The association between GAD1 gene polymorphisms and cerebral palsy in Chinese infants

Studies suggest that GAD1 gene was a functional candidate susceptibility gene for cerebral palsy (CP). In order to investigate the contribution of GAD1 gene to the etiology of CP in Chinese infants, we carried out a case-control association study between GAD1 gene and CP. In this study, 374 health controls and 392 infants with CP were recruited. Genomic DNA was extracted from venous blood and all three single nucleotide polymorphisms in GAD1 (rs3791874, rs3791862 and rs16858977) were genotyped by Sequenom’s MassARRAY system. There were no significant differences in allele or genotype frequencies between CP or mixed CP patients and controls at any of the three genetic polymorphisms. Through haplotype analysis we found that haplotype GG (rs3791862, rs16858977) frequency demonstrated significantly statistical difference between mixed CP patients and controls (p= 0.0371). Our positive findings of haplotype GG suggested that variation of GAD1 gene was an important risk factor for mixed CP.Предполагается, что ген GAD1 является функциональным кандидатом на роль гена подверженности церебральному параличу (ЦП). Для исследования вклада гена GAD1 в этиологию ЦП у китайских детей методом случай – контроль проведено исследование ассоциации между наличием гена GAD1 и ЦП. В исследовании были задействованы 374 здоровых ребенка (контроль) и 392 ребенка с ЦП. Геномную ДНК выделяли из венозной крови, и все три единичных нуклеотидных полиморфизма гена GAD1 (rs3791874, rs3791862 и rs16858977) были генотипированы в системе Sequenom MassARRAY. Ни для одного из трех генетических полиморфизмов не обнаружено существенных различий в частотах аллелей или генотипов между больными ЦП или смешанными больными ЦП и контролем. Анализ гаплотипов показал существенные статистические различия в частоте гаплотипа GG (rs3791862, rs16858977) у смешанных больных ЦП и контрольной группы (p = 0.0371). Позитивный результат по гаплотипу GG свидетельствует о том, что вариация гена GAD1 является важным фактором риска для смешанного ЦП

The Potential Role of Ferroptosis in Neonatal Brain Injury

Ferroptosis is an iron-dependent form of cell death that is characterized by early lipid peroxidation and different from other forms of regulated cell death in terms of its genetic components, specific morphological features, and biochemical mechanisms. Different initiation pathways of ferroptosis have been reported, including inhibition of system Xc-, inactivation of glutathione-dependent peroxidase 4, and reduced glutathione levels, all of which ultimately promote the production of reactive oxygen species, particularly through enhanced lipid peroxidation. Although ferroptosis was first described in cancer cells, emerging evidence now links mechanisms of ferroptosis to many different diseases, including cerebral ischemia and brain hemorrhage. For example, neonatal brain injury is an important cause of developmental impairment and of permanent neurological deficits, and several types of cell death, including iron-dependent pathways, have been detected in the process of neonatal brain damage. Iron chelators and erythropoietin have both shown neuroprotective effects against neonatal brain injury. Here, we have summarized the potential relation between ferroptosis and neonatal brain injury, and according therapeutic intervention strategies

Iron Metabolism and Brain Development in Premature Infants

Iron is important for a remarkable array of essential functions during brain development, and it needs to be provided in adequate amounts, especially to preterm infants. In this review article, we provide an overview of iron metabolism and homeostasis at the cellular level, as well as its regulation at the mRNA translation level, and we emphasize the importance of iron for brain development in fetal and early life in preterm infants. We also review the risk factors for disrupted iron metabolism that lead to high risk of developing iron deficiency and subsequent adverse effects on neurodevelopment in preterm infants. At the other extreme, iron overload, which is usually caused by excess iron supplementation in iron-replete preterm infants, might negatively impact brain development or even induce brain injury. Maintaining the balance of iron during the fetal and neonatal periods is important, and thus iron status should be monitored routinely and evaluated thoroughly during the neonatal period or before discharge of preterm infants so that iron supplementation can be individualized

Routes of administration for adeno-associated viruses carrying gene therapies for brain diseases

Gene therapy is a powerful tool to treat various central nervous system (CNS) diseases ranging from monogenetic diseases to neurodegenerative disorders. Adeno-associated viruses (AAVs) have been widely used as the delivery vehicles for CNS gene therapies due to their safety, CNS tropism, and long-term therapeutic effect. However, several factors, including their ability to cross the blood&ndash;brain barrier, the efficiency of transduction, their immunotoxicity, loading capacity, the choice of serotype, and peripheral off-target effects should be carefully considered when designing an optimal AAV delivery strategy for a specific disease. In addition, distinct routes of administration may affect the efficiency and safety of AAV-delivered gene therapies. In this review, we summarize different administration routes of gene therapies delivered by AAVs to the brain in mice and rats. Updated knowledge regarding AAV-delivered gene therapies may facilitate the selection from various administration routes for specific disease models in future research. &nbsp;</p

Lithium Treatment Is Safe in Children With Intellectual Disability

Lithium is a widely used and effective treatment for individuals with psycho-neurological disorders, and it exhibits protective and regenerative properties in multiple brain injury animal models, but the clinical experience in young children is limited due to potential toxicity. As an interim analysis, this paper reports the safety/tolerability profiles of low-dose lithium treatment in children with intellectual disability (ID) and its possible beneficial effects. In a randomized, single-center clinical trial, 124 children with ID were given either oral lithium carbonate 6 mg/kg twice per day or the same dose of calcium carbonate as a placebo (n = 62/group) for 3 months. The safety of low-dose lithium treatment in children, and all the adverse events were monitored. The effects of low-dose lithium on cognition was evaluated by intelligence quotient (IQ), adaptive capacity was assessed by the Infant-Junior Middle School Students Social-Life Abilities Scale (IJMSSSLAS), and overall performance was evaluated according to the Clinical Global Impression-Improvement (CGI-I) scale. After 3 months of lithium treatment, 13/61 children (21.3%) presented with mild side effects, including 4 (6.6%) with gastrointestinal symptoms, 4 (6.6%) with neurological symptoms, 2 (3.3%) with polyuria, and 3 (4.9%) with other symptoms—one with hyperhidrosis, one with alopecia, and one with drooling. Four children in the lithium group had elevated blood thyroid stimulating hormone, which normalized spontaneously after lithium discontinuation. Both IQ and IJMSSSAS scores increased following 3 months of lithium treatment (F = 11.03, p = 0.002 and F = 7.80, p = 0.007, respectively), but such increases were not seen in the placebo group. CGI-I scores in the lithium group were 1.25 points lower (better) than in the placebo group (F = 82.66, p &lt; 0.001) after 3 months of treatment. In summary, lithium treatment for 3 months had only mild and reversible side effects and had positive effects on cognition and overall performance in children with ID.Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IPR-15007518

Metagenomic next-generation sequencing for detecting lower respiratory tract infections in sputum and bronchoalveolar lavage fluid samples from children

Lower respiratory tract infections are common in children. Bronchoalveolar lavage fluid has long been established as the best biological sample for detecting respiratory tract infections; however, it is not easily collected in children. Sputum may be used as an alternative yet its diagnostic accuracy remains controversial. Therefore, this study sought to evaluate the diagnostic accuracy of sputum for detecting lower respiratory tract infections using metagenomic next-generation sequencing. Paired sputum and bronchoalveolar lavage fluid samples were obtained from 68 patients; pathogens were detected in 67 sputum samples and 64 bronchoalveolar lavage fluid samples by metagenomic next-generation sequencing, respectively. The combined pathogen-detection rates in the sputum and bronchoalveolar lavage fluid samples were 80.90% and 66.2%, respectively. For sputum, the positive predictive values (PPVs) and negative predictive values (NPVs) for detecting bacteria were 0.72 and 0.73, respectively, with poor Kappa agreement (0.30; 95% confidence interval: 0.218–0.578, P &lt; 0.001). However, viral detection in sputum had good sensitivity (0.87), fair specificity (0.57), and moderate Kappa agreement (0.46; 95% confidence interval: 0.231–0.693, P &lt; 0.001). The PPVs and NPVs for viral detection in sputum were 0.82 and 0.67, respectively. The consistency between the sputum and bronchoalveolar lavage fluid was poor for bacterial detection yet moderate for viral detection. Thus, clinicians should be cautious when interpreting the results of sputum in suspected cases of lower respiratory tract infections, particularly with regards to bacterial detection in sputum. Viral detection in sputum appears to be more reliable; however, clinicians must still use comprehensive clinical judgment

Correction: Dying transplanted neural stem cells mediate survival bystander effects in the injured brain

The original version of this article contained an error in the author affiliations. Klas Blomgren is not affiliated with the University of Gothenburg anymore. The original article has been corrected.</p

Grafting Neural Stem and Progenitor Cells Into the Hippocampus of Juvenile, Irradiated Mice Normalizes Behavior Deficits

The pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus of the hippocampus is reduced by ionizing radiation. This explains, at least partly, the learning deficits observed in patients after radiotherapy, particularly in pediatric cases. An 8 Gy single irradiation dose was delivered to the whole brains of postnatal day 9 (P9) C57BL/6 mice, and BrdU-labeled, syngeneic NSPCs (1.0 × 105 cells/injection) were grafted into each hippocampus on P21. Three months later, behavior tests were performed. Irradiation impaired novelty-induced exploration, place learning, reversal learning, and sugar preference, and it altered the movement pattern. Grafting of NSPCs ameliorated or even normalized the observed deficits. Less than 4% of grafted cells survived and were found in the dentate gyrus 5 months later. The irradiation-induced loss of endogenous, undifferentiated NSPCs in the dentate gyrus was completely restored by grafted NSPCs in the dorsal, but not the ventral, blade. The grafted NSPCs did not exert appreciable effects on the endogenous NSPCs; however, more than half of the grafted NSPCs differentiated. These results point to novel strategies aimed at ameliorating the debilitating late effects of cranial radiotherapy, particularly in children

Dying transplanted neural stem cells mediate survival bystander effects in the injured brain

Neural stem and progenitor cell (NSPC) transplants provide neuroprotection in models of acute brain injury, but the underlying mechanisms are not fully understood. Here, we provide evidence that caspase-dependent apoptotic cell death of NSPCs is required for sending survival signals to the injured brain. The secretome of dying NSPCs contains heat-stable proteins, which protect neurons against glutamate-induced toxicity and trophic factor withdrawal in vitro, and from ischemic brain damage in vivo. Our findings support a new concept suggesting a bystander effect of apoptotic NSPCs, which actively promote neuronal survival through the release of a protective “farewell” secretome. Similar protective effects by the secretome of apoptotic NSPC were also confirmed in human neural progenitor cells and neural stem cells but not in mouse embryonic fibroblasts (MEF) or human dopaminergic neurons, suggesting that the observed effects are cell type specific and exist for neural progenitor/stem cells across species.</p

The immune response after hypoxia-ischemia in a mouse model of preterm brain injury

Background: Preterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury. Methods: C57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining. Results: HI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model. Conclusions: We have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury