Distinguishing Laterality in Brain Injury in Rabbit Fetal MRI Using Novel Volume Rendering Techniques.

INTRODUCTION: Our laboratory has been exploring the MRI detection of fetal brain injury, which previously provided a prognostic biomarker for newborn hypertonia in an animal model of cerebral palsy (CP). The biomarker relies on distinct patterns of diffusion-weighted imaging-defined apparent diffusion coefficient (ADC) in fetal brains during uterine ischemia (H-I). Despite the challenges posed by small brains and tissue acquisition, our objective was to differentiate between left and right brain ADC changes. METHODS: A novel aspect involved utilizing three-dimensional rendering techniques to refine ADC measurements within spheroids encompassing fetal brain tissue. 25-day gestation rabbit fetuses underwent global hypoxia due to maternal uterine ischemia. RESULTS: Successful differentiation of left and right brain regions was achieved in 28% of the fetal brains. Ordinal analysis revealed predominantly higher ADC on the left side compared to the right at baseline and across the entire time series. During H-I and reperfusion-reoxygenation, the right side exhibited a favored percentage change. Among these fetal brains, 73% exhibited the ADC pattern predictive of hypertonia. No significant differences between left and right sides were observed in patterns predicting hypertonia, except for one time point during hypoxia-ischemia. This study also highlights a balance between left-sided and right-sided alterations within the population. CONCLUSION: This study emphasizes the importance of investigating laterality and asymmetric hemispheric lesions for early diagnosis of brain injury leading to CP. The technological limitations in obtaining a clear picture of the entire fetal brain for every fetus mirror the challenges encountered in human studies.

Development of A New Scoring System in Higher Animals for Testing Cognitive Function in the Newborn Period: Effect of Prenatal Hypoxia-Ischemia.

Introduction Enhanced models for assessing cognitive function in the neonatal period are imperative in higher animals. Postnatal motor deficits, characteristic of cerebral palsy, emerge in newborn kits within our prenatal-rabbit model of hypoxia-ischemia (HI). In humans, prenatal HI leads to intellectual disability and cerebral palsy. In a study examining cognitive function in newborn rabbits, we explored several questions. Is there a distinction between conditioned and unconditioned kits? Can the kits discern the human face or the lab coat? Do motorically-normal kits, born after prenatal HI, exhibit cognitive deficits? Methods The conditioning protocol was randomly assigned to kits from each litter. For conditioning, the same human, wearing a lab coat, fed the rabbit kits for 9 days before the cognitive test. The 6-arm radial maze was chosen for its simplicity and ease of use. Normally appearing kits, born after uterine ischemia at 79% or 92% term in New Zealand White rabbits, were compared to Naïve kits. On postpartum day 22/23 or 29/30, the 6-arm maze helped determine if the kits recognized the original feeder from bystander (Test-1) or the lab coat on bystander (Test-2). The use of masks of feeder/bystander (Test-3) assessed confounding cues. A weighted score was devised to address variability in entry to maze arms, time, and repeated-trial learning. Results In conditioned kits, both Naïve and HI kits exhibited a significant preference for the face of the feeder, but not the lab coat. Cognitive deficits were minimal in normal-appearing HI kits. Conclusion The weighted score system was amenable to statistical manipulation.

Toward Lung Ventilation Imaging Using Hyperpolarized Diethyl Ether Gas Contrast Agent.

Hyperpolarized 129Xe gas was FDA-approved as an inhalable contrast agent for magnetic resonance imaging of a wide range of pulmonary diseases in December 2022. Despite the remarkable success in clinical research settings, the widespread clinical translation of HP 129Xe gas faces two critical challenges: the high cost of the relatively low-throughput hyperpolarization equipment and the lack of 129Xe imaging capability on clinical MRI scanners, which have narrow-bandwidth electronics designed only for proton (1H) imaging. To solve this translational grand challenge of gaseous hyperpolarized MRI contrast agents, here we demonstrate the utility of batch-mode production of proton-hyperpolarized diethyl ether gas via heterogeneous pairwise addition of parahydrogen to ethyl vinyl ether. An approximately 0.1-liter bolus of hyperpolarized diethyl ether gas was produced in 1 second and injected in excised rabbit lungs. Lung ventilation imaging was performed using sub-second 2D MRI with up to 2×2 mm2 in-plane resolution using a clinical 0.35 T MRI scanner without any modifications. This feasibility demonstration paves the way for the use of inhalable diethyl ether as a gaseous contrast agent for pulmonary MRI applications using any clinical MRI scanner.

Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series).

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Unsupervised abnormality detection in neonatal MRI brain scans using deep learning.

Analysis of 3D medical imaging data has been a large topic of focus in the area of Machine Learning/Artificial Intelligence, though little work has been done in algorithmic (particularly unsupervised) analysis of neonatal brain MRI's. A myriad of conditions can manifest at an early age, including neonatal encephalopathy (NE), which can result in lifelong physical consequences. As such, there is a dire need for better biomarkers of NE and other conditions. The objective of the study is to improve identification of anomalies and prognostication of neonatal MRI brain scans. We introduce a framework designed to support the analysis and assessment of neonatal MRI brain scans, the results of which can be used as an aid to neuroradiologists. We explored the efficacy of the framework through iterations of several deep convolutional Autoencoder (AE) unsupervised modeling architectures designed to learn normalcy of the neonatal brain structure. We tested this framework on the developing human connectome project (dHCP) dataset with 97 patients that were previously categorized by severity. Our framework demonstrated the model's ability to identify and distinguish subtle morphological signatures present in brain structures. Normal and abnormal neonatal brain scans can be distinguished with reasonable accuracy, correctly categorizing them in up to 83% of cases. Most critically, new brain anomalies originally missed during the radiological reading were identified and corroborated by a neuroradiologist. This framework and our modeling approach demonstrate an ability to improve prognostication of neonatal brain conditions and are able to localize new anomalies.

Neuroprotective therapies in the NICU in term infants: present and future.

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

Using Temporal Data Mining on Patient Data for Clinical Decision Making in the Care of the Sick Newborn.

Background: In a neonatal intensive care unit, streaming healthcare data comes from many sources, but humans are unable to understand relationships between data variables. Data mining and analysis are just beginning to get utilized in critical care. We present a case study using electronic medical record data in the neonatal intensive care unit and explore possible avenues of advancement using temporal data analytics. Case Presentation: Electronic medical record data were collected for physiological monitor data. Heart rate, respiratory rate, oxygen saturation and temperature data were retrospectively analyzed by temporal data mining. Three premature babies were selected and data de-identified. The first case of a urinary tract infection showed nursing ability to synthesize data streams coming from a patient. For the second case of necrotizing enterocolitis, Temporal-Data-Mining analysis of combinations of clinical events based on deviations from the mean showed specific heuristic biomarkers related to events before discovery of necrotizing enterocolitis. Specific sequences 6-event and 5-event in length were identified with nursing unease at clinical deterioration, which were 100- and 87-times unlikely to occur randomly with 99.5% confidence. No such sequences were found in the rest of the 37 days for the second case and entire 133 days of stay in the third case of an uneventful premature baby. Conclusion: Temporal data mining is a possible clinical tool in providing useful information in the neonatal intensive care unit for diagnosis of adverse clinical occurrences such as necrotizing enterocolitis. There is the possibility of changing the clinical paradigm of episodic watchfulness to constant vigilance using real-time data gathering.

Mimicking partial to total placental insufficiency in a rabbit model of cerebral palsy.

All placental abruptions begin as partial abruptions, which sometimes manifest as fetal bradycardia. The progression from partial to total abruption was mimicked by a new rabbit model of placental insufficiency, and we compared it, with sufficient statistical power, with the previous model mimicking total placental abruption. The previous model uses total uterine ischemia at E22 or E25 (70% or 79% term, respectively), in pregnant New Zealand white rabbits for 40 min (Full H-I). The new model, Partial+Full H-I, added a 30-min partial ischemia before the 40-min total ischemia. Fetuses were delivered either at E31.5 (full term) vaginally for neurobehavior testing, or by C-section at E25 for ex vivo brain cell viability evaluation. The onset of fetal bradycardia was within the first 2 min of either H-I protocol. There was no difference between Full H-I (n = 442 for E22, 312 for E25) and Partial+Full H-I (n = 154 and 80) groups in death or severely affected kits at E22 (76% vs. 79%) or at E25 (66% vs. 64%), or normal kits at E22 or E25, or any of the individual newborn neurobehavioral tests at any age. No sex differences were found. Partial+Full H-I (n = 6) showed less cell viability than Full H-I (n = 8) at 72-hr ex vivo in the brain regions studied. Partial+Full H-I insult produced similar cerebral palsy phenotype as our previous Full H-I model in a sufficiently powered study and may be more suitable for testing of potential neuroprotectants.

Neonatal encephalopathy prediction of poor outcome with diffusion-weighted imaging connectome and fixel-based analysis.

BACKGROUND: Better biomarkers of eventual outcome are needed for neonatal encephalopathy. To identify the most potent neonatal imaging marker associated with 2-year outcomes, we retrospectively performed diffusion-weighted imaging connectome (DWIC) and fixel-based analysis (FBA) on magnetic resonance imaging (MRI) obtained in the first 4 weeks of life in term neonatal encephalopathy newborns. METHODS: Diffusion tractography was available in 15 out of 24 babies with MRI, five each with normal, abnormal motor outcome, or death. All 15 except one underwent hypothermia as initial treatment. In abnormal motor and death groups, DWIC found 19 white matter pathways with severely disrupted fiber orientation distributions. RESULTS: Using random forest classification, these disruptions predicted the follow-up outcomes with 89-99% accuracy. These pathways showed reduced integrity in abnormal motor and death vs. normal tone groups (p < 10-6). Using ranked supervised multi-view canonical correlation and depicting just three of the five dimensions of the analysis, the abnormal motor and death were clearly differentiated from each other and the normal tone group. CONCLUSIONS: This study suggests that a machine-learning model for prediction using early DWIC and FBA could be a possible way of developing biomarkers in large MRI datasets having clinical outcomes. IMPACT: Early connectome and FBA of clinically acquired DWI provide a new noninvasive imaging tool to predict the long-term motor outcomes after birth, based on the severity of white matter injury. Disrupted white matter connectivity as a novel neonatal marker achieves high accuracy of 89-99% to predict 2-year motor outcomes using conventional machine-learning classification. The proposed neonatal marker may allow better prognostication that is important to elucidate neural repair mechanisms and evaluate treatment modalities in neonatal encephalopathy.

A systematic review of noninflammatory cerebrospinal fluid biomarkers for clinical outcome in neonates with perinatal hypoxic brain injury that could be biologically significant.

Neonatal encephalopathy (NE) that purportedly arises from hypoxia-ischemia is labeled hypoxic-ischemic encephalopathy (HIE). Perinatal asphyxia is a clinical syndrome involving acidosis, a low Apgar score and the need for resuscitation in the delivery room; asphyxia alerts one to the possibility of NE. In the present systematic review, we focused on the noninflammatory biomarkers in cerebrospinal fluid (CSF) that are involved in the development of possible brain injury in asphyxia or HIE. A literature search in PubMed and EMBASE for case-control studies was conducted and 17 studies were found suitable by a priori criteria. Statistical analysis used the Mantel-Haenszel model for dichotomous data. The pooled mean difference and 95% confidence intervals (CIs) were determined. We identified the best biomarkers, based on the estimation approach in evaluating the biological significance, out of hundreds in three categories: cell adhesion and proliferation, oxidants and antioxidants, and cell damage. The following subtotal-population comparisons were made: perinatal asphyxia versus no asphyxia, asphyxia with HIE versus asphyxia without HIE, asphyxia with HIE versus no asphyxia, and term versus preterm HIE newborn with asphyxia. Biological significance of the biomarkers was determined by using a modification of the estimation approach, by ranking the biomarkers according to the difference in the bounds of the CIs. The most promising CSF biomarkers for prognostication especially for the severest HIE include creatine kinase, xanthine oxidase, vascular endothelial growth factor, neuron-specific enolase, superoxide dismutase, and malondialdehyde. Future studies are recommended using such a combined test to prognosticate the most severely affected patients.

Tetrahydrobiopterin in Cell Function and Death Mechanisms.

Significance: Tetrahydrobiopterin (BH4) is most well known as a required cofactor for enzymes regulating cellular redox homeostasis, aromatic amino acid metabolism, and neurotransmitter synthesis. Less well known are the effects dependent on the cofactor's availability, factors governing its synthesis and recycling, redox implications of the cofactor itself, and protein-protein interactions that underlie cell death. This review provides an understanding of the recent advances implicating BH4 in the mechanisms of cell death and suggestions of possible therapeutic interventions. Recent Advances: The levels of BH4 often reflect the sum of synthetic and recycling enzyme activities. Enhanced expression of GTP cyclohydrolase, the rate-limiting enzyme in biosynthesis, increases BH4, leading to improved cell function and survival. Pharmacologically increasing BH4 levels has similar beneficial effects, leading to enhanced production of neurotransmitters and nitric oxide or reducing oxidant levels. The GTP cyclohydrolase-BH4 pairing has been implicated in a type of cell death, ferroptosis. At the cellular level, BH4 counteracts anticancer therapies directed to enhance ferroptosis via glutathione peroxidase 4 (GPX4) activity inhibition. Critical Issues: Because of the multitude of intertwined mechanisms, a clear relationship between BH4 and cell death is not well understood yet. The possibility that the cofactor directly influences cell viability has not been excluded in previous studies when modulating BH4-producing enzymes. Future Directions: The importance of cellular BH4 variations and BH4 biosynthetic enzymes to cell function and viability makes it essential to better characterize temporal changes, cofactor activity, and the influence on redox status, which in turn would help develop novel therapies. Antioxid. Redox Signal. 37, 171-183.

Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels.

Hypertonia is pathognomonic of cerebral palsy (CP), often caused by brain injury before birth. To understand the early driving events of hypertonia, we utilized magnetic resonance imaging (MRI) assessment of early critical brain injury in rabbit fetuses (79% term) that will predict hypertonia after birth following antenatal hypoxia-ischemia. We examined if individual variations in the tetrahydrobiopterin cofactor in the parts of the brain controlling motor function could indicate a role in specific damage to motor regions and disruption of circuit integration as an underlying mechanism for acquiring motor disorders, which has not been considered before. The rabbit model mimicked acute placental insufficiency and used uterine ischemia at a premature gestation. MRI during the time of hypoxia-ischemia was used to differentiate which individual fetal brains would become hypertonic. Four brain regions collected immediately after hypoxia-ischemia or 48 h later were analyzed in a blinded fashion. Age-matched sham-operated animals were used as controls. Changes in the reactive nitrogen species and gene expression of the tetrahydrobiopterin biosynthetic enzymes in brain regions were also studied. We found that a combination of low tetrahydrobiopterin content in the cortex, basal ganglia, cerebellum, and thalamus brain regions, but not a unique low threshold of tetrahydrobiopterin, contributed etiologically to hypertonia. The biggest contribution was from the thalamus. Evidence for increased reactive nitrogen species was found in the cortex. By 48 h, tetrahydrobiopterin and gene expression levels in the different parts of the brain were not different between MRI stratified hypertonia and non-hypertonia groups. Sepiapterin treatment given to pregnant dams immediately after hypoxia-ischemia ameliorated hypertonia and death. We conclude that a developmental tetrahydrobiopterin variation is necessary with fetal hypoxia-ischemia and is critical for disrupting normal motor circuits that develop into hypertonia. The possible mechanistic pathway involves reactive nitrogen species.

A Non-Lethal Osteogenesis Imperfecta Type II Mutation.

BACKGROUND: We discuss the ethical decision points in a case report that describes a novel COL1A1 mutation associated to Osteogenesis Imperfecta type II, but with a non-lethal outcome. CASE: A 33-year-old female underwent a 21-week ultrasound that revealed short bowed femurs and humeri with old fractures and bowed tibias and fibulas. Amniotic fluid testing revealed a novel COL1A1 mutation (c.1840G>A; p.Gly614Arg). OI Type II diagnosis was made. A previously reported mutation of the same gene but different locus (c.1840G>C; p.Gly614Arg) led to a lethal form of OI type II. The newborn was delivered via a cesarean delivery and intravenous bisphosphonates (Zaledronic acid) was administered every 3 months. Currently the infant is 22 months old, is growing, with mild bilateral conductive hearing loss. CONCLUSION: The unexpected clinical outcome should serve as a reminder that phenotypic variability can occur with genetic mutations. Our case shows that the diagnosis of the type of OI should be based not only on clinical findings and genetic investigations but also on the clinical course over time.

Ascending Lipopolysaccharide-Induced Intrauterine Inflammation in Near-Term Rabbits Leading to Newborn Neurobehavioral Deficits.

BACKGROUND: Chorioamnionitis from ascending bacterial infection through the endocervix is a potential risk factor for cerebral palsy. Tetrahydrobiopterin, an essential cofactor for nitric oxide synthase (NOS) and amino acid hydroxylases, when augmented in the fetal brain, prevents some of the cerebral palsy-like deficits in a rabbit hypoxia-ischemia model. OBJECTIVES: To study the effect of lipopolysaccharide (LPS)-induced intrauterine inflammation in preterm gestation on motor deficits in the newborn, and whether biosynthesis of tetrahydrobiopterin or inflammatory mediators is affected in the fetal brain. METHODS: Pregnant rabbits at 28 days gestation (89% term) were administered either saline or LPS into both endocervical openings. One group underwent spontaneous delivery, and neurobehavioral tests were performed at postnatal day (P) 1 and P11, with some kits being sacrificed at P1 for histological analysis. Another group underwent Cesarean section 24 h after LPS administration. Gene sequences for rabbit biosynthetic enzymes of tetra-hydrobiopterin pathways were determined and analyzed in addition to cytokines, using quantitative real-time polymerase chain reaction. RESULTS: Exposure to 200 µg/kg/mL LPS caused a locomotion deficit and mild hypertonia at P1. By P11, most animals turned into normal-appearing kits. There was no difference in neuronal cell death in the caudate between hypertonic and nonhypertonic kits at P1 (n = 3-5 in each group). Fetal brain GTP cyclohydrolase I was increased, whereas sepiapterin reductase and 6-pyruvoyltetrahydropterin synthase were decreased, 24 h after LPS administration. Neuronal NOS was also increased. Regardless of the position in the uterus or the brain region, expression of TNF-α and TGF-ß was decreased, whereas that of IL-1ß, IL-6, and IL-8 was increased (n = 3-4 in each group). CONCLUSIONS: This is the first study using an ascending LPS-induced intrauterine inflammation model in rabbits, showing mostly transient hypertonia and mainly locomotor deficits in the kits. Not all proinflammatory cytokines are increased in the fetal brain following LPS administration. Changes in key tetrahydro-biopterin biosynthetic enzymes possibly indicate different effects of the inflammatory insult.

Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor impairments and cerebral palsy.

Antenatal brain hypoxia-ischemia, which occurs in cerebral palsy, is considered a significant cause of motor impairments in children. The mechanisms by which antenatal hypoxia-ischemia causes brain injury and motor deficits still need to be elucidated. Tetrahydrobiopterin is an important enzyme cofactor that is necessary to produce neurotransmitters and to maintain the redox status of the brain. A genetic deficiency of this cofactor from mutations of biosynthetic or recycling enzymes is a well-recognized factor in the development of childhood neurological disorders characterized by motor impairments, developmental delay, and encephalopathy. Experimental hypoxia-ischemia causes a decline in the availability of tetrahydrobiopterin in the immature brain. This decline coincides with the loss of brain function, suggesting this occurrence contributes to neuronal dysfunction and motor impairments. One possible mechanism linking tetrahydrobiopterin deficiency, hypoxia-ischemia, and neuronal injury is oxidative injury. Evidence of the central role of the developmental biology of tetrahydrobiopterin in response to hypoxic ischemic brain injury, especially the development of motor deficits, is discussed.

Chorioamnionitis in the Development of Cerebral Palsy: A Meta-analysis and Systematic Review.

CONTEXT: Chorioamnionitis (CA) has often been linked etiologically to cerebral palsy (CP). OBJECTIVES: To differentiate association from risk of CA in the development of CP. DATA SOURCES: PubMed, Cochrane Library, Embase, and bibliographies of original studies were searched by using the keywords (chorioamnionitis) AND ((cerebral palsy) OR brain). STUDY SELECTION: Included studies had to have: (1) controls, (2) criteria for diagnoses, and (3) neurologic follow-up. Studies were categorized based on: (1) finding incidence of CP in a CA population, or risk of CP; and (2) incidence of CA in CP or association with CP. DATA EXTRACTION: Two reviewers independently verified study inclusion and extracted data. RESULTS: Seventeen studies (125 256 CA patients and 5 994 722 controls) reported CP in CA. There was significantly increased CP inpreterm histologic chorioamnionitis (HCA; risk ratio [RR] = 1.34, P < .01), but not in clinical CA (CCA). Twenty-two studies (2513 CP patients and 8135 controls) reported CA in CP. There was increased CCA (RR = 1.43, P < .01), but no increase in HCA in preterm CP. Increased HCA was found (RR = 4.26, P < .05), as well as CCA in term/near-term CP (RR = 3.06, P < .01). CONCLUSIONS: The evidence for a causal or associative role of CA in CP is weak. Preterm HCA may be a risk factor for CP, whereas CCA is not. An association with term and preterm CP was found for CCA, but only with term CP for HCA.

Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model.

Cerebral palsy (CP) has a significant impact on both patients and society, but therapy is limited. Human umbilical cord blood cells (HUCBC), containing various stem and progenitor cells, have been used to treat various brain genetic conditions. In small animal experiments, HUCBC have improved outcomes after hypoxic-ischemic (HI) injury. Clinical trials using HUCBC are underway, testing feasibility, safety and efficacy for neonatal injury as well as CP. We tested HUCBC therapy in a validated rabbit model of CP after acute changes secondary to HI injury had subsided. Following uterine ischemia at 70% gestation, we infused HUCBC into newborn rabbit kits with either mild or severe neurobehavioral changes. Infusion of high-dose HUCBC (5 × 10(6) cells) dramatically altered the natural history of the injury, alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test, however, showed that joint function did not restore to naïve control function in either group. Tracing HUCBC with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. This is the first study to show that HUCBC improve motor performance in a dose-dependent manner, perhaps by improving compensatory repair processes.

A Critical Review of Models of Perinatal Infection.

One of the central, unanswered questions in perinatology is why preterm infants continue to have such poor long-term neurodevelopmental, cognitive and learning outcomes, even though severe brain injury is now rare. There is now strong clinical evidence that one factor underlying disability may be infection, as well as nonspecific inflammation, during fetal and early postnatal life. In this review, we examine the experimental evidence linking both acute and chronic infection/inflammation with perinatal brain injury and consider key experimental determinants, including the microglia response, relative brain and immune maturity and the pattern of exposure to infection. We highlight the importance of the origin and derivation of the bacterial cell wall component lipopolysaccharide. Such experimental paradigms are essential to determine the precise time course of the inflammatory reaction and to design targeted neuroprotective strategies to protect the perinatal brain from infection and inflammation.