual bicarbonate(AB)content significantly decreased(P＜0.05),and the brain and lung coefficients were significantly elevated(P＜0.05).In addition,pathological section results showed that the brain and lung tissues in the model group,G1 sensitive group,and G1 tolerant group all suffered from significant damage,with no evident differences in the gene expression levels of hypoxia-inducible factor-1 α(HIF-1α)and vascular endothelial growth factor A(VEG FA)in brain tissues amongthe three groups(P＞0.05).Conclusion Compared with standard rats,G1 generation hypoxia-sensitive/tolerant rats exhibit good signs of hypoxia sensitivity/tolerance traits,but further screening and passage are still needed to purify them.

Objective A comparative study was conducted on rapid high-altitude models established in SD rats under two hypoxic stress modes,namely,a high-altitude field and simulated high-altitude environment,to evaluate the reliability of the simulated high-altitude test chamber.Methods SD rats were placed in a simulated rapid high-altitude animal experimental chamber(4000 m)or rapid high-altitude field laboratory(4010 m)to establish a rapid high-altitude rat model.After 24 or 72 h of exposure,physiological and pathological indicators related to high-altitude changes were collected and measured,mainly routine blood parameters,blood biochemistry,blood gas,oxidative damage indicators(superoxide dismutase(SOD),malondialdehyde(MDA),glutathione peroxidase(GSH-Px)),and inflammation indicators(interleukin 1β(IL-1 β),interferon-γ(IFN-γ),monocyte chemotactic protein 1(MCP-1)and interleukin 6(IL-6)),and pathological tissue analysis and hypoxia sensitive gene(hypoxia inducible factor-1α(Hif-1α)and vascular endothelial growth factor A(Vegfa))testing were performed.Finally,differential analysis was conducted on the result to obtain a differential evaluation report.Results At the same altitude,both high-altitude field and simulated high-altitude exposure for 72 h caused significant lung and brain damage.Under the same exposure time,the routine blood parameter,blood biochemistry,and blood gas result for the rats were similar.There were no significant differences in the detection of inflammation indicators(IL-6,IL-1β,MCP-1,and IFN-y),oxidative damage indicators(MDA,SOD,and GSH),or hypoxia-sensitive gene expression(Hif-1α and Vegfa)in the brain.However,partial pressure of carbon dioxide(PaCO2)and base excess(BE)were significantly higher in the simulated-72 h group than the other treatment group.The lung hypoxia-sensitive genes(Hif-1α and Vegfa)in the simulated-72 h group showed no significant expression difference with control group,and the brain coefficient of the high-altitude field treatment group was significantly higher than that of the simulated high-altitude treatment group.These result indicate that there may be slight differences between models prepared in high-altitude field and simulated high-altitude environments.Conclusions The simulated high-altitude animal experimental chamber can successfully establish a rapid high-altitude animal model.The simulated altitude can be appropriately increased on the basis of 4000 m.If an altitude of 4000 meters is used,the exposure time should be greater than 24 h but slightly shorter than 72 h.The simulated high-altitude experimental module has good reliability,but it is advisable to use plateaus for on-site experiments as much as possible,if conditions permit.

Mendelian Randomization Analysis ; Bone Density ; Genome-Wide Association Study ; Minerals ; Life Expectancy ; Polymorphism, Single Nucleotide

Objective: To conduct a systematic review and meta-analysis of studies evaluating the oncological and fertility outcomes of early-stage endometrial cancer (EC) treated with the levonorgestrel-releasing intrauterine system (LIUS)-based regimens. Methods: The Meta-analyses Of Observational Studies in Epidemiology statement for meta-analyses was followed. Searches were conducted on MEDLINE, Embase, PubMed, Preprints, and the Cochrane Central Register of Controlled Trials from January 1990 to August 4, 2022. The Joanna Briggs Institute Critical Appraisal Checklist was used for quality assessment. The primary endpoint was the complete response (CR) rate and the secondary endpoints were relapse, pregnancy, and live birth rate. Results: A total of 25 studies (821 women) were included. The CR rate of LIUS-based regimens was 63.4% (95% confidence interval [CI]=52.3%–73.2%), with 29.6% (95% CI=23.3%–36.8%) of cases experiencing recurrence during follow-up. In sensitivity analyses, patients younger than 45 years of age with a body mass index <30 kg/m2 who were treated with LIUS-based regimens achieved a high CR rate of 84.6% (95% CI=80.3%–88.1%) over a median follow-up of more than 24 months. Overall pregnancy and live birth rates were 37.9% (95% CI=24.1%–53.9%) and 39.3% (95% CI=24.0%–57.0%), respectively. No statistical differences were apparent in CR or relapse rates among the LIUS+GnRH agonist, LIUS+oral progesterone, or hysteroscopic resection followed by LIUS subgroups. Conclusion LIUS-based therapies are viable for the conservative management of early-stage endometrioid EC on CR and fertility outcome.

Objective:To investigate the impact of uterine volume prior to fresh embryo transfer on reproductive outcomes in infertile patients with adenomyosis.Methods:A retrospective cohort study was conducted for the clinical data of patients diagnosed with adenomyosis and aged ≤40 years undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) with ultra-long downregulation stimulation protocol in Center for Reproductive Medicine, Department of Obstetrics and Gynecology of Peking University Third Hospital between January 2009 and December 2018. Logistic regression model was used to analyze the correlation between uterine volume and clinical outcomes. Study subjects were divided into three groups based on uterine volume before embryo transfer: group A 56-90 cm 3 (equivalent to uterine size within 6 weeks of pregnancy); group B 90-130 cm 3 (equivalent to 6-8 weeks gestation); group C ≥130 cm 3 (equivalent to uterine size greater than 8 weeks gestation), the effect of uterine volume on clinical outcomes was compared. Results:Totally 232 patients were included, 153 patients in group A, 52 patients in group B, 27 patients in group C. The data showed no statistical difference among the three groups in basic characteristics ( P>0.05). There was no significant difference in clinical pregnancy rate among three groups ( P>0.05). The incidence of miscarriage among three groups were significantly different [group A, 24.59% (15/61); group B, 64.71% (11/17); group C, 55.56% (5/9), P=0.018]. Compared with group A [30.07% (46/153)], the live birth rate of group B [11.54% (6/52)] was significantly reduced ( P=0.009). Logistic regression analysis showed that uterine volume before ET was not related to clinical pregnancy rate ( OR=0.762, 95% CI=0.481-1.208, P=0.248), and was positively related to miscarriage rate ( OR=2.822, 95% CI=1.165-6.835, P=0.022) while negatively correlated with live birth rate ( OR=0.458, 95% CI=0.238-0.881, P=0.019). Conclusion:An increased level of uterine volume prior to embryo transfer (especially larger than 90 cm 3) increases miscarriage rate and reduces the live birth rate in infertile patients with adenomyosis. Therefore, controlling uterine volume is still a key to improve the clinical outcome of IVF-ET in adenomyosis patients.

Objective:To investigate the impact of uterine volume prior to fresh embryo transfer on reproductive outcomes in infertile patients with adenomyosis.Methods:A retrospective cohort study was conducted for the clinical data of patients diagnosed with adenomyosis and aged ≤40 years undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) with ultra-long downregulation stimulation protocol in Center for Reproductive Medicine, Department of Obstetrics and Gynecology of Peking University Third Hospital between January 2009 and December 2018. Logistic regression model was used to analyze the correlation between uterine volume and clinical outcomes. Study subjects were divided into three groups based on uterine volume before embryo transfer: group A 56-90 cm 3 (equivalent to uterine size within 6 weeks of pregnancy); group B 90-130 cm 3 (equivalent to 6-8 weeks gestation); group C ≥130 cm 3 (equivalent to uterine size greater than 8 weeks gestation), the effect of uterine volume on clinical outcomes was compared. Results:Totally 232 patients were included, 153 patients in group A, 52 patients in group B, 27 patients in group C. The data showed no statistical difference among the three groups in basic characteristics ( P>0.05). There was no significant difference in clinical pregnancy rate among three groups ( P>0.05). The incidence of miscarriage among three groups were significantly different [group A, 24.59% (15/61); group B, 64.71% (11/17); group C, 55.56% (5/9), P=0.018]. Compared with group A [30.07% (46/153)], the live birth rate of group B [11.54% (6/52)] was significantly reduced ( P=0.009). Logistic regression analysis showed that uterine volume before ET was not related to clinical pregnancy rate ( OR=0.762, 95% CI=0.481-1.208, P=0.248), and was positively related to miscarriage rate ( OR=2.822, 95% CI=1.165-6.835, P=0.022) while negatively correlated with live birth rate ( OR=0.458, 95% CI=0.238-0.881, P=0.019). Conclusion:An increased level of uterine volume prior to embryo transfer (especially larger than 90 cm 3) increases miscarriage rate and reduces the live birth rate in infertile patients with adenomyosis. Therefore, controlling uterine volume is still a key to improve the clinical outcome of IVF-ET in adenomyosis patients.

Objective To analyze the clinical and pathological features of chronic hepatitis B (CHB) patients with hepatic steatosis.Methods Clinical and pathological data of 841 patients with CHB who underwent liver biopsy in Zhejiang Provincial People’s Hospital during September 2015 to September 2018 were retrospectively reviewed.One hundred and thirty five gender and age-matched pairs of steatosis and non-steatosis patients entered the analysis.Multivariable Logistic regression and rank sum test were used to analyze the clinical features and risk factors of hepatic steatosis in CHB patients .Spearman correlation test was used to analyze the correlation between hepatic steatosis and HBV DNA , hepatic inflammation and fibrosis status.Results Logistic regression analysis showed that overweight ／obesity ( χ2 ＝3.947, OR ＝1.436, 95%CI 1.005-2.051, P＜0.05) and hyperlipidemia (χ2 ＝4.277,OR＝1.803,95%CI 1.031-3.151, P＜0.05) were the risk factors for hepatic steatosis in CHB patients.There was no correlation of hepatic steatosis with serum HBeAg and HBV DNA levels (Z＝-1.762,r＝-0.011, both P＞0.05). However, hepatic steatosis was negatively correlated with inflammatory grade and fibrosis grade of the liver (r＝-0.146 and -0.192, both P＜0.05).Conclusions Overweight／obesity and hyperlipidemia are associated with steatosis in CHB patients.Hepatic steatosis may not aggravate the degree of liver inflammation and fibrosis in CHB patients.

Objective To compare the organ coefficients and expressions of hypoxia-related genes in Bama and Juema pigs.Method Real-time quantitative PCR was used to detect the changes of hypoxia gene expressions in the heart,liver,spleen,lung,and kidney of Juema and Bama miniature pigs.Results The organ coefficients of kidney and spleen of Juema pigs were significantly lower than Bama miniature pigs (P<0.05 for both).The heart and lung coefficients of Juema pigs were significantly higher than that of Bama miniature pigs (P<0.05 for both).The VEGF and HIF-1α expressions in the lung and kidney in Juema pigs were significantly higher than Bama pigs (P<0.05 or P<0.01).Only the EPO expression in in the lung of Juema pigs was significantly higher than that of the Bama miniature pigs (P<0.05).Conclusions These results indicate that the variation in organ coefficients may be resulted from evolutionary factors such as adaptiveness to environmental physical and energy conditions,pathogens,and energy metabolism demands,etc.in combination.Juema miniature pigs showing a significantly higher expression of hypoxia-related genes than that in Bama minipigs indicate that it has a strong plateau adaptability by higher gene expressions.