Neonatal neurobehavioral abnormalities and MRI brain injury in encephalopathic newborns treated with hypothermia

Background Neonatal Encephalopathy (NE) is a prominent cause of infant mortality and neurodevelopmental disability. Hypothermia is an effective neuroprotective therapy for newborns with encephalopathy. Post-hypothermia functional–anatomical correlation between neonatal neurobehavioral abnormalities and brain injury findings on MRI in encephalopathic newborns has not been previously described. Aim To evaluate the relationship between neonatal neurobehavioral abnormalities and brain injury on magnetic resonance imaging (MRI) in encephalopathic newborns treated with therapeutic hypothermia. Study design Neonates with hypoxic ischemic encephalopathy (HIE) referred for therapeutic hypothermia were prospectively enrolled in this observational study. Neurobehavioral functioning was assessed with the NICU network neurobehavioral scale (NNNS) performed at target age 14 days. Brain injury was assessed by MRI at target age 7–10 days. NNNS scores were compared between infants with and without severe MRI injury. Subjects & outcome measures Sixty-eight term newborns (62% males) with moderate to severe encephalopathy underwent MRI at median 8 days (range 5–16) and NNNS at median 12 days of life (range 5–20). Fifteen (22%) had severe injury on MRI. Results Overall Total Motor Abnormality Score and individual summary scores for Non-optimal Reflexes and Asymmetry were higher, while Total NNNS Z-score across cognitive/behavioral domains was lower (reflecting poorer performance) in infants with severe MRI injury compared to those without (p \u3c 0.05). Conclusions Neonatal neurobehavioral abnormalities identified by the NNNS are associated with MRI brain injury in encephalopathic newborns post-hypothermia. The NNNS can provide an early functional assessment of structural brain injury in newborns, which may guide rehabilitative therapies in infants after perinatal brain injury

Touch and Massage for Medically Fragile Infants

Research investigating the efficacy of infant massage has largely focused on premature and low birth weight infants. The majority of investigations have neglected highly acute patients in academic neonatal intensive care units (NICUs). The current study was developed with two aims: (Phase 1) to develop, implement and demonstrate the feasibility and safety of a parent-trained compassionate touch/massage program for infants with complex medical conditions and (Phase 2) to conduct a longitudinal randomized control trial (RCT) of hand containment/massage versus standard of care in a level III academic Center for Newborn and Infant Critical Care (CNICC). Certified infant massage instructors (CIMIs) taught parents to massage their hospitalized infants. Massage therapy and instruction were performed for seven consecutive days and health outcomes were collected for up to 1 month following treatment. Caregivers, nurses and certified infant massage therapists indicated moderate to high levels of satisfaction and feasibility with the implementation of hand containment/massage in a level III academic center CNICC. In addition, infant behavioral and physiological measures were within safe limits during the massage sessions. All caregivers participating in the massage group reported high levels of satisfaction 7 days into the intervention and at the 1-month follow-up with regards to their relationship with their infant, the massage program's impact on that relationship and the massage program. Due to unequal and small sample sizes, between group analyses (control versus massage) were not conducted. Descriptive infant characteristics of health outcomes are described. Preliminary data from this study indicates feasibility and safety of infant massage and satisfaction among the caregivers, CIMIs and the nurses in the CNICC. An important contribution from this study was the demonstration of the infants’ safety based on physiological stability and no change in agitation/pain scores of the infants receiving massage. Massage in a tertiary urban academic NICU continues to be an area of needed study. Future studies examining infant health outcomes, such as weight gain, decreased length of hospitalization and caregiver–infant bonding, would provide greater insight into the impact of massage for medically fragile infants

The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50). We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG primary tumor cells in vitro. NG2 expression is altered (symmetric segregation) in mitotic human DIPG and mouse tumor cells. These mitotic cells co-express oligodendrocyte (Olig2) and astrocyte (glial fibrillary acidic protein, GFAP) markers, indicating lack of terminal differentiation. NG2 knockdown retards cellular migration in vitro, while NG2 expressing neurospheres are highly tumorigenic in vivo, resulting in rapid growth of pontine tumors. NG2 expression is targetable in vivo using miR129-2 indicating a potential avenue for therapeutic interventions. This data implicates NG2 as a molecule of interest in DIPGs especially those with H3.3 mutation

GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury.

Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. NG2-expressing oligodendrocyte precursor cells (NG2 cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2 cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABAA receptor-mediated synaptic input to NG2 cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABAA receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. Conversely, blockade of GABA catabolism or GABA uptake reduced NG2 cell numbers and increased the formation of mature oligodendrocytes both in control and hypoxic mice. Our results indicate that GABAergic signaling regulates NG2 cell differentiation and proliferation in vivo, and suggest that its perturbation is a key factor in DWMI

A Developmental Profile of Glucose Transport and Utilization in the Brains of Mice

The brain is known to use glucose and related substrates for energy, as opposed to fatty acids and amino acids. How the brain specifically transports and uses glucose during development, however, has not been completely characterized. The aim of this project is to compile an age-specific, region-specific, and cell-specific profile of glucose transport and utilization during development using a mouse model. This profile, once completed, can be used to better understand changes to metabolism in pediatric disease states such as perinatal hypoxia, epilepsy, hyperglycemia, and mitochondrial disease. Mouse brains were harvested at ages P11, P15, and P30, which correspond to neonates, young children, and adolescents respectively. Dissected brains were probed by Western Blot for glucose transporters GLUT1, GLUT2, GLUT3, GLUT4, and GLUT8. We expected to see a shift in glucose metabolism between the ages of P15 and P30 based on an observed behavioral shift (increased activity and self-directed search for food). Results showed a significant increase in GLUT2, a transporter localized to astrocytes, and GLUT8, an insulin-dependent transporter. GLUT3, which is said to be neuron-specific, did not show any significant changes in expression over time. GLUT2 expression was significantly increased by P30 in the frontal cortex and the hippocampus but showed no significant difference in white matter. The increase in expression of GLUT2 makes sense as the proportion of astrocytes increases greatly during development. In the hippocampus. the astrocyte-neuronal lactate shuttle is implicated in the development of long-term memory; therefore, glucose uptake must be positively regulated here in order to provide enough substrate for the shuttle. The large increase in GLUT8 expression can be explained by the feeding pattern of mice during development. From birth to P15, the mice are still in their suckling phase, receiving mostly proteins and fatty acids through their mothers’ milk. These are broken down into ketones that are used as energy for the brain. By P30, however, the mice are feeding on their own and consume a diet significantly higher in carbohydrates, likely causing greater insulin release. Since GLUT8 is an insulin-dependent glucose transporter, this increase in insulin should cause an increase in expression of GLUT8. Although insulin-dependent GLUT4 should have shown similar patterns in expression, it is only weakly expressed in the brain and more prevalent in other peripheral tissues. Therefore, GLUT8 may be the key insulin-dependent glucose transporter in the brain. GLUT8 activity in diabetic patients, therefore, should be further explored

Air Flow in Automotive Engines

This project analyzed and optimized the flow of incoming air and outgoing exhaust through an automotive internal combustion engine to improve the engine power output reliably. The testing vehicle was a 1997 Chevrolet Corvette that started with the factory V8 engine. Engine build design choices were made through research and analysis to optimize airflow and to support the increased component stresses due to the increase in power. Computational fluid dynamics software was utilized to model fluid flow throughout both intake manifolds and further analyze changes that occurred between engine components. Horsepower output measurements were taken before and after modifications to determine power gains and evaluate build design choices

Rhône River: Restoration Recommendations for the Miribel Canal

The Miribel Canal is in need of restoration due to issues with incision and sediment management. The team aimed to research restoration projects that will aid with these issues by looking at case studies and interviewing experts in the field. We identified five viable restoration techniques: widening the river, steepening the banks, replenishing sediment, plant barriers, and bank armoring. The team analyzed the strengths and weaknesses of each technique to determine how applicable they could be for the Miribel Canal. Small-scale field applications of these techniques are recommended for the Miribel Canal to further analyze their applicability

Experience-dependent regulation of NG2 progenitors in the developing barrel cortex

International audienceWe found that, during the formation of the mouse barrel cortex, NG2 cells received glutamatergic synapses from thalamocortical fibers and preferentially accumulated along septa separating the barrels. Sensory deprivation reduced thalamocortical inputs on NG2 cells and increased their proliferation, leading to a more uniform distribution in the deprived barrels. Thus, early sensory experience regulates thalamocortical innervation on NG2 cells, as well as their proliferation and distribution during development