CHARGE syndrome with early fetal ear abnormalities: A case report.

Key Clinical Message: CHARGE syndrome is a rare genetic disorder characterized by several distinct features. The presence of fetal ear abnormalities could be the early indicator of CHARGE syndrome. Subsequent prenatal diagnosis is essential to confirm the disorder. This is significant because the patient may receive genetic counseling and appropriate disposal based on the accurate diagnosis. Abstract: CHARGE syndrome is a rare genetic disorder with multiple specific clinical features. The prenatal diagnosis is crucial but rarely achieved. We report a fetus with fetal external ear abnormality detected by ultrasound at 22nd week of gestation. Postnatal examination revealed an external ear abnormality, a mild atrial septal defect, and other clinical signs of CHARGE syndrome. A de novo pathogenic nonsense mutation in the CHD7 gene (c.406C > T, p.Q136X in exon 2) was identified to cause the disorder. Our study demonstrated that prenatal diagnosis and genetic testing were recommended to obtain a solid diagnosis of CHARGE syndrome when fetal external ear abnormality was detected by ultrasound examination.

Comparative Analysis of Doppler Ultrasound Combined with Serum PAPP-A in Diagnosis and Pathology of Placenta Accreta.

Objective: To explore the value of Doppler ultrasound combined with the serum pregnancy associated plasma protein A (PAPP-A) in the diagnosis and pathology of placenta accreta. Methods: For the method of retrospective study, the data of 250 pregnant women with cesarean section delivery in our hospital from February 2020 to February 2021 were analyzed, and the prenatal examination of pregnant women was performed by Doppler ultrasound and the serum PAPP-A level was determined by serology detection. They were divided into the placenta accreta group (n=152) and non-placenta accreta group (n=98) according to the pathological results after delivery to compare the imaging data and the serum PAPP-A levels in the two groups. The receiver operating characteristic curve (ROC curve) was drawn with the pathological results as the gold standard. Results: The serum PAPP-A level in the placenta accreta group was overtly lower than that in the non-placenta accreta group (698.65±9.65 vs 910.57±9.65, t = 169.52, P < .001). In the placenta accreta group, there were 126 cases (82.89%) with irregular gyrate liquid dark area formed in the placenta of pregnant women, 78 cases (51.32%) with partial or all disappearance of posterior placenta space, 22 cases (14.74%) with the attenuation or disappearance of myometrium in the placental attachment, and 20 cases (13.16%) with abnormal placental thickening. The sensitivity, specificity, positive predictive value and negative predictive value of the Doppler ultrasound combined with serum diagnosis of PAPP-A were 86.84%, 79.59%, 86.84% and 79.59%, respectively. ROC analysis showed that the area under the curve (AUC) of Doppler ultrasound combined with serum diagnosis of PAPP-A was 0.835, with the asymptotic Sig.b < .001 and an asymptotic 95% confidence interval (CI) of 0.780-0.891. Conclusion: Doppler ultrasound could analyze the pathological manifestations of placenta accreta, and serum PAPP-A could be combined to improve the detection rate of placenta accreta, with a certain clinical application value.

Analysis of autophagy deficiency and cytotoxicity in autophagy-deficient human embryonic stem cell-derived neurons.

Autophagy, a catabolic process governing cellular and energy homeostasis, is essential for cell survival and human health. Here, we present a protocol for generating autophagy-deficient (ATG5-/-) human neurons from human embryonic stem cell (hESC)-derived neural precursors. We describe steps for analyzing loss of autophagy by immunoblotting. We then detail analysis of cell death by luminescence-based cytotoxicity assay and fluorescence-based TUNEL staining. This hESC-based experimental platform provides a genetic knockout model for undertaking autophagy studies relevant to human biology. For complete details on the use and execution of this protocol, please refer to Sun et al. (2023).1.

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.

Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects.

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5-/-) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5-/- neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5-/- neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5-/- neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

Cardiac structural and functional remodeling in the fetuses associated with maternal hypothyroidism during pregnancy.

OBJECTIVES: We sought to investigate the effect of maternal hypothyroidism during pregnancy on fetal cardiac structural and functional remodeling using fetal echocardiography. METHODS: A total of 59 pregnant women with history of hypothyroidism were prospectively enrolled as the study group, and 74 normal fetuses as the control group. Fetal echocardiography was performed on each subject. Demographic, clinical, and fetal echocardiographic variables were measured, including left ventricular (LV) and right ventricular (RV) free wall and ventricular septal thickness, fractional shortening (FS), stroke volume (SV), cardiac output (CO), combined cardiac output (CCO), cardiac index (CI), combined cardiac index (CCI), aortic and pulmonary artery velocity, ductus venosus (DV) and pulmonary vein (PV) spectral Doppler, and Tei index. RESULTS: The incidence of echogenic intracardiac foci (EIF) was higher in the study group than that in the control group (18.6% vs. 6.8%, p = .036). The thickness of LV free wall and interventricular septum was reduced, the pulmonary velocities and CCI, RV FS, CO, and CI were lower, the S, D, S/A, and pulsatility index (PI) of DV were higher, and LV Tei index was higher in the study group compared with the control group. There was no significant difference in other variables between the two groups. CONCLUSIONS: There is cardiac remodeling, and systolic, diastolic functional alterations in fetuses with maternal hypothyroidism. Further investigation is warranted to develop strategies to optimize the outcome of these fetuses.

The autophagy-NAD axis in longevity and disease.

Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.

Nomogram based on the O-RADS for predicting the malignancy risk of adnexal masses with complex ultrasound morphology.

OBJECTIVE: The accurate preoperative differentiation of benign and malignant adnexal masses, especially those with complex ultrasound morphology, remains a great challenge for junior sonographers. The purpose of this study was to develop and validate a nomogram based on the Ovarian-Adnexal Reporting and Data System (O-RADS) for predicting the malignancy risk of adnexal masses with complex ultrasound morphology. METHODS: A total of 243 patients with data on adnexal masses with complex ultrasound morphology from January 2019 to December 2020 were selected to establish the training cohort, while 106 patients with data from January 2021 to December 2021 served as the validation cohort. Univariate and multivariate analyses were used to determine independent risk factors for malignant tumors in the training cohort. Subsequently, a predictive nomogram model was developed and validated in the validation cohort. The calibration, discrimination, and clinical net benefit of the nomogram model were assessed separately by calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Finally, we compared this model to the O-RADS. RESULTS: The O-RADS category, an elevated CA125 level, acoustic shadowing and a papillary projection with color Doppler flow were the independent predictors and were incorporated into the nomogram model. The area under the ROC curve (AUC) of the nomogram model was 0.958 (95% CI, 0.932-0.984) in the training cohort. The specificity and sensitivity were 0.939 and 0.893, respectively. This nomogram also showed good discrimination in the validation cohort (AUC = 0.940, 95% CI, 0.899-0.981), with a sensitivity of 0.915 and specificity of 0.797. In addition, the nomogram model showed good calibration efficiency in both the training and validation cohorts. DCA indicated that the nomogram was clinically useful. Furthermore, the nomogram model had higher AUC and net benefit than the O-RADS. CONCLUSION: The nomogram based on the O-RADS showed a good predictive ability for the malignancy risk of adnexal masses with complex ultrasound morphology and could provide help for junior sonographers.

Autophagy promotes cell survival by maintaining NAD levels.

Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.

Qualitative and quantitative study of fetal posterior fossa during the first trimester in a Chinese population.

BACKGROUND: To establish the normal reference ranges for parameters related to the fetal posterior fossa in the first trimester (11 ~ 13+6 weeks of gestation) and to analyze the relationship between them and crown-rump length (CRL) among the Chinese population. METHODS: Singleton pregnancies of 11 ~ 13+6 weeks (CRL:45 ~ 84 mm) with both parents from China were randomly selected from January 2021 to November 2021. The related parameters of the posterior fossa including cisterna magna (CM), intracranial translucency (IT), brain stem (BS), brain stem to the occipital bone (BSOB), and brain stem/brain stem to occipital bone (BS/BSOB) were evaluated and measured in nuchal translucency (NT) mid-sagittal section clearly by an experienced sonographer (operator 1). To assess the reproducibility of the measurements, we randomly selected 50 pregnant women. According to the blind method, operators 1 and 2 respectively screened and measured relevant parameters. In addition, operator 1 examined and measured relevant parameters again 2 h after the first. RESULTS: This study included 1663 fetuses. All fetuses can clearly show the three spaces of the fetal posterior fossa. The ICCs (95% CI) of intra-operator reproducibility of CM, IT, BS, BSOB, BS/BSOB were 0.981 (0.952 ~ 0.991, P < 0.001), 0.929 (0.866 ~ 0.961, P < 0.001), 0.970 (0.946 ~ 0.983, P < 0.001), 0.991 (0.974 ~ 0.996, P < 0.001), 0.939 (0.892 ~ 0.965, P < 0.001), respectively; The ICCs (95% CI) of inter-operator reproducibility 0.926 (0.860 ~ 0.960, P < 0.001), 0.810 (-0.083 ~ 0.940, P < 0.001), 0.820 (0.645 ~ 0.904, P < 0.001), 0.804 (0.656 ~ 0.888, P < 0.001), 0.772 (0.599 ~ 0.871, P < 0.001), respectively. There was a linear correlation between CRL and the parameters related to the posterior fossa (CM, IT, BS, BSOB, BS/BSOB). CM (mm) = -1.698 + 0.532 × CRL (cm) (r = 0.829, P < 0.001); IT (mm) = 0.701 + 0.179 × CRL (cm) (r = 0.548, P < 0.001); BS (mm) = 0.403 + 0.349 × CRL (cm) (r = 0.716, P < 0.001); BSOB (mm) = -0.277 + 0.719 × CRL (cm) (r = 0.829, P < 0.001); BS/BSOB = 0.747-0.021 × CRL (cm) (r = 0.196, P < 0.001). CONCLUSIONS: Qualitative and quantitative assessment of the fetal posterior fossa structure was feasible in the first trimester. We constructed the normal reference ranges of CM, IT, BS, BSOB, and BS/BSOB. Furthermore, CM, IT, BS, and BSOB were positively correlated with CRL, but BS/BSOB was negatively correlated with CRL.

Early Assessment of Cardiac Function by Echocardiography in Patients with Gestational Diabetes Mellitus.

Objective: To offer a baseline for clinical diagnosis, echocardiography was performed to evaluate the disparities in heart function comparing pregnant women with diabetes mellitus (GDM) and ordinary pregnant women. Methods: A prospective case-control study is being conducted on pregnant women with or without gestational diabetes. The sample size for both the intervention and control groups is the same: no diabetes diagnosis or previous forms, a single pregnancy, and no issues (such as preeclampsia or fetal growth restriction). The females were all subjected to routine echocardiograms to examine the morphology and function of their left and right hearts. Results: In the research, 51 women with GDM and 50 healthy controls volunteered. Women with GDM had a significantly higher heartrate (82 ± 9 vs. 74 ± 8), left ventricular (LV) relative wall thickness (0.39 ± 0.06 vs. 0.31 ± 0.07; P < 0.001), LV early diastolic transmitral valve velocity (E) (0.79 ± 0.14 vs. 0.72 ± 0.13 m/s; P = 0.031), and LV late diastolic implementing regulations valve velocity (0.6). Speckle-tracking analysis showed significant decrease in LV right ventricular (RV). A study indicated a reduced pulmonary acceleration time (59 ± 9 vs. 68 ± 12 ms; P = 0.001), RV E/A ratio (1.21 ± 0.19 vs. 1.31 ± 0.31; P = 0.022), and a greater RV myocardial systolic annular velocity (0.17 ± 0.03 vs. 0.12 ± 0.03; P = 0.023). Conclusions: Our results revealed that the heart function of diabetic pregnant women differed considerably from that of the control group, such as LV-RWT, LV diastolic transmitral valve speed, and LV late diastolic transmitral valve speed. Given these results, further research into the postpartum cardiovascular healing of pregnant women with gestational diabetes mellitus is required.

Development and Validation of a Deep Learning Model to Screen for Trisomy 21 During the First Trimester From Nuchal Ultrasonographic Images.

Importance: Accurate screening of trisomy 21 in the first trimester can provide an early opportunity for decision-making regarding reproductive choices. Objective: To develop and validate a deep learning model for screening fetuses with trisomy 21 based on ultrasonographic images. Design, Setting, and Participants: This diagnostic study used data from all available cases and controls enrolled at 2 hospitals in China between January 2009 and September 2020. Two-dimensional images of the midsagittal plane of the fetal face in singleton pregnancies with gestational age more than 11 weeks and less than 14 weeks were examined. Observers were blinded to subjective fetus nuchal translucency (NT) marker measurements. A convolutional neural network was developed to construct a deep learning model. Data augmentation was applied to generate more data. Different groups were randomly selected as training and validation sets to assess the robustness of the deep learning model. The fetal NT was shown and measured. Each detection of trisomy 21 was confirmed by chorionic villus sampling or amniocentesis. Data were analyzed from March 1, 2021, to January 3, 2022. Main Outcomes and Measures: The primary outcome was detection of fetuses with trisomy 21. The receiver operating characteristic curve, metrics of accuracy, area under the curve (AUC), sensitivity, and specificity were used for model performance evaluation. Results: A total of 822 case and control participants (mean [SD] age, 31.9 [4.6] years) were enrolled in the study, including 550 participants (mean [SD] age, 31.7 [4.7] years) in the training set and 272 participants (mean [SD] age, 32.3 [4.7] years) in the validation set. The deep learning model showed good performance for trisomy 21 screening in the training (AUC, 0.98; 95% CI, 0.97-0.99) and validation (AUC, 0.95; 95% CI, 0.93-0.98) sets. The deep learning model had better detective performance for fetuses with trisomy 21 than the model with NT marker and maternal age (training: AUC, 0.82; 95% CI, 0.77-0.86; validation: AUC, 0.73; 95% CI, 0.66-0.80). Conclusions and Relevance: These findings suggest that this deep learning model accurately screened fetuses with trisomy 21, which indicates that the model is a potential tool to facilitate universal primary screening for trisomy 21.

Systematic review and meta-analysis of the efficacy and pregnancy outcomes of levothyroxine sodium tablet administration in pregnant women complicated with hypothyroidism.

BACKGROUND: In recent years, the detection rate of pregnancy complicated with hypothyroidism [subclinical hypothyroidism (SCH) during pregnancy] has increased significantly. Levothyroxine sodium tablet is the main drug for the treatment of SCH during pregnancy, but its effect on the treatment of SCH during pregnancy and the effect of pregnancy outcome are still controversial. METHODS: PubMed, Web of Science, Medline, and Embase databases were screened to retrieve clinical studies on levothyroxine sodium tablets in the treatment of pregnancy complicated with hypothyroidism from the date of establishment to June 2021. Meta-analysis was performed with RevMan5.3 software. The differences in the incidence of preterm birth, miscarriage, gestational hypertension, postpartum hemorrhage, placental abruption, and abnormal neonatal weight were compared between the observation group and the control group. Heterogeneity of results was assessed with chi-square test and I2 in RevMan5.3 software. RESULTS: Nine articles with a total of 2,873 pregnant women were included. The Cochrane assessments were all grade B and above, and the Jadad scale scores were all >3 points. The incidences of preterm birth, abortion, postpartum hemorrhage, and low birth weight infants in the pregnant women treated with levothyroxine sodium were lower than those in the control group [odds ratio (OR) =0.42, 0.34, 0.40, and 0.08, respectively; 95% confidence interval (CI): 0.30-0.58, 0.23-0.52, 0.22-0.74, and 0.01-0.51, respectively; Z=5.23, 5.08, 2.97, and 2.70, respectively; P<0.00001, <0.00001, =0.003, and =0.007, respectively]. DISCUSSION: Levothyroxine sodium in the treatment of SCH can significantly reduce the incidence of premature birth, miscarriage, postpartum hemorrhage, and low birth weight infants. Due to the limited number of included studies, it remained to be further verified whether levothyroxine sodium treatment in SCH patients would affect the incidence of gestational hypertension.

Systematic review and meta-analysis on the influence of thyroid dysfunction in early pregnancy on pregnancy outcomes under ultrasound guidance.

BACKGROUND: Thyroid dysfunction during pregnancy has a certain impact on pregnancy outcomes and neonatal growth, but there is no systematic evaluation of the influence of thyroid dysfunction during early pregnancy under ultrasound guidance on pregnancy outcomes. METHODS: PubMed, Web of Science, Springer, and Science Direct databases were used to screen clinical studies on the effect of thyroid dysfunction during pregnancy on pregnancy outcomes from January 2010 to June 2021. Meta-analysis of data was conducted using RevMan 5.3 software. Differences of indicators were compared between the normal and abnormal thyroid function groups, including the ratio of primiparas, anemia, intrauterine growth restriction, perinatal fetal death, preterm delivery, fetal distress syndrome, cesarean section, preeclampsia, placental abruption, postpartum hemorrhage, and neonatal complications. Heterogeneity of results was assessed by chi-square test and I2 test in RevMan5.3. RESULTS: A total of 788,867 pregnant women were included in 13 studies. Cochrane scores were grade B or above, and Jadad scale scores were higher than 3. Anemia [odds ratio (OR) =0.82, 95% confidence interval (CI): 0.70-0.96, Z=2.48, P=0.01], premature birth (OR =0.56, 95% CI: 0.36-0.86, Z=2.66, P=0.008), fetal distress syndrome (OR =0.76, 95% CI: 0.68-0.85, Z=4.74, P<0.00001), Apgar score <7 (OR =0.52, 95% CI: 0.34-0.80, Z=2.97, P=0.003), preeclampsia (OR =0.65, 95% CI: 0.48-0.87, Z=2.91, P=0.004), placental abruption (OR =0.27, 95% CI: 0.19-0.38, Z=7.31, P<0.00001), and the rate of postpartum hemorrhage (OR =0.62, 95% CI: 0.42-0.92, Z=2.38, P=0.02) were dramatically higher in the abnormal thyroid function group compared with the normal group. DISCUSSION: Few studies were included on the effect of thyroid dysfunction on abortion, and further validation is needed. Thyroid dysfunction was proven to be associated with a variety of adverse pregnancy outcomes.

Analysis of Mitochondrial Dysfunction by Microplate Reader in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Disorders.

Mitochondria are responsible for many vital pathways governing cellular homeostasis, including cellular energy management, heme biosynthesis, lipid metabolism, cellular proliferation and differentiation, cell cycle regulation, and cellular viability. Electron transport and ADP phosphorylation coupled with proton pumping through the mitochondrial complexes contribute to the preservation of mitochondrial membrane potential (ΔΨm). Importantly, mitochondrial polarization is essential for reactive oxygen species (ROS) production and cytosolic calcium (Ca2+) handling. Thus, changes in mitochondrial oxidative phosphorylation (OXPHOS), ΔΨm, and ATP/ADP may occur in parallel or stimulate each other. Brain cells like neurons are heavily reliant on mitochondrial OXPHOS for its high-energy demands, and hence improper mitochondrial function is detrimental for neuronal survival. Indeed, several neurodegenerative disorders are associated with mitochondrial dysfunction. Modeling this disease-relevant phenotype in neuronal cells differentiated from patient-derived human induced pluripotent stem cells (hiPSCs) provide an appropriate cellular platform for studying the disease pathology and drug discovery. In this review, we describe high-throughput analysis of crucial parameters related to mitochondrial function in hiPSC-derived neurons. These methodologies include measurement of ΔΨm, intracellular Ca2+, oxidative stress, and ATP/ADP levels using fluorescence probes via a microplate reader. Benefits of such an approach include analysis of mitochondrial parameters on a large population of cells, simultaneous analysis of different cell lines and experimental conditions, and for drug screening to identify compounds restoring mitochondrial function.

Autophagy Dysfunction as a Phenotypic Readout in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Diseases.

Autophagy is an evolutionarily conserved catabolic pathway for the degradation of cytoplasmic constituents in eukaryotic cells. It is the primary disposal route for selective removal of undesirable cellular materials like aggregation-prone proteins and damaged organelles for maintaining cellular homeostasis, and for bulk degradation of intracellular macromolecules and recycling the breakdown products for providing energy homeostasis during starvation. These functions of autophagy are attributed to cellular survival and thus pertinent for human health; however, malfunction of this process is detrimental to the cells, particularly for post-mitotic neurons. Thus, basal autophagy is vital for maintaining neuronal homeostasis, whereas autophagy dysfunction contributes to neurodegeneration. Defective autophagy has been demonstrated in several neurodegenerative diseases wherein pharmacological induction of autophagy is beneficial in many of these disease models. Elucidating the mechanisms underlying defective autophagy is imperative for the development of therapies targeting this process. Disease-affected human neuronal cells can be established from patient-derived human induced pluripotent stem cells (hiPSCs) that provide a clinically relevant platform for studying disease mechanisms and drug discovery. Thus, modeling autophagy dysfunction as a phenotypic readout in patient-derived neurons provides a more direct platform for investigating the mechanisms underlying defective autophagy and evaluating the therapeutic efficacy of autophagy inducers. Toward this, several hiPSC-derived neuronal cell models of neurodegenerative diseases have been employed. In this review, we highlight the key methodologies pertaining to hiPSC maintenance and neuronal differentiation, and studying autophagy at an endogenous level in hiPSC-derived neuronal cells.

Reference ranges of fetal heart function using a Modified Myocardial Performance Index: a prospective multicentre, cross-sectional study.

OBJECTIVES: The primary aim of this study was to establish the normal reference ranges of the fetal left ventricular (LV) Modified Myocardial Performance Index (Mod-MPI). A secondary aim was to evaluate the agreement between manual and automatic measurements for fetal Mod-MPI. DESIGN: A prospective, multicentre, cross-sectional study. PARTICIPANTS: Normal singleton pregnancies. METHODS: The LV functions of normal singleton pregnancies were assessed in nine centres covering eight provinces in China using unified ultrasound protocols and settings and standardised measurements by pulsed Doppler at 20-24, 28-32 and 34-38 weeks of gestation. The isovolumetric relaxation time (IRT), isovolumetric contraction time, ejection time (ET) and Mod-MPI were measured both automatically and manually. RESULTS: This cross-sectional study included 2081 fetuses, and there was a linear correlation between gestational age (GA) and Mod-MPI (0.416+0.001×GA (weeks), p<0.001, r2=0.013), IRT (36.201+0.162× GA (weeks), p<0.001, r2=0.021) and ET (171.418-0.078*GA (weeks), p<0.001, r2=0.002). This finding was verified using longitudinal data in a subgroup of 610 women. The agreement between the manual and automated measurements for Mod-MPI was good. CONCLUSIONS: We constructed normal reference values of fetal LV Mod-MPI. Automatic measurement can be considered for ease of measurement in view of the good agreement between the automatic and manual values.

Human Induced Pluripotent Stem Cell Models of Neurodegenerative Disorders for Studying the Biomedical Implications of Autophagy.

Autophagy is an intracellular degradation process that is essential for cellular survival, tissue homeostasis, and human health. The housekeeping functions of autophagy in mediating the clearance of aggregation-prone proteins and damaged organelles are vital for post-mitotic neurons. Improper functioning of this process contributes to the pathology of myriad human diseases, including neurodegeneration. Impairment in autophagy has been reported in several neurodegenerative diseases where pharmacological induction of autophagy has therapeutic benefits in cellular and transgenic animal models. However, emerging studies suggest that the efficacy of autophagy inducers, as well as the nature of the autophagy defects, may be context-dependent, and therefore, studies in disease-relevant experimental systems may provide more insights for clinical translation to patients. With the advancements in human stem cell technology, it is now possible to establish disease-affected cellular platforms from patients for investigating disease mechanisms and identifying candidate drugs in the appropriate cell types, such as neurons that are otherwise not accessible. Towards this, patient-derived human induced pluripotent stem cells (hiPSCs) have demonstrated considerable promise in constituting a platform for effective disease modeling and drug discovery. Multiple studies have utilized hiPSC models of neurodegenerative diseases to study autophagy and evaluate the therapeutic efficacy of autophagy inducers in neuronal cells. This review provides an overview of the regulation of autophagy, generation of hiPSCs via cellular reprogramming, and neuronal differentiation. It outlines the findings in various neurodegenerative disorders where autophagy has been studied using hiPSC models.

Prenatal diagnosis of bilateral congenital microphthalmia in two fetuses from the same parents.

Congenital microphthalmia (CM) is a rare anomaly of the fetal orbit, results from developmental defects of the primary optic vesicle, and is characterized by a reduced eyeball volume and axial diameter. Fetal CM cases have rarely been reported. Herein, we present a case of two fetuses with bilateral CM from the same parents, diagnosed using ultrasonography (US) and magnetic resonance imaging (MRI). We found that the antepartum US and MRI measurements were smaller than the postpartum ones. Genetic testing of the parents and fetuses revealed that GL12 gene mutation may be associated with CM.

Prenatal diagnosis of caudal regression with heterotaxy syndrome: "A mermaid with a broken heart".

Caudal regression syndrome (CRS) is a rare congenital malformation with varying degrees of early gestational developmental failure. It is characterized by agenesis of the sacrum and lumbar spine, with lower limb neurological deficit and accompanying deformities of the pelvis, lower extremities, genitourinary, and gastrointestinal systems. We report a case of CRS associated with rare complex congenital heart defect, that is, heterotaxy syndrome, diagnosed prenatally.