Maternal gestational weight gain and adverse pregnancy outcomes in non-diabetic women.

OBJECTIVE: This study investigated the relationship between maternal gestational weight gain (GWG) and the risk of adverse pregnancy outcomes in gestational diabetes mellitus (GDM)-negative pregnant women. METHODS: We did a retrospective cohort study between 1 July 2017, and 1 January 2020, at Women's Hospital, Zhejiang University School of Medicine. Firstly, pregnant women were divided into subgroups according to the entire GWG (inadequate GWG, adequate GWG, and excessive GWG) and GDM status (positive and negative) during pregnancy. Secondly, the whole population of pregnant women with GDM was used as a reference to evaluate the relationship between GWG and adverse pregnancy outcomes in GDM-negative pregnant women. Lastly, subgroup analysis was conducted based on pre-pregnancy body mass index (pp-BMI). RESULTS: A total of 30,910 pregnant women were analysed. Included pregnancy women were divided into three groups based on GWG: 7569 (24.49%) pregnancy women had inadequate GWG, 13088 (42.34%) had adequate GWG, and 10,253 (33.17%) had excessive GWG. In addition to preterm birth and small for gestational age (SGA), the incidence of macrosomia and large for gestational age (LGA) continues to increase from inadequate GWG to excessive GWG groups. Pregnant women without GDM who have excessive GWG are at higher risk of macrosomia and LGA than pregnant women with GDM. Moreover, this risk increased with increasing pp-BMI. Pregnant women without GDM with inadequate GWG were at risk of preterm birth regardless of pp-BMI. Only those with inadequate GWG and pp-BMI < 18.5 kg/m2 had an increased risk of SGA. CONCLUSIONS: In conclusion, inappropriate GWG is strongly associated with adverse pregnancy outcomes, even if they do not have GDM. Therefore, this population should receive attention and management before and during pregnancy.Impact StatementWhat is already known on this subject? Several studies have focused on the GDM population and the risk of adverse pregnancy outcomes, but few have focused on GDM-negative populations. This is because GDM-negative women are perceived to be "safe," leading to less focus on themselves, which can lead to subsequent excessive weight gain during pregnancy. Whether this factor increases the risk of adverse pregnancy outcomes in this population remains unknown.What do the results of this study add? Our study found an inverse relationship between GWG and GDM. Therefore, our study focuses on this group of GDM-negative pregnant women. Their excessive weight gain increases the risk of adverse pregnancy outcomes, even higher than GDM pregnant women.What are the implications of these findings for clinical practice and/or further research? GWG is associated with adverse pregnancy outcomes. Therefore, pregnant women without GDM also need increased attention and management of their weight before and during pregnancy. Prenatal care providers can utilise tools such as diet, exercise counselling, weight tracking, and setting weight gain goals to reduce inappropriate weight gain and mitigate its adverse effects on pregnancy outcomes.

ATAD3A gene variations in a family with Harel-Yoon syndrome. / Harel-Yoon综合征一家系临床表型及ATAD3AåŸºå› å˜å¼‚åˆ†æž.

An 11-day-old female neonate was admitted for cough with mouth foaming and feeding difficulties. The laboratory results indicated hyperlactatemia, elevated markers of myocardial injury and inflammation, and high levels of acylcarnitine octanoylcarnitine and decanoylcarnitine in tandem mass spectrometry. Ultrasonography and MRI suggested cardiac insufficiency and hypertrophic cardiomyopathy. Whole exome sequencing showed that both the proband and her elderly sister had a compound heterozygous variant of c.1492dup (p.T498Nfs*13) and c.1376T>C (p.F459S) in the ATAD3A gene, inherited from their father and mother, respectively. The diagnosis of Harel-Yoon syndrome was confirmed. The proband and her sister were born with clinical manifestations of metabolic acidosis, hyperlactatemia, feeding difficulties, elevated markers of myocardial injury as well as cardiac insufficiency, and both died in early infancy.

[Screening and clinical analysis of isovaleric acidemia newborn in Zhejiang province].

OBJECTIVE: To investigate the incidence,clinical,biochemical and genetic characteristics of isovaleric acidemia (IVA) in Zhejiang province. METHODS: Between January 2009 and December 2019, a total of 3 510 004 newborns were screened for IVA using tandem mass spectrometry. Patients of IVA were confirmed by urine organic acid and IVD gene detection. IVA patients were given diet and life management, supplemented with L-carnitine and glycine treatment, long-term followed up to observe and evaluate the growth and intellectual development. RESULTS: A total of 15 patients with IVA were diagnosed, with an incidence of 1/234 000. Three patients had acute neonatal IVA, and the rest were asymptomatic. The isovalerylcarnitine (C5) levels were increased in all patients. Twelve children underwent urinary organic acid analysis, of which 11 cases had elevated isovalerylglycine levels, 4 cases with 3-hydroxyisovalerate increased simultaneously. Eleven IVA patients underwent genetic testing, 9 patients were compound heterozygous variants in IVD gene, one with homozygous variants in IVD gene, and one harbored one IVD variant. Nineteen IVD variants (14 missense mutations, 3 intron mutations, 1 code shift mutation, and 1 synonymous mutation) were identified, 11 of which were not reported. Among the 15 IVA patients, one patient died and two patients were followed up locally. The remaining patients had no obvious clinical symptoms during the follow-up (2-79 months). Three patients presented with growth and development delay, the remaining had normal physical and mental development. CONCLUSIONS: The clinical manifestations of IVA are non-specific, and the gene spectrum is scattered. Newborn patients screened by tandem mass spectrometry can receive early diagnosis and treatment, so as to correct metabolic defects and pathophysiological changes.

[Effects of delivery and storage conditions on concentrations of amino acids and carnitines in neonatal dried blood spots].

OBJECTIVE: To explore effects of different delivery and storage conditions on concentrations of amino acids and carnitines in neonatal dried blood spots (DBS), so as to provide evidence for improving accurate and reliable detection by tandem mass spectrometry. METHODS: A total of 1 254 616 newborn DBS samples in Newborn Screening Center of Zhejiang Province were delivered and stored at room temperature (group A, n=338 467), delivered by cold-chain logistics system and stored at low temperature (group B, n=480 021), or delivered by cold-chain logistics system and stored at low temperature and low humidity (group C, n= 436 128), respectively. The concentrations of amino acids and carnitines in DBS were detected by tandem mass spectrometry. Data analysis was performed by SPSS 24.0 to explore the influence of temperature and humidity on the concentrations of amino acids and carnitines. RESULTS: The concentrations of amino acids and carnitines in the three groups were skewed, and the differences in amino acid and carnitine concentrations among groups were statistically significant (all P<0.01). The median concentration of tyrosine was lower in group A than those in group B and group C by 18%and 16%respectively, while there was no significant difference between the last two groups. The median concentrations of methionine were lower in group A and group B than that in group C by 15%and 11%, respectively. The median concentrations of arginine were lower in group A and group B than that in group C by 12%and 25%, respectively. The median concentration of free carnitine (C0) was higher in group A than that in group C by 12%, while there was no significant difference between group A and group B. The median concentrations of acetylcarnitine (C2), propionyl carnitine (C3), C3DC+C4OH, C5DC+C6OH and hexadecanoyl carnitine (C16) were lower in group A than those in group B and group C by 21%-64%. The concentrations of other amino acids and acylcarnitines differed little among three groups. The monthly median coefficients of variation of other amino acids and carnitines in group A were higher than those in group B and group C except for citrulline, C4DC+C5OH and isovalerylcarnitine (C5). CONCLUSIONS: Cold-chain logistics system and storage in low temperature and low humidity can effectively reduce degradation of some amino acids and carnitines in DBS, improve the accuracy and reliability of detection, and thus ensures the quality of screening for neonatal metabolic diseases.

Rapid detection of common variants and deletions of CYP21A2 using MALDI-TOF MS.

Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) based on hormonal testing is successfully implemented in many countries. However, this method cannot detect non-classic CAH and has high false positive rates. We have developed a novel MALDI-TOF MS assay that can identify common variants and deletions of CYP21A2 in the Chinese population. Thirty-seven clinical patients with CAH confirmed by Sanger sequencing and MLPA analysis were detected by MALDI-TOF MS assay. Two CYP21A2 variants were detected in 30 patients and one CYP21A2 variant was detected in 7 patients. The MALDI-TOF MS assay detected 67 mutant alleles in 37 patients with a detection rate of 90.5%. Sanger sequencing revealed that three variants in seven patients were not included in the designed panel. Eleven distinct CYP21A2 variants were identified, including five missense variants, two nonsense variants, two large gene deletions, one splice variant, and one frameshift variant. The most frequent variant was c.293-13C > G (37.84%), followed by c.518T > A (21.62%) and exon 1-7 deletion (17.57%). The high-throughput MALDI-TOF MS assay that can simultaneously detect common variants and deletions of CYP21A2. This assay can be used for population-based genetic screening and rapid detection of suspected patients, and is expected to be a valuable complement to biochemical-based testing for the detection of CAH.

Long Circulating Cancer Cell-Targeted Bionic Nanocarriers Enable Synergistic Combinatorial Therapy in Colon Cancer.

Cancer nanomedicine treatment aims to achieve highly specific targeting and localization to cancer cells. Coating of nanoparticles with cell membranes endows them with homologous cellular mimicry, enabling nanoparticles to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused a human-derived HCT116 colon cancer cell membrane (cM) with a red blood cell membrane (rM) to fabricate an erythrocyte-cancer cell hybrid membrane (hM). Oxaliplatin and chlorin e6 (Ce6) co-encapsulated reactive oxygen species-responsive nanoparticles (NPOC) were camouflaged by hM and obtained a hybrid biomimetic nanomedicine (denoted as hNPOC) for colon cancer therapy. hNPOC exhibited prolonged circulation time and recognized homologous targeting ability in vivo since both rM and HCT116 cM proteins were maintained on the hNPOC surface. hNPOC showed enhanced homologous cell uptake in vitro and considerable homologous self-localization in vivo, producing effective synergistic chemophotodynamic therapy efficacy under irradiation with a homologous HCT116 tumor compared to that with a heterologous tumor. Together, the biomimetic hNPOC nanoparticles showed prolonged blood circulation and preferential cancer cell-targeted function in vivo to provide a bioinspired strategy for chemophotodynamic synergistic therapy of colon cancer.

Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathways.

Chronic arsenic exposure has been linked to an increased risk of vascular diseases. To clarify the molecular mechanisms through which arsenic causes injuries to blood vessels, we analyzed the effects of arsenic trioxide on the cytotoxicity, intracellular reactive oxygen species (ROS), the expression of related genes, and signaling pathways involved in the SVEC4-10 mouse endothelial cells. Arsenic dose-dependently caused SVEC4-10 cell death, which is completely inhibited by α-lipoic acid (LA), a thioreductant, but partially ameliorated by Tiron, a potent superoxide scavenger. The mRNA levels of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were significantly increased by arsenic. The up-regulation of these can be blocked by LA instead of Tiron, suggesting ROS is not important in their increase. HO-1 competitive inhibitor zinc protoporphyrin improved the cytotoxicity of arsenic in an inverted-U dose-response curve, indicating the biphasic hormetic effect of HO-1. HO-1 siRNA decreased VEGF expression in response to arsenic. Arsenic exposure also enhanced NF-E2-related factor 2 (Nrf2) expression and increased activation of nuclear factor-κB (NF-κB). NF-κB inhibitor Bay 11-7082 reduced arsenic-mediated expression of HO-1 and IL-6. Selective blocking of the MAPK pathways with p38 inhibitor SB203580 significantly decreased arsenic-induced HO-1 and VEGF expression, while JNKs inhibitor SP600125 increased IL-6 expression. These results suggest that in arsenic-treated SVEC4-10 cells, HO-1 expression is mediated through Nrf2-, NF-κB-, and p38 MAPK-dependent signaling pathways and serves as an upstream regulator of VEGF. IL-6 expression is regulated by NF-κB and JNKs. In conclusion, oxidative stress may be associated with arsenic-induced cytotoxicity and endothelial gene up-regulation, but signaling transduction dominates the direct effects of ROS.

Gestational diabetes mellitus in the COVID-19 pandemic: A retrospective study from Hangzhou, China.

AIMS: Our study aimed to investigate changes in the prevalence of gestational diabetes mellitus (GDM) in the COVID-19 pandemic and postpandemic era and the risk of adverse pregnancy outcomes in pregnant women diagnosed with GDM during the blockade period. METHODS: First, we investigated changes in the prevalence of GDM and the population undergoing oral glucose tolerance tests (OGTT) after the COVID-19 pandemic. We then collected clinical information from pregnant women diagnosed with GDM to explore the risk of adverse pregnancy outcomes in pregnant women with GDM during the COVID-19 pandemic. RESULTS: After the COVID-19 pandemic, the proportion of pregnant women in the total number of outpatient OGTT tests decreased yearly. The ratio was 81.30%, 79.71%, and 75.48% from 2019 to 2021, respectively, with the highest proportion of pregnant women in February 2020 (92.03%). The prevalence of GDM was higher in March 2020 compared to the same period in 2019. However, from 2019 to 2021, the prevalence decreased year by year with 21.46%, 19.81%, and 18.48%, respectively. The risk of adverse pregnancy outcomes for pregnant women diagnosed with GDM during the most severe period of the COVID-19 pandemic did not differ from before the COVID-19 pandemic. CONCLUSIONS: After the COVID-19 pandemic, the prevalence of GDM increased during the most severe period of the epidemic, but the overall prevalence of GDM decreased year by year. In addition, the pandemic did not change the risk of adverse pregnancy outcomes in pregnant women with GDM.

Association of higher HbA1c within the normal range with adverse pregnancy outcomes: a cross-sectional study.

OBJECTIVE: The aim of this study was to investigate the association between a relatively high HbA1c level within the normal range and the risk of adverse pregnancy outcomes. METHODS: This retrospective cohort study was conducted between March 2018 and March 2019 at Women's Hospital, School of Medicine, Zhejiang University. Multiple logistic regression models after adjusting for plausible confounders were implemented to assess the relationships between the level of HbA1c and adverse pregnancy outcomes. RESULTS: A total of 8585 women were included in our study. The rates of preterm birth, macrosomia and preeclampsia were 4.4% (380/8585), 5.3% (457/8585) and 1.7% (149/8585), respectively. After adjusting for potential confounding variables, an HbA1c range of 5.5-5.9% (37-41 mmol/mol) remained significantly associated with an increased risk of preterm delivery (a-OR 2.27; 95% CI, 1.50-3.43), macrosomia (a-OR 1.97; 95% CI, 1.32-2.94) and preeclampsia (a-OR 3.70; 95% CI, 2.07-6.60). GDM-negative pregnant women with an HbA1c level in the range of 5.5-5.9% (37-41 mmol/mol) had an increased risk of preterm delivery (a-OR 2.84; 95% CI, 1.71-4.71) and preeclampsia (a-OR 3.82; 95% CI, 1.81-8.04). However, GDM-positive pregnant women had an increased risk of macrosomia (a-OR 2.12; 95% CI, 1.13-3.97) and preeclampsia (a-OR 2.62; 95% CI, 1.01-6.81). CONCLUSION: A higher HbA1c level within the normal range is an independent risk factor for preterm delivery and preeclampsia, especially among GDM-negative women. Therefore, relevant medical staff should enhance the awareness of risk and prevention to strengthen pregnancy monitoring.

Synthesis of Tower-Like ZnO Nanostructures and Its Optical Properties.

A peculiar tower-like ZnO nanostructure was synthesized using an economical and facile hydrothermal method, with zinc acetate [ZAc, Zn(CH3COO)2 · 2H2O] and hexamethylenetetramine (HMTA, C6H12N4) as the source materials. The as-synthesized tower-like ZnO was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD). The characterization results indicated that the tower-like ZnO nanostructures are high-quality monocrystals. The as-synthesized ZnO nanostructures may have application in sensing area due to its high specific surface areas. The growth mechanism, as well as the optical properties of the as-synthesized tower-like ZnO nanostructures was also studied.

Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography-tandem mass spectrometry: A reliable follow-up method for propionylcarnitine-related disorders in newborn screening.

OBJECTIVES: Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography-tandem mass spectrometry has usually been used as a second-tier test to improve performance of newborn screening for propionylcarnitine-related disorders. However, factors that potentially affect its detection results have not been investigated, and we aimed to evaluate these influencing factors and explore their potential utility in newborn screening and initial follow-up for propionylcarnitine-related disorders. METHODS: This study comprised a prospective group (1998 healthy infants, to establish cutoff values and investigate the influencing factors) and a retrospective group (804 suspected positive cases screened from 381, 399 newborns for propionylcarnitine-related disorders by tandem mass spectrometry, to evaluate the performance of newborn screening and initial follow-up). RESULTS: Cutoff values for methylmalonic acid, 2-methylcitric acid, and total homocysteine were 2.12, 0.70, and 10.05 µmol/l, respectively. Concentration of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots is not impacted by sex, age, birth weight, gestational age, or dried blood spot storage time. A total of 75 of 804 cases were screened positive by combined tandem mass spectrometry and liquid chromatography-tandem mass spectrometry, thus eliminating 90% of the false positives without compromising sensitivity. Eighteen propionylcarnitine-related disorders were successfully identified, including one CblX case missed in the initial follow-up by tandem mass spectrometry. CONCLUSIONS: Methylmalonic acid, 2-methylcitric acid, and total homocysteine detected in dried blood spots by liquid chromatography-tandem mass spectrometry is a reliable, specific, and sensitive approach for identifying propionylcarnitine-related disorders. We recommend this assay should be performed rather than tandem mass spectrometry in follow-up for propionylcarnitine-related disorders besides second-tier tests in newborn screening.

Acute toxicity and effects of 1-alkyl-3-methylimidazolium bromide ionic liquids on green algae.

In the present study, the acute toxicity of 1-Alkyl-3-methylimidazolium bromide ([Cnmim]Br) on the green algal Scenedesmus obliquus and Chlorella ellipsoidea was determined. The length of alkyl side chain of these imidazolium ionic liquids were C4, C6, C8, C10 and C12. The primary production of S. obliquus was also assessed after they were exposed to 0.01, 0.05, 0.10, 0.50 and 1.00 mg/L of [C10mim]Br for 96 h. The results showed that the acute toxicity of these ionic liquids was positively correlated with the alkyl chain length. Meanwhile, the concentration of the ionic liquid strongly influenced the primary production of algae. These results indicate that [Cnmim]Br with longer alkyl length have toxic effects on the green algae, and the risk to aquatic ecosystems by ionic liquid's leaking into the water body must be evaluated in the future.

A Facile Chemical Solution Route to Synthesize ZnO/Graphene Composite and the Improved Photocatalytic Property.

ZnO/graphene composite was synthesized through a facile and economical chemical solution method at moderate temperature of 90 °C. The as-synthesized composite was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and Raman spectrum. Results indicated that in the growth process graphene oxide was reduced to graphene, in which ZnO was embedded in the form of nanoparticles. As an application, the photocatalytic performance of the composite was investigated using the methylene blue (MB) in aqueous solution under ultraviolet (UV) light irradiation. The photocatalytic experiment showed that the as-synthesized ZnO/graphene composite exhibited improved photocatalytic property in comparison with that of the pure ZnO powder.

Screening 3.4 million newborns for primary carnitine deficiency in Zhejiang Province, China.

Testing for primary carnitine deficiency (PCD) has been implemented in many newborn screening (NBS) programs, but few large-scale studies on NBS for PCD have been reported in China. This study aimed to assess the incidence and biochemical, clinical, and genetic characteristics of PCD discovered by NBS. Dried blood spots from newborns were analyzed by tandem mass spectrometry (MS/MS) and suspected positive patients were further tested using molecular genetic analysis. Infants who carried two variants in SLC22A5 or those with extremely low free carnitine levels during recall were referred for follow-up and treatment. Over 3.4 million newborns were screened and 113 newborns were diagnosed with PCD, yielding a positive predictive value of 1.93%. In addition, 63 mothers with PCD were identified. The incidence of PCD in newborns and mothers in Zhejiang was 1:30,182 and 1:54,137, respectively. Thirty-seven distinct variants were identified in SLC22A5 of which 10 were novel. c.1400C > G (p.S467C) was the most prevalent variant in both newborns and mothers with PCD, while c.760C > T (p.R254*), which is reportedly common in other Chinese regions, was rarely detected in maternal PCD patients. This study reports the largest series of patients with PCD detected by NBS and identifies 10 novel variants, expanding the variant spectrum of SLC22A5.

rGO quantum dots/ZnO hybrid nanofibers fabricated using electrospun polymer templates and applications in drug screening involving an intracellular H2O2 sensor.

Throughout the years, reported intracellular H2O2 sensors just focused on unrelated measurements of intracellular H2O2 generated from the stimulus of Cd2+, ascorbic acid (AA) etc., leading to difficulty in data interpretation. Here, a novel reduced graphene oxide quantum dots (rGO QDs)/ZnO hybrid nanofibers-based electrochemical biosensor for the detection of intracellular H2O2 released from cancer and normal cells under the stimuli of the corresponding anticancer drugs permits a quantitative study of the interaction between the target drug compound and the cancer cell, which is suitable for candidate drug screening. Nylon 6/6 nanofibers are used as robust templates for the facile fabrication of novel rGO QDs/ZnO hybrid nanofibers via electrospinning followed by a step hydrothermal growth method. The as-made sensor was applied to determine H2O2 released from a prostate cancer cell (PC-3) versus a noncancerous cell (BPH-1) under the stimuli of the corresponding anticancer drugs (apigenin, antisense CK2αetc.). The amount of H2O2 released from the PC-3 cancer cell is about (320 ± 12) amol per cell and about (210 ± 6) amol per cell for the BPH-1 noncancerous cell under the stimuli of specific therapy drug antisense CK2α. These results demonstrate that the rGO QDs/ZnO hybrid nanofibers-based electrochemical biosensor can efficiently detect the distinct amounts of H2O2 released from cancer and noncancer cells.

Luteolin modulates 6-hydroxydopamine-induced transcriptional changes of stress response pathways in PC12 cells.

The neurotoxin 6-hydroxydopamine (6-OHDA), which causes transcriptional changes associated with oxidative and proteotoxic stress, has been widely used to generate an experimental model of Parkinson's disease. The food-derived compound luteolin has multi-target actions including antioxidant, anti-inflammatory and neurotrophic activities. The aim of this study is to investigate how luteolin affects 6-OHDA-mediated stress response pathways. The results showed that when PC12 cells were pre-treated with luteolin (20 µM) 30 min prior to 6-OHDA (100 µM) exposure, 6-OHDA-induced ROS overproduction, cytotoxicity, caspase-3 activation, and mRNA expression of BIM, TRB3 and GADD34 were significantly attenuated. Moreover, 6-OHDA-mediated cell cycle arrest and transcription of p53 target genes, p21, GADD45α and PUMA, were reduced by luteolin. Luteolin also significantly down-regulated 6-OHDA-mediated unfolded protein response (UPR), leading to decreases in phospho-eIF2α, ATF4, GRP78 and CHOP. In addition, luteolin attenuated 6-OHDA-induced Nrf2-mediated HO-1 and GCLC. Taken together, these results suggest that diminishing intracellular ROS formation and down-regulation of p53, UPR and Nrf2-ARE pathways may be involved in the neuroprotective effect of luteolin.