Efficacy of post-insult minocycline administration to alter long-term hypoxia-ischemia-induced damage to the serotonergic system in the immature rat brain

Neuroinflammation is a key mechanism contributing to long-term neuropathology observed after neonatal hypoxia-ischemia (HI). Minocycline, a second-generation tetracycline, is a potent inhibitor of neuroinflammatory mediators and is successful for at least short-term amelioration of neuronal injury after neonatal HI. However the long-term efficacy of minocycline to prevent injury to a specific neuronal network, such as the serotonergic (5-hydroxytryptamine, 5-HT) system, is not known. In a post-natal day 3 (P3) rat model of preterm HI we found significant reductions in 5-HT levels, 5-HT transporter expression and numbers of 5-HT-positive dorsal raphé neurons 6 weeks after insult compared to control animals. Numbers of activated microglia were significantly elevated in the thalamus and dorsal raphé although the greatest numbers were observed in the thalamus. Brain levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were also significantly elevated on P45 in the thalamus and frontal cortex. Post-insult administration of minocycline for 1 week (P3-P9) attenuated the P3 HI-induced increases in numbers of activated microglia and levels of TNF-α and IL-1β on P45 with concurrent changes in serotonergic outcomes. The parallel prevention of P3 HI-induced serotonergic changes suggests that inhibition of neuroinflammation within the first week after P3 HI injury was sufficient to prevent long-term neuroinflammation as well as serotonergic system damage still evident at 6 weeks. Thus early, post-insult administration of minocycline may target secondary neuroinflammation and represent a long-term therapy to preserve the integrity of the central serotonergic network in the preterm neonate. © 2011 IBRO

Transient liver elastography in unsedated control children: Impact of age and intercurrent illness

Transient elastography (TE) is a rapid, non-invasive, reproducible assessment of liver fibrosis by liver stiffness measurement (LSM). Uncertainty remains regarding utility in children, unsedated an

Accuracy of transient elastography data combined with APRI in detection and staging of liver disease in pediatric patients with cystic fibrosis

Liver disease develops in 15%-72% of patients with cystic fibrosis, and 5%-10% develop cirrhosis or portal hypertension, usually during childhood. Transient elastography (TE) is a noninvasive method to measure liver stiffness. We aimed to validate its accuracy in detection of liver disease and assessment of fibrosis in children with cystic fibrosis.We performed a cross-sectional study to evaluate the accuracy of TE in analysis of liver fibrosis in 160 consecutive children who presented with cystic fibrosis (9.0±0.4 years old, 53% male) at a tertiary referral pediatric center in Australia, from 2011 through 2016. Patients were classified as having cystic fibrosis-associated liver disease (CFLD) or cystic fibrosis without liver disease (CFnoLD) based on clinical, biochemical, and imaging features. Fibrosis severity was determined from histologic analysis of dual-pass liver biopsies from children with CFLD, as the reference standard. Data from healthy children without cystic fibrosis (n=64, controls) were obtained from a separate study. Liver stiffness measurements (LSMs) were made by Fibroscan analysis, using the inter-quartile range/median ≤30% of 10 valid measurements. Children with macronodularity or portal hypertension with heterogeneous changes on ultrasound without available biopsy were assigned to the category of stage F3-F4 fibrosis.LSM was made reliably in 86% of children; accuracy increased with age. LSMs were significantly higher in children with CFLD (10.7±2.4 kPa, n=33) than with CFnoLD (4.6±0.1 kPa, n=105) (

Deficits of brainstem and spinal cord functions after neonatal hypoxia–ischemia in mice

International audienc

Selective Losses of Brainstem Catecholamine Neurons After Hypoxia-Ischemia in the Immature Rat Pup.

Hypoxic-ischemic (HI) injury in the preterm neonate incurs numerous functional deficits, however little is known about the neurochemically-defined brain nuclei that may underpin them. Key candidates are the brainstem catecholamine neurons. Using an immature animal model, the postnatal day (P)-3 (P3) rat pup, we investigated the effects of HI on brainstem catecholamine neurons in the locus coeruleus, nucleus tractus solitarius (NTS), and ventrolateral medulla (VLM). On P21, we found that prior P3 HI significantly reduced numbers of catecholaminergic neurons in the locus coeruleus, NTS, and VLM. Only locus coeruleus A6, NTS A2, and VLM A1 noradrenergic neurons, but not NTS C2 and VLM C1 adrenergic neurons, were lost. There was also an associated reduction in dopamine-beta-hydroxylase-positive immunolabeling in the forebrain. These findings suggest neonatal HI can affect specific neurochemically-defined neuronal populations in the brainstem and that noradrenergic neurons are particularly vulnerable to HI injury