Clinical characteristics and outcomes of COVID-19-associated encephalopathy in children.

Apart from the typical respiratory symptoms, coronavirus disease 2019 (COVID-19) also affects the central nervous system, leading to central disorders such as encephalopathy and encephalitis. However, knowledge of pediatric COVID-19-associated encephalopathy is limited, particularly regarding specific subtypes of encephalopathy. This study aimed to assess the features of COVID-19-associated encephalopathy/encephalitis in children. We retrospectively analyzed a single cohort of 13 hospitalized children with COVID-19-associated encephalopathy. The primary outcome was the descriptive analysis of the clinical characteristics, magnetic resonance imaging and electroencephalography findings, treatment progression, and outcomes. Thirteen children among a total of 275 (5%) children with confirmed COVID-19 developed associated encephalopathy/encephalitis (median age, 35 months; range, 3-138 months). Autoimmune encephalitis was present in six patients, acute necrotizing encephalopathy in three, epilepsy in three, and central nervous system small-vessel vasculitis in one patient. Eight (62%) children presented with seizures. Six (46%) children exhibited elevated blood inflammatory indicators, cerebrospinal fluid inflammatory indicators, or both. Two (15%) critically ill children presented with multi-organ damage. The magnetic resonance imaging findings varied according to the type of encephalopathy/encephalitis. Electroencephalography revealed a slow background rhythm in all 13 children, often accompanied by epileptic discharges. Three (23%) children with acute necrotizing encephalopathy had poor prognoses despite immunotherapy and other treatments. Ten (77%) children demonstrated good functional recovery without relapse. This study highlights COVID-19 as a new trigger of encephalopathy/encephalitis in children. Autoimmune encephalitis is common, while acute necrotizing encephalopathy can induce poor outcomes. These findings provide valuable insights into the impact of COVID-19 on children's brains.

Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary.

Di(2-ethylhexyl) phthalate (DEHP) is a widely recognized environmental endocrine disruptor that potentially impacts female reproductive function, although the specific mechanisms leading to such impairment remain unclear. A growing body of research has revealed that the endoplasmic reticulum and mitochondrial function significantly influence oocyte quality. The structure of mitochondria-associated endoplasmic reticulum membranes (MAMs) is crucial for facilitating the exchange of Ca2+, lipids, and metabolites. This study aimed to investigate the alterations in the composition and function of MAMs after DEHP exposure and to elucidate the underlying mechanisms of ovarian toxicity. The female mice were exposed to DEHP at doses of 5 and 500 mg/kg/day for one month. The results revealed that DEHP exposure led to reduced serum anti-Müllerian hormone levels and increased atretic follicles in mice. DEHP induced endoplasmic reticulum stress and disrupted calcium homeostasis in oocytes. Furthermore, DEHP impaired the mitochondrial function of oocytes and reduced their membrane potential, and promoting apoptosis. Similar results were observed in human granulosa cells after exposure to mono-(2-ethylhexyl) phthalate (MEHP, metabolites of DEHP) in vitro. Proteomic analysis and transmission electron microscopy revealed modifications in the functional proteins and structure of the MAMs, and the suppression of oxidative phosphorylation pathways. The findings of this investigation provide a new perspective on the mechanism underlying the reproductive toxicity of DEHP in females.

A comparative analysis of quantitative detection methods for viable food-borne pathogens using RT-qPCR and PMA-qPCR.

The accurate quantification of viable pathogens in food is crucial for ensuring food safety. This study mainly aimed to investigate the quantification of viable pathogens using PMA-qPCR and RT-qPCR, taking into account bacterial species, food matrices, and inactivation methods. The detection limit of PMA-qPCR for Salmonella serovars in simple matrices, such as culture broth, lake, or tap water, was found to be 102 cells per ml. Regarding the detection of Staphylococcus aureus and Escherichia coli in culture broth, as well as Salmonella in more complex matrices, such as juices and lab-made broth, both methods exhibited a detection limit of 103 cells per ml. Besides that, in adverse situations, there was a risk of overestimating the number of viable pathogens using PMA-qPCR. In addition, a conspicuous discrepancy between the results of PMA-qPCR/RT-qPCR and those of the plate counting assay was observed when Salmonella was exposed to isopropanol, H2O2, NaClO, sonication, or thermosonication. This suggests that it may survive in a viable but non-culturable state and poses a challenge for accurate quantification of viable cells using plate counting assay. Therefore, the results obtained by RT-qPCR were more objective compared to PMA-qPCR due to potential influences from bacteria species, surrounding media, and inactivation methods.

Associations between phthalate metabolites and cytokines in the follicular fluid of women undergoing in vitro fertilization.

Many studies have showed that phthalates have reproductive and embryonic toxicity, while the potential mechanisms are mostly unknown. Inflammation may play a mediating part in phthalate exposure and adverse reproductive endpoints. A cross-sectional survey was conducted to investigate the associations of phthalate metabolites with inflammatory cytokines in the follicular fluid (FF) of women undergoing in vitro fertilization (IVF). We determined the levels of eight phthalate metabolites and five cytokines in the FF of 76 women, including interleukin (IL)- 6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). The associations of individual phthalate exposure with cytokines in FF samples were explored by multiple linear regression. We further evaluated the combined effects of multiple phthalate exposures on FF levels of cytokines by using Bayesian kernel machine regression (BKMR) models. We found that there was a positive relationship between mono-ethyl phthalate (MEP) and IL-6 in the FF (percent change:12.4%; 95% CI: 1.3%, 24.9%). In contrast, elevated mono-benzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP) and %MEHP levels were associated with decreased MCP-1. In the BKMR models, phthalate metabolite mixtures were positively associated with TNF-α when the mixtures were lower than 65th percentile compared with their medians. In the stratified analyses, MEHP was inversely associated with MCP-1 among women with BMI ≥ 23 kg/m2 (test for interaction <0.05). Our results suggest that certain phthalate metabolites or their mixtures may alter levels of inflammatory cytokines in the FF, and further research is necessary to elucidate the mechanisms underlying the relationship between phthalates exposure, ovarian dysfunction and adverse pregnancy outcomes.

[Clinical characteristics and genetic analysis of a case of infantile Schaaf-Yang syndrome due to a heterozygous variant of MAGEL2 gene].

OBJECTIVE: To explore the diagnosis, treatment and genetic analysis of an infant with Schaaf-Yang syndrome (SYS). METHODS: An infant suspected for SYS at the Hunan Provincial Children's Hospital on June 10, 2022 was subjected to trio-whole exome sequencing, and Sanger sequencing was used to verify the candidate variant. Structure of the wild-type and mutant proteins was constructed to analyze the potential hazard. RESULTS: The infant was found to harbor a heterozygous frameshifting variant of c.1908delG (p.R637Gfs*65) of the MAGEL2 gene, which was found in neither of his parents. The variant has not been recorded by the public databases, and no relevant literature was retrieved. As the result of the variant, the MAGEL2 protein only retained part of its proline domain, which may lead to destruction and/or down-regulation of its function. CONCLUSION: The c.1908delG (p.R637Gfs*65) variant of the MAGEL2 gene probably underlay the pathogenesis in this child. Combined with his clinical characteristics, the child was diagnosed with SYS. Above finding has also enriched the mutational spectrum of the MAGEL2 gene.

Genetic analysis of developmental and epileptic encephalopathy caused by novel biallelic SZT2 gene mutations in three Chinese Han infants: a case series and literature review.

BACKGROUND: Developmental and epileptic encephalopathy (DEE) exhibits phenotypic and genetic heterogeneity. Biallelic variants of the SZT2 gene can lead to DEE18, of which few cases have been reported. This study aimed to analyze the potential pathogenic factors in three cases of DEE18. METHODS: Trio-whole exome sequencing and crystal structure simulation analysis were performed, along with a literature review of DEE18 cases. RESULTS: All three patients had compound heterozygous variants in the SZT2 gene (patient 1, c.2887A > G/c.7970G > A; patient 2, c.3508A > G/c.7936C > T; and patient 3, c.2489G > T/c.8640_8641insC). The variants were predicted to have structural effects on the protein. Particularly, c.3508A > G/p.Ser1170Gly may lead to impaired binding of SZT2 to GATOR1, potentially resulting in the overactivation of the mTORC1 signaling pathway, causing seizures. Through the literature review, we observed that 27 patients with DEE had different degrees of intellectual and developmental disorders (DDs), and the variants leading to protein truncation cause severe DD and refractory epilepsy. Therefore, the phenotypic severity of patients may be related to the residual activity of variant SZT2 protein. CONCLUSION: We provide recently developed knowledge on the DEE18 genotype-phenotype spectrum and suggest that gene detection is of great value for the accurate diagnosis of patients with early-onset epilepsy. Further research is required for the development of individualized interventions for patients with DEE.

Development of real-time intelligent films from red pitaya peel and its application in monitoring the freshness of pork.

BACKGROUND: Red pitaya peel (RPP) is a good source of polysaccharides, which can be used in the production of biodegradable material. Betacyanins in it possess antioxidant and pH-sensitive properties. However, RPP is commonly discarded during fruit processing. This study aimed to develop real-time intelligent film using RPP to evaluate pork freshness. RESULTS: Real-time intelligent films were developed with film-forming substrates (FFS) composed of 60-100% (w/w) RPP and 0-4% (v/w) glycerol in pH 4.3 ~ 8.0. Rheology tests revealed that the FFS exhibited shear-thinning behavior. Fourier-transform infrared (FTIR) analysis showed that molecules in the RPP interacted with glycerol and formed hydrogen bonds. It showed that the film developed with FFS of 80% RPP and 2% (v/w) glycerol had strong molecular interaction, dense structure, and optimal tensile strength and elongation at break. Film with pH adjusted to 7.0 had greater sensitivity to ammonia than film that was prepared at an original pH of 4.3, so this film was used to monitor freshness of pork. A visible change in the color of the film was observed during the spoiling process of pork, which correlated with the accumulated total volatile base nitrogen. CONCLUSION: Based on its sensitivity to ammonia, the film made of 80% (w/w) RPP and 2% (v/w) glycerol at pH 7.0 was recommended for use in monitoring the freshness of protein-rich food. Our findings are of great significance for ensuring meat quality and safety and for reducing food waste. © 2022 Society of Chemical Industry.

Clinical and genetic analysis of six Chinese children with Poirier-Bienvenu neurodevelopmental syndrome caused by CSNK2B mutation.

Mutations in CSNK2B lead to Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), a rare neurodevelopmental disorder. Only 14 cases of POBINDS have been reported worldwide. The main manifestations are seizures, often tonic-clonic, with or without intellectual disability, growth retardation, and developmental language retardation. We conducted a comprehensive phenotypic mining and trio-whole exome sequencing on six children with POBINDS for gene diagnosis and analyzed the different variants using bioinformatics analysis software and related experiments. This paper reviews previous literature and discusses two common missense variants that lead to structural changes. Among the six patients, four, one, and one had tonic-clonic, myoclonic, and febrile seizures, respectively. Language development disorder, motor development disorder, and developmental delay/intellectual disability (DD/ID) are the main clinical features. All children had de novo mutations in CSNK2B, including three missense variants (c.410G > T/p.(Cys137Phe), c.494A > G/p.(His165Arg), and c.3G > A/p.(Met1Ile)), two splice variants (c.292-2A > T, c.558-3 T > G), and one frameshift variant (c.499delC/p.(Leu167Serfs*60)). Three missense variants were predicted to be harmful by various software programs, and two splicing variants were found to produce new exonic splicing enhancers by the minigene assay. Western blot analysis showed that the frameshift variant resulted in decreased protein expression. According to a literature review, c.3G > A/p.(Met1Ile), c.292-2A > T, c.558-3 T > G, and c.499delC/p.(Leu167Serfs*60) are novel variants of CSNK2B. The decrease or loss of protein function caused by CSNK2B mutations may be a pathogenic factor in this cohort. The severity of the POBINDS phenotype differs, and refractory epilepsy may be accompanied by a more serious DD/ID, language disorder, and motor retardation. At present, there is no specific treatment, and antiepileptic therapy usually requires the combination of two or more anti-epileptic drugs.

A Chinese patient with developmental and epileptic encephalopathies (DEE) carrying a TRPM3 gene mutation: a paediatric case report.

BACKGROUND: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of chronic encephalopathies characterized by epilepsy with comorbid intellectual disability that are frequently associated with de novo nonsynonymous coding variants in ion channels, cell-surface receptors, and other neuronally expressed genes. Mutations in TRPM3 were identified as the cause of DEE. We report a novel patient with DEE carrying a de novo missense mutation in TRPM3, p.(S1202T); this missense mutation has never been reported. CASE PRESENTATION: A 7-year and 2-month-old Chinese patient who had recurrent polymorphic seizures was clinically diagnosed with DEE. A de novo missense mutation in TRPM3, which has not yet been reported, was identified in this case. The patient had a clinical phenotype consistent with previous reports. CONCLUSIONS: These findings could expand the spectrum of TRPM3 mutations and might also support that de novo substitutions of TRPM3 are a cause of DEE.

[Analysis of a child with carnitine palmitoyl transferase 1A deficiency due to variant of CPT1A gene].

OBJECTIVE: To report on the clinical, metabolic and genetic characteristics of a child with carnitine palmitoyl transferase 1A (CPT1A) deficiency. METHODS: Clinical data and the level of acylcarnitine for a child who initially presented as epilepsy were analyzed. Genomic DNA was extracted from peripheral blood samples of the child and her parents and subjected to next-generation sequencing (NGS). RESULTS: Mass spectrometry of blood acylcarnitine indicated increased carnitine 0 (C0) and significantly increased C0/ (C16+C18). DNA sequencing revealed that the child has carried compound heterozygous variants of the CPT1A gene, namely c.1846G>A and c.2201T>C, which were respectively inherited from her mother and father. CONCLUSION: CPT1A presenting initially as epilepsy was unreported previously. Analysis of blood acylcarnitine C0 and C0/ (C16 + C18) ratio and NGS are necessary for the identification and diagnosis of CPT1A deficiency. The c.1846G>A and c.2201T>C variants of the CPT1A gene probably underlay the disease in this child. Above finding has also enriched the spectrum of CPT1A gene variants.

Cys-functionalized AuNP substrates for improved sensing of the marine toxin STX by dynamic surface-enhanced Raman spectroscopy.

Saxitoxin (STX) as one of the most harmful and typical paralytic shellfish toxins, is posing a serious threat to environmental and human health, thus it is essential to develop a sensitive and reliable analytical method for STX detection. Herein, we proposed a strategy for rapid and sensitive detection of STX with surface-enhanced Raman spectroscopy (SERS), by employing cysteine modified gold nanoparticles (Cys-AuNPs) as SERS probe to capture STX molecules through electrostatic interactions and multiple hydrogen bonds between Cys and STX molecules. Moreover, the XPS and zeta potential results indicated that Cys could bond to AuNPs through Au-S bonds and the addition of STX could induce the efficient aggregation of Cys-AuNPs owing to the presence of electrostatic interactions and multiple hydrogen bonds between Cys and STX molecules. Furthermore, considering the high sensitivity and stability of the dynamic surface-enhanced Raman spectroscopy (D-SERS) strategy with the formation of a 3D hotspot matrix, the highly sensitive detection of STX was realized to a level of 1 × 10-7 M by using the D-SERS strategy. Consequently, Cys-AuNPs as high affinity substrates can provide high sensitivity for the detection of STX through the D-SERS strategy. Graphical abstract.

Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report.

BACKGROUND: PPP3CA gene encodes the catalytic subunit A of a calcium-dependent protein phosphatase called calcineurin. However, two distinct mechanisms in PPP3CA deficiency would cause two clinically different diseases. Gain-of-function mutations in the autoinhibitory domain at the C-terminus would cause ACCIID that stands for arthrogryposis, cleft palate, craniosynostosis and impaired intellectual development. While loss-of-function mutations in PPP3CA would cause infantile or early childhood onset epileptic encephalopathy1, named as IECEE1. IECEE1 is a severe epileptic neurodevelopmental disorder and mainly characterized by psychomotor delay. Here, we report a Chinese patient who was clinically and genetically diagnosed as IECEE1. We also extensively analyzed electroencephalogram (EEG) features of the patient in this study. CASE PRESENTATION: A 2-year-old Chinese patient who had recurrent polymorphic seizures was clinically and genetically diagnosed as IECEE1. A frameshift variant c.1283insC (p.T429NfsX22) was identified in this case. Multiple types of abnormal features were observed in the EEG, comparing with the previous reports. CONCLUSIONS: These findings could expand the spectrum of PPP3CA mutations and might also support the diagnosis and further study of IECEE1.

Screening and Analysis of SARS-CoV-2 Antibody Among Unvaccinated Blood Donors in Chongqing, China.

OBJECTIVE: To investigate the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody among unvaccinated voluntary blood donors in Chongqing, and to provide evidence for epidemic surveillance. METHODS: A total of 10,208 voluntary blood donors from January 5 to January 20, 2021, in the Chongqing area were collected, and the SARS-CoV-2 immunoglobulin (Ig) G and IgM antibodies were detected by chemiluminescence, and the differences of antibody-positive rate in different gender, age, ABO blood group, and different risk areas were analyzed. RESULTS: Among 10208 blood donors, 10 were found to be positive for SARS-COV-2 IgG antibody, giving a positivity rate of SARS-COV-2 IgG at 0.10%, and 29 were positive for SARS-CoV-2 IgM antibody, with a positivity rate of SARS-CoV-2 IgM at 0.28%. There was no statistical difference in the positive rate of antibody among different genders, ages, and ABO blood types, but it was related to the number of confirmed coronavirus disease 2019 (COVID-19) cases in each city. CONCLUSIONS: The SARS-CoV-2 seroprevalence rate in Chongqing was low and correlated with the number of confirmed COVID-19 cases.

A novel splicing variant in MICAL-1 gene is associated with epilepsy.

Germline MICAL1 defects have been rarely reported in patients with epilepsy and the genotype-phenotype association remains unclear. In this study, the patient was a 4.6 years old girl who presented with onset of recurrent focal seizures with onset at age 3.4 years. EEG showed abnormal δ-wave activity in the right central and middle temporal lobe. Trio WES showed a novel heterozygous variant c.-43-1G > A in the MICAL1 gene in the patient and her normal mother. Minigene verified two abnormal transcripts due to the mutation, which was predicted to interrupt 5'UTR structures of MICAL1. The patient was clinically diagnosed with benign childhood epilepsy with centrotemporal spike (BECTS). As far as we know, this is the first BECTS case with documented MICAL1 mutation. Novel MICAL1 variant c.-43-1G > A putatively interrupted MICAL1 translation by changing 5'UTR structures and, however, further functioning study is needed.

HCN1 pathogenic variants associated with childhood epilepsy in a cohort of Chinese patients.

OBJECTIVE: HCN ion channel family has a widespread expression in neurons, and recently, increasing studies have demonstrated their roles in epilepsies. METHODS: Clinical data of the patients were gathered in a retrospective study. Exon sequencing was used for the patients with unexplained recurrent seizures and varying levels of developmental delay. RESULTS: In this study, eight de novo variants of HCN1 genes were uncovered in eight patients, including six missense variants, one nonsense variant and one frameshift insertion variant; five of them were reported for the first time. The onset age for eight patients ranges from one month to one year. Their main clinical manifestations are epilepsy and varying degrees of developmental delay, and the main type of seizure is focal secondary generalized tonic-clonic seizure. Importantly, in our study, one case presented with a form of migrating focal seizure that has not been reported in the literature. Seizures from five of the eight children were effectively controlled with antiepileptic drugs including valproic acid, levetiracetam and oxcarbazepine. One child developed normally and four children developed mild delay. One child was treated with topiramate, and the convulsion was partially controlled and showed moderate to severe developmental delay. The antiepileptic treatment failed for the other two children, and the two children were treated with sodium valproate, oxcarbazepine, lamotrigine, chlorbazan, levetiracetam and nitrodiazepam successively, but their convulsions were not controlled and showed moderate to severe developmental delay. SIGNIFICANCE: Our research reported eight variants in HCN1 gene causing epilepsy; among these variants, five variants were never reported before. HCN1-related epilepsy usually starts infantile period, and focal secondary generalized tonic-clonic seizure is the most common seizure type. Importantly, we reported the case with migrating focal seizure was rarely reported. Our study expanded both genotype and phenotype for HCN1-related epilepsy.

Video-electroencephalographic findings and clinical characteristics of bathing seizures in children.

Objective: To explore the electroencephalogram (EEG) and clinical characteristics of childhood bathing epilepsy. Methods: We conducted a prospective summary of the clinical data from 10 children with bathing epilepsy who were admitted to Hunan Children's Hospital from April 2019 to November 2023 and analyzed their EEGs and clinical characteristics. Results: Our 10 patients included eight males and two females, with seizure-onset ages ranging from 4 months and 20 days to 14 months. Nine cases showed normal intellectual development, and one case manifested delayed development. The Video-EEG (VEEG) findings showed that nine cases exhibited normal background with no interictal epileptic discharge. The seizures were characterized by lip cyanosis, tachycardia or bradycardia, weakness, paleness, and loss of consciousness. Ictal EEG revealed rhythmic fast waves, spike waves, spike-slow waves, or slow and sharp-wave activity over the temporal region (eight cases) or the occipital and temporal regions (one case), finally evolving into a delta rhythm that lasted for 57-201 s. These children exhibited no seizures after discontinuing bathing and were not administered antiseizure medication. The interictal EEG of one case reflected mild slow background and focal interictal epileptic discharge; and her semiology was eyes gazing to right, with clonic movements of the right face and lips, lip cyanosis, bradycardia, and impaired consciousness. Ictal EEG showed spike-wave and spike-slow-wave rhythms over the left central, parietal, and temporal regions; these then spread to the left hemisphere, lasting for approximately 104 s. This patient did not exhibit bathing seizures after stopping her bathing but later experienced frequent spontaneous and drug-resistant seizures. The interictal EEG background slowed down, while focal epileptic discharge increased. Her intellectual development was significantly delayed, and a novel pathogenic mutation in the SMC1A gene, c.298+2T>C, was detected. She was diagnosed with developmental and epileptic encephalopathy. Conclusion: A majority of children with bathing epilepsy in our study showed focal autonomic seizures accompanied by impaired consciousness. Stopping bathing could control the seizures and showed a good prognosis. A few infants manifested a poor prognosis, and we posit that bathing seizure rarely constitute the early manifestations of developmental and epileptic encephalopathy. VEEG findings and clinical features can also indicate the prognosis.

LMGATCDA: Graph Neural Network With Labeling Trick for Predicting circRNA-Disease Associations.

Previous studies have proven that circular RNAs (circRNAs) are inextricably connected to the etiology and pathophysiology of complicated diseases. Since conventional biological research are frequently small-scale, expensive, and time-consuming, it is essential to establish an efficient and reasonable computation-based method to identify disease-related circRNAs. In this article, we proposed a novel ensemble model for predicting probable circRNA-disease associations based on multi-source similarity information(LMGATCDA). In particular, LMGATCDA first incorporates information on circRNA functional similarity, disease semantic similarity, and the Gaussian interaction profile (GIP) kernel similarity as explicit features, along with node-labeling of the three-hop subgraphs extracted from each linked target node as graph structural features. After that, the fused features are used as input, and further implied features are extracted by graph sampling aggregation (GraphSAGE) and multi-hop attention graph neural network (MAGNA). Finally, the prediction scores are obtained through a fully connected layer. With five-fold cross-validation, LMGATCDA demonstrated excellent competitiveness against gold standard data, reaching 95.37% accuracy and 91.31% recall with an AUC of 94.25% on the circR2Disease benchmark dataset. Collectively, the noteworthy findings from these case studies support our conclusion that the LMGATCDA model can provide reliable circRNA-disease associations for clinical research while helping to mitigate experimental uncertainties in wet-lab investigations.

Monomethyl Phthalate Causes Early Embryo Development Delay, Apoptosis, and Energy Metabolism Disruptions Through Inducing Redox Imbalance.

Phthalates are a class of environmental endocrine disrupting chemicals which can cause reproductive system damages. However, data about reproductive toxicity spectrum of phthalate metabolites among Chinese women undergoing in vitro fertilization (IVF) treatments are scarce yet. Previous studies regarding underlying embryo toxicities focused on oxidative stress and apoptosis, while energy metabolism abnormality might be another key cause for embryo developmental disruptions. Here, we found that among the measured eight phthalate metabolites, monomethyl phthalate (MMP) had the second highest urinary concentration in women receiving IVF. Compare to the lowest exposure level group, MMP in tertile 3 was associated with fewer counts of oocyte retrieved and good-quality embryos, and MMP in tertile 2 was correlated with reduced good-quality embryo rate. The direct embryo toxicities of MMP were studied using mouse 2-cell embryos. Consistent to results found in human populations, exposure to MMP induced mouse early embryo developmental delay. Furthermore, MMP exposure led to excessive reactive oxygen species production in early embryos, and antioxidant can partially rescue the early embryo development slow down. Embryo apoptosis could also be caused by oxidative stress. To be noted, elevated apoptosis level was not found in live "slow" embryos but dead embryos, which suggested that apoptosis was not related to early embryo developmental delay. Additionally, MMP exposure depleted adenosine triphosphate (ATP) synthesis of early embryos, which could be reversed by antioxidant. In conclusion, MMP, as the newly found embryonic toxicant in Chinese women, resulted in early embryo development delay, apoptosis, and energy metabolism disruptions via inducing redox imbalance.

Phthalate metabolites in urine and follicular fluid in relation to menstrual cycle characteristics in women seeking fertility assistance.

BACKGROUND: Phthalates have been shown to disrupt the estrous cycle in animal studies. However, epidemiological research investigating their associations with menstrual cycle characteristics is limited. OBJECTIVE: To explore the relationships between phthalate exposure and menstrual cycle characteristics among women seeking fertility assistance. METHODS: We determined the levels of eight phthalate metabolites in both follicular fluid (FF) and urine specimens collected from 441 women in the Tongji Reproductive and Environmental (TREE) cohort, using high-performance liquid chromatography and tandem mass spectrometry. Information about menstrual cycle parameters was obtained through a questionnaire. The impacts of individual and joint exposure to phthalates on menstrual cycle characteristics were assessed using multivariable linear regression, Poisson regression, and quantile g-computation approaches. RESULTS: After adjusting for relevant covariates, we found that per log10-unit increase in mono(2-ethylhexyl) phthalate (MEHP) level in urine specimens was associated with a decrease of 0.20 days (95 % CI: -0.37, -0.03) in bleeding duration. We also observed that mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) and the sum of di(2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHP) concentrations in FF samples were inversely related to cycle length [ß = -1.92 (95 % CI: -3.10, -0.75) and -1.87 (95 % CI: -3.56, -0.19), respectively]. However, we generally observed null associations between phthalate metabolites and irregular cycle, dysmenorrhea, hypomenorrhea, or cycle length variation. Furthermore, we also found that phthalate metabolite mixtures in FF and urine were generally unrelated to menstrual cycle characteristics. CONCLUSION: Our findings suggest that some DEHP metabolites in FF and urine are inversely associated with menstrual cycle length and menstrual bleeding duration in women attending a fertility center.

Serum globulin in children with myasthenia gravis: predicting relapse and prognosis.

OBJECTIVE: Serum globulin is associated with inflammatory or immune disorders. However, it has not been established whether it is associated with myasthenia gravis (MG). We investigated the association between globulin with relapse and prognosis in children with MG. METHODS: A cohort of 148 MG cases and 150 healthy children were retrospectively enrolled from January 2015 to December 2021. Multivariate logistic and Cox regression models were used to analyze the treatment outcomes and recurrence of case group, exploring the influence of globulin. RESULTS: Compared with the control group, globulin levels in the MG group were slightly increased (t = 7.244, p < 0.001). After a mean follow-up of 2.25 ± 1.05 years, 35 cases relapsed, with a relapse rate of 23.65%. Logistic regression analysis showed that globulin levels at admission [adjusted odds ratio (OR) = 1.233, 95% confidence interval (CI) 1.028-1.472, p = 0.018] were independent risk factors for relapse. Cox regression analysis confirmed that globulin levels at admission affects relapse-free time [adjusted hazard ratio (HR) = 0.552, 95% CI 0.357-0.852, p = 0.007]. Receiver operating characteristic curve determined 25.10 as the optimal cutoff value for globulin. Cox regression showed that high globulin levels (>25.10) at admission (adjusted HR = 0.607, 95% CI 0.383-0.961, p = 0.033) were independent risk factors for poor therapeutic outcomes at follow-up. Ordinal logistic regression showed that globulin affects the treatment plan (OR = 1.445, 95% CI 1.223-1.847, p = 0.014). CONCLUSIONS: Elevated globulin levels in children with MG on admission predicts a high relapse rate and poor long-term therapeutic efficacies.

Serum globulin in children with myasthenia gravis: predicting relapse and prognosisFirst, the globulin in the MG children was higher than in the healthy controls, and there was some correlation between the globulin and the level of systemic inflammation.Second, globulin has been associated with relapse of MG in children. The higher the globulin, the higher the relapse rate and the shorter the time to prevent a relapse.Third, both initial and final globulin were related to the effect of MG in children, and the higher the long-term effect, the worse the long-term effect. It also influenced the change in treatment plan.