Two risk assessment models for predicting white matter injury in extremely preterm infants.

BACKGROUND: Extremely preterm infants (EPIs) are at high-risk of white matter injury (WMI), leading to long-term neurodevelopmental impairments. We aimed to develop nomograms for WMI. METHODS: The study included patients from 31 provinces, spanning ten years. 6074 patients before 2018 were randomly divided into a training and internal validation group (7:3). The external validation group comprised 1492 patients from 2019. Predictors were identified using the least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression and nomograms were constructed. Models' performance was evaluated using receiver operating characteristic (ROC), decision curve analysis (DCA) and calibration curves. RESULTS: The prenatal nomogram included multiple gestation, premature rupture of membranes (PROM), chorioamnionitis, prenatal glucocorticoids, hypertensive disorder complicating pregnancy (HDCP) and Apgar 1 min, with area under the curve (AUC) of 0.805, 0.816 and 0.799 in the training, internal validation and external validation group, respectively. Days of mechanical ventilation (MV), shock, patent ductus arteriosus (PDA) ligation, intraventricular hemorrhage (IVH) grade III-IV, septicemia, hypothermia and necrotizing enterocolitis (NEC) stage II-III were identified as postpartum predictors. The AUCs were 0.791, 0.813 and 0.823 in the three groups, respectively. DCA and calibration curves showed good clinical utility and consistency. CONCLUSION: The two nomograms provide clinicians with precise and efficient tools for prediction of WMI. IMPACT: This study is a large-sample multicenter study, spanning 10 years. The two nomograms are convenient for identifying high-risk infants early, allowing for reducing poor prognosis.

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The patient, a male newborn, was admitted to the hospital 2 hours after birth due to prematurity (gestational age 27+5 weeks) and respiratory distress occurring 2 hours postnatally. After admission, the infant developed fever and elevated C-reactive protein levels. On the fourth day after birth, metagenomic next-generation sequencing of cerebrospinal fluid indicated a positive result for Mycoplasma hominis (9 898 reads). On the eighth day, a retest of cerebrospinal fluid metagenomics confirmed Mycoplasma hominis (56 806 reads). The diagnosis of purulent meningitis caused by Mycoplasma hominis was established, and the antibiotic treatment was switched to moxifloxacin [5 mg/(kg·day)] administered intravenously for a total of 4 weeks. After treatment, the patient's cerebrospinal fluid tests returned to normal, and he was discharged as cured on the 76th day after birth. This article focuses on the diagnosis and treatment of neonatal Mycoplasma hominis purulent meningitis, introducing the multidisciplinary diagnosis and treatment of the condition in extremely preterm infants.

[Clinical features and magnetic resonance imaging evaluation of encephalopathy in high-risk late preterm infants].

OBJECTIVE: To investigate the risk factors, clinical features, and magnetic resonance imaging (MRI) changes of encephalopathy in high-risk late preterm infants. METHODS: Head MRI scan was performed for late preterm infants with high-risk factors for brain injury who were hospitalized between January 2009 and December 2014. The risk factors, clinical features, and head MRI features of encephalopathy in late preterm infants were analyzed. RESULTS: A total of 1 007 late preterm infants underwent MRI scan, among whom 313 (31.1%) had imaging features in accordance with the features of encephalopathy of prematurity. Of all infants, 76.7% had white matter damage. There was no association between the development of encephalopathy and gestational age in late preterm infants, but the detection rate of encephalopathy gradually increased with the increasing birth weight (P<0.05). The logistic regression analysis showed that a history of resuscitation was an independent risk factor for encephalopathy of prematurity (P<0.01). CONCLUSIONS: Encephalopathy of prematurity is commonly seen in high-risk late preterm infants, especially white matter damage. A history of resuscitation is an independent risk factor for encephalopathy in late preterm infants.

A translational mouse model for investigation of the mechanism of preterm diffuse white matter injury.

Background: The increasing incidence of preterm birth has led to a global problem of adverse neurodevelopmental outcomes in preterm neonates as a result of brain injury. There is still a lack of models mimicking diffuse white matter injury (WMI) in preterm neonates that can be applied to transgenic mice. Methods: The right common carotid artery of the neonatal mouse was ligated on postnatal day 3 (P3) C57BL/6 mice and followed by 80, 90, or 100 min of hypoxia using a mixture of 10%±0.2% oxygen-nitrogen. The most suitable model was chosen by characterizing the effects of this hypoxic-ischemic insult on development of myelin, glial cell conditions, and neurological outcomes by hematoxylin-eosin (HE) staining performed at postnatal day 17 (P17), western blot measuring myelin basic protein (MBP) at postnatal day 10 (P10) and P17, immunofluorescence staining of MBP-neurofilament protein heavy chain (NFH), oligodendrocyte transcription factor-2 (Olig2)-adenomatous polyposis coli clone (CC1), glial fibrillary acidic protein (GFAP) and ionic calcium linker protein (Iba-1) at P17, electron microscopy observing myelin microstructure at postnatal day 52 (P52) and behavioral testing at postnatal day 45-50 (P45-P50). Results: The 90-min group showed neuroanatomical changes in the ipsilateral side of the brain, the 80-min group showed minor changes, and the 100-min group showed severe injury. Mice in the 90-min group subsequently showed marked activation of astrocytes, augmentation of microglia, a notable decrease in expression of MBP with a normal level of NFH, long-term cognitive dysfunction, and impairment of the myelin ultrastructure in adulthood. Conclusions: In conclusion, a mouse model of preterm diffuse WMI rather than cystic periventricular leukomalacia was successfully achieved by ligating one of the common carotid arteries on P3 followed by 90 min of hypoxia in a mixture of 10%±0.2% oxygen-nitrogen. The attempt provides an adequate translational animal model for elucidating the underlying mechanism.

Effects of delayed HIF-1α expression in astrocytes on myelination following hypoxia-ischaemia white matter injury in immature rats.

BACKGROUND: The underlying cause of neurological sequelae after immature cerebral hypoxia-ischaemia (HI) white matter injury is impaired myelination. Previous studies have indicated that astrocyte activation is closely related to impaired myelination. However, the mechanism of reactive gliosis in white matter injury post-HI remains poorly understood. METHODS: Studies using adult ischaemic animal models demonstrated that hypoxia inducible factor-1α (HIF-1α) expression was involved in the formation of reactive astrocytes. Here, we investigated the temporal expression of HIF-1α and its impact on reactive gliosis and further myelination using a perinatal HI white matter injury model induced in rats at postnatal day 3. The temporal pattern of HIF-1α expression post-HI injury was tested by western blotting and immunofluorescence. Rats were treated with a HIF-1α inhibitor at 72 hours post-HI injury. Reactive gliosis and myelination were assessed with western blotting, immunofluorescence and electron microscopy, and neurological functions were examined by behavioural testing. RESULTS: Our results showed that the expression of HIF-1α was upregulated in neurons at 24 hours and in astrocytes at 7 days post-HI. Inhibiting delayed HIF-1α expression post-HI injury could restrain reactive gliosis, ameliorate hypomyelination, and improve the performance of rats in the Morris water maze test. CONCLUSIONS: Our findings suggest that a delayed increase in HIF-1α in astrocytes is involved in glial scar formation and leads to arrested oligodendrocyte maturation, impaired myelination, and long-term neurological function after experimental white matter injury in immature rats.

Galectin-3 administration drives remyelination after hypoxic-ischemic induced perinatal white matter injury.

Hypoxic-ischemic (HI) induced perinatal white matter injury (PWMI) is a major cause of neurologic disabilities characterized by selective oligodendroglial death and myelin disruption. Galectin-3 (Gal-3) modulates postnatal subventricular zone gliogenesis and attenuates ischemic injury. However, the association between Gal-3 and myelin formation still remains unclear. In this study, we first perform Gal-3 knockdown (KD) to identify the importance of Gal-3 on myelin formation. Our results show impeded myelin formation, manifested by Olig2/CC1 (+) mature oligodendrocytes number, expression of oligodendroglial maturation-associated markers (MBP and CNPase), and myelin thickness and integrity. Then we perform recombinant Gal-3 (rGal-3) administration by intracerebroventricular injection. Notably, although rGal-3 administration shows no beneficial effect on oligodendrogenesis and myelin formation under normal condition, our results show that rGal-3 administration attenuates cognitive deficits and drives remyelination after PWMI, which are coupled to signs of enhanced myelin resiliency and cognition. Also, our results indicates that the significant increases in substrates for remyelination of rGal-3 administration are accompanied by enhanced Iba-1 (microglia marker)/ Mrc1 (M2 marker) (+) microglia and decreased Iba-1/ iNOS (M1 marker) (+) microglia. Altogether, our data in this research confirm the association between Gal-3 and myelin formation, underscore its position for the capacity for remyelination and restoration of function, and unveils the efficacy of rGal-3 administration with anti-inflammatory phenotype microglia (M2 microglia) activation. Thus, the findings suggest that Gal-3 plays a significant role in myelin formation and remyelination restoration.

The role of hyaluronan in myelination and remyelination after white matter injury.

Hyaluronan is one of the major components of the neural extracellular matrix (ECM) and provides structural support in physiological conditions. Altered hyaluronan regulation is implicated in the pathogenesis of white matter injury (WMI), such as perinatal WMI, multiple sclerosis (MS), traumatic brain injury (TBI). Early research reported diverse central nervous system (CNS) insults led to accumulated high-molecular-weight (HMW) hyaluronan in hypomyelinating/demyelinating lesions. Furthermore, recent findings have shown an elevated production of hyaluronan fragments in WMI, possibly resulting from HMW hyaluronan degradation. Subsequent in vitro studies identified bioactive hyaluronan fragments with a specific molecular weight (around 2x105 Da) regulating oligodendrocyte precursor cells (OPCs) maturation and myelination/remyelination in WMI. However, it is unclear about the effective hyaluronidases in generating bioactive hyaluronan fragments. Several hyaluronidases are proposed recently. Although PH20 is shown to block OPCs maturation by generating bioactive hyaluronan fragments in vitro, it seems unlikely to play a primary role in WMI with negligible expression levels in vivo. The role of other hyaluronidases on OPCs maturation and myelination/remyelination is still unknown. Other than hyaluronidases, CD44 and Toll-like receptors 2 (TLR2) are also implicated in HMW hyaluronan degradation in WMI. Moreover, recent studies elucidated bioactive hyaluronan fragments interact with TLR4, initiating signaling cascades to mediate myelin basic protein (MBP) transcription. Identifying key factors in hyaluronan actions may provide novel therapeutic targets to promote OPCs maturation and myelination/remyelination in WMI.

Combining Metagenomic Sequencing With Whole Exome Sequencing to Optimize Clinical Strategies in Neonates With a Suspected Central Nervous System Infection.

Objectives: Central nervous system (CNS) infection has a high incidence and mortality in neonates, but conventional tests are time-consuming and have a low sensitivity. Some rare genetic diseases may have some similar clinical manifestations as CNS infection. Therefore, we aimed to evaluate the performance of metagenomic next-generation sequencing (mNGS) in diagnosing neonatal CNS infection and to explore the etiology of neonatal suspected CNS infection by combining mNGS with whole exome sequencing (WES). Methods: We prospectively enrolled neonates with a suspected CNS infection who were admitted to the neonatal intensive care unit(NICU) from September 1, 2019, to May 31, 2020. Cerebrospinal fluid (CSF) samples collected from all patients were tested by using conventional methods and mNGS. For patients with a confirmed CNS infection and patients with an unclear clinical diagnosis, WES was performed on blood samples. Results: Eighty-eight neonatal patients were enrolled, and 101 CSF samples were collected. Fourty-three blood samples were collected for WES. mNGS showed a sample diagnostic yield of 19.8% (20/101) compared to 4.95% (5/101) for the conventional methods. In the empirical treatment group, the detection rate of mNGS was significantly higher than that of conventional methods [27% vs. 6.3%, p=0.002]. Among the 88 patients, 15 patients were etiologically diagnosed by mNGS alone, five patients were etiologically identified by WES alone, and one patient was diagnosed by both mNGS and WES. Twelve of 13 diagnoses based solely on mNGS had a likely clinical effect. Six patients diagnosed by WES also experienced clinical effect. Conclusions: For patients with a suspected CNS infections, mNGS combined with WES might significantly improve the diagnostic rate of the etiology and effectively guide clinical strategies.

Spatiotemporal expression patterns of Galectin-3 in perinatal rat hypoxic-ischemic brain injury model.

In this research, we intended to evaluate the expression pattern, distribution and sources of Galectin-3 (Gal-3) in perinatal hypoxic-ischemic brain injury rat model. Postnatal day 3 Sprague-Dawley rat pups were subjected to right carotid artery ligation followed by 2.5 h of hypoxia (6% oxygen). Expression and distribution of Gal-3 were evaluated by western blotting and immunofluorescence. Sources of Gal-3 were evaluated by double staining with neuronic, oligodendrocytic, astrocytic, microglial and endotheliocytic markers. Our results indicated Gal-3 significantly upregulated from 12 h and maintained an increasing tendency within 72 h post injury. Although the relative expression of Gal-3 decreased after 72 h, we detected significant differences until 14d. We found Gal-3 started to distribute in cortex and thalamus area and maintained an increasing tendency. Gal-3 could be detected in cortex, thalamus, corpus callosum and hippocampus area at 72 h post injury. After that, expression of Gal-3 in cortex and thalamus area downregulated, the expression in corpus callosum and hippocampus area vanished. We found astrocyte, microglia, neuron and endotheliocyte were sources of Gal-3 in cortex area; astrocyte, microglia and endotheliocyte were sources of Gal-3 in thalamus area; oligodendrocyte precursor cell and endotheliocyte were sources of Gal-3 in corpus callosum; neuron, microglia and endotheliocyte were sources of Gal-3 in hippocampus. In conclusion, we demonstrated spatiotemporal expression patterns of Galectin-3 post perinatal hypoxic-ischemic brain injury in this research.

Assessment of the performance of blood glucose monitoring systems for monitoring dysglycaemia in neonatal patients.

OBJECTIVE: To validate a three-step protocol that assesses the clinical risk associated with using blood glucose monitoring systems (BGMS) in neonates for the management of dysglycaemia. METHOD: The three-step validation approach included confirmation of the accuracy of the reference method using National Institute of Standards and Technology (NIST) glucose standards, assessment of analytical risk performed on whole blood collected from paediatric patients routinely tested for glucose and a clinical risk assessment performed using heel stick capillary samples collected from 147 new-born babies and neonates admitted to intensive care. BGMS glucose measurements were compared with the NIST aligned laboratory reference method. RESULTS: The accuracy of the laboratory reference method was confirmed with the NIST standards. Specificity studies demonstrated that the accuracy of one of the BGMS was affected, particularly, in the hypoglycaemic range, by known interference factors including haematocrit, ascorbic acid, lactose, galactose, N-acetylcysteine and glutathione. The accuracy of the other BGMS was unaffected. The clinical performance of this BGMS in neonates met the system accuracy criteria of Clinical and Laboratory Standards Institute (CLSI) POCT 12-A3 standard for evaluating hospital BGMS with 95.1% of glucose measurements within±0.67 mmol/L for samples ≤5.55 mmol/L and 95.6% within±12.5% for samples>5.55 mmol/L. CONCLUSIONS: This three-step validation protocol provides a challenging approach for determining the accuracy and reliability of BGMS for managing dysglycaemia in neonates. StatStrip BGMS achieved analytical and clinical performance criteria confirming its suitability for use in neonates. We advocate that this validation approach should be considered for performance evaluations of both BGMS and continuous glucose monitoring systems going forward.

[Expression of phosphorylated NMDA receptor 1 in the cerebral cortex after NMDA microinjection in vivo].

OBJECTIVE: The activation of N-methyl-D-aspartate(NMDA) receptors plays critical roles in the pathogenesis of diseases of the brain. This study aimed to examine the expression of phosphor-NR1 S897 in the cerebral cortex after NMDA microinjection in vivo. METHODS: Forty seven-day-old Sprague-Dawley rats were randomly assigned into normal control and NMDA injection groups. The rats from the NMDA injection group were injected with 10 mmol of NMDA and were sacrificed 1 hr after injection. 2, 3, 5-triphenyltetrazolium chloride (TTC) and fluorescent immunohistochemical stainings were conducted and the fluorescence intensity OD value between the two groups was compared. RESULTS: TTC staining from the two groups was normal. Expression of phosphor-NR1 S897 in the cerebral cortex of the ipsilateral hemisphere to injection in the NMDA injection group decreased significantly compared with the normal control group, with OD values of 0.366 +/- 0.087 vs 1.364 +/- 0.268 (P < 0.01). CONCLUSIONS: NMDA microinjection, as a hypoxia-ischemia (HI) insult, significantly decreased the expression of phosphor-NR1 S897. This indicates the importance of the "HI-NMDA-phospho-NR1 S897 dephosphorylation-cell damage" pathway in HI brain damage.

Chondroitin sulfate proteoglycans inhibit the migration and differentiation of oligodendrocyte precursor cells and its counteractive interaction with laminin.

Cerebral white matter injury (WMI) is a recognized problem in premature infants, particularly in those with very low birth weights. Although the survival rate of premature infants has notably increased due to the advancement of modern medical treatments, their likelihood of developmental disability is higher than infants with an average birth weight. It has been previously reported that oligodendrocyte precursor cells (OPCs) are selectively vulnerable to WMI in premature infants. Following brain injury, glial scars may develop within the white matter. Their main constituent is chondroitin sulphate proteoglycans (CSPGs), revealing a potential association between CSPGs and OPCs. In the present study rat OPCs were cultured in vitro, and the effect of CSPGs on the proliferation, migration and differentiation of OPCs was determined. It was revealed that CSPGs did not affect proliferation, but they did inhibit the migration and differentiation of OPCs. It was also identified that the inhibitory effect of CSPGs was counteracted by laminin. Factor analysis revealed that CSPGs and laminin served interactive roles in OPC differentiation. The effect of CSPGs on OPCs was associated with the downregulation of ß1-integrin, indicating that CSPGs potentially competitively inhibit the ß1-integrin signaling pathway. Collectively, these results suggest that CSPGs serve a role as inhibitors of OPC differentiation and migration, as well as indicating an interaction between CSPGs and laminin. The present study has revealed a potential novel therapeutic target for WMI in premature infants, and identified ß1-integrin signaling as a pathological mechanism for dysfunctional myelination in white matter.

Epidemiology and clinical features of segmental/lobar pattern Mycoplasma pneumoniae pneumonia: A ten-year retrospective clinical study.

Mycoplasma pneumoniae plays an important role in community-acquired pneumonia. However, epidemiological and clinical studies on the segmental/lobar pattern (S/L) radiographic-pathologic subtype of pediatric Mycoplasma pneumoniae pneumonia (MPP) are rare. The current study retrospectively analyzed the epidemiological and clinical characteristics of pediatric MPP patients. A total of 1,933 children with MPP received treatment at a single hospital between 2000 and 2009, of which 684 (35.4%) were diagnosed with S/L-MPP. The annual incidence of S/L-MPP in children with MPP increased throughout the duration of this study (from 6.4 to 59.6%, P<0.001), which was particularly evident after 2003. S/L-MPP was predominantly found in pre-school-aged children (4-6 years old; 56.6%). Compared with non-S/L-MPP, S/L-MPP was more closely associated with severe manifestations, including higher rates of fever (90.2 vs. 83.3%), pleural effusion (3.9 vs. 1.3%), extrapulmonary manifestations (26.2 vs. 21.2%), abnormal white blood cell counts (65.5 vs. 55.2%), abnormal C-reactive protein levels (30.9 vs. 23.7%) and bacterial co-infection (32.0 vs. 24.9%), as well as longer durations of fever (4.13±4.28 vs. 3.02±2.22 days) and hospitalization (12.70±4.54 vs. 9.22±5.12 days). Older S/L-MPP patients showed higher rates and longer durations of fever and cough; however, they also displayed a lower rate of extrapulmonary manifestations when compared with younger patients. In conclusion, the annual incidence of S/L-MPP has increased in recent years. Pre-school-aged children (4-6 years) with MPP are more likely to display a segmental/lobar pattern, which is associated with more severe clinical manifestations than other MPP infection patterns.