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Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxia-ischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI.We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. The response to rHI was compared against corresponding early or later single episodes of HI. An ordinal rating scale of WMI was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microglial activation. Late oligodendrocyte progenitors (preOLs) were quantified by stereology. Analysis of hyaluronan and the hyaluronidase PH20 defined the progressive response of the extracellular matrix to WMI.rHI resulted in a more severe spectrum of WMI with a greater burden of necrosis, but an expanded population of preOLs that displayed reduced susceptibility to cell death. WMI from single episodes of HI or rHI was accompanied by elevated HA levels and increased labeling for PH20. Expression of PH20 in fetal ovine WMI was confirmed by RT-PCR and RNA-sequencing.rHI is associated with an increased risk for more severe WMI with necrosis, but reduced risk for preOL degeneration compared to single episodes of HI. Expansion of the preOL pool may be linked to elevated hyaluronan and PH20.

Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103-104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p

The majority of pre-clinical studies of hypoxic-ischemic encephalopathy at term-equivalent have focused on either relatively mild insults, or on functional paradigms of cerebral ischemia or hypoxia-ischemia/hypotension. There is surprisingly little information on the responses to single, severe 'physiological' insults. In this study we examined the evolution and pattern of neural injury after prolonged umbilical cord occlusion (UCO). 36 chronically instrumented fetal sheep at 125-129 days gestational age (term = 147 days) were subjected to either UCO until mean arterial pressure was

Spontaneous antenatal hypoxia is associated with high risk of adverse outcomes, however, there is little information on neural adaptation to labor-like insults. Chronically instrumented near-term sheep fetuses (125 ± 3 days, mean ± SEM) with baseline PaO2 < 17 mmHg (hypoxic group: n = 8) or > 17 mmHg (normoxic group: n = 8) received 1-minute umbilical cord occlusions repeated every 5 minutes for a total of 4 hours, or until mean arterial blood pressure (MAP) fell below 20 mmHg for two successive occlusions. 5/8 fetuses with pre-existing hypoxia were unable to complete the full series of occlusions (vs. 0/8 normoxic fetuses). Pre-existing hypoxia was associated with progressive metabolic acidosis (nadir: pH 7.08 ± 0.04 vs. 7.33 ± 0.02, p

Fetal susceptibility to hypoxic brain injury increases over the last third of gestation. This study examined the hypothesis that this is associated with impaired mitochondrial adaptation, as measured by more rapid oxidation of cytochrome oxidase (CytOx) during profound asphyxia.Chronically instrumented fetal sheep at 0.6, 0.7, and 0.85 gestation were subjected to either 30 min (0.6 gestational age (ga), n = 6), 25 min (0.7 ga, n = 27) or 15 min (0.85 ga, n = 17) of complete umbilical cord occlusion. Fetal EEG, cerebral impedance (to measure brain swelling) and near-infrared spectroscopy-derived intra-cerebral oxygenation (ΔHb = HbO(2) - Hb), total hemoglobin (THb) and CytOx redox state were monitored continuously. Occlusion was associated with profound, rapid fall in ΔHb in all groups to a plateau from 6 min, greatest at 0.85 ga compared to 0.6 and 0.7 ga (p

BACKGROUND: GH therapy requires daily injections over many years and compliance can be difficult to sustain. As growth hormone (GH) is expensive, non-compliance is likely to lead to suboptimal growth, at considerable cost. Thus, we aimed to assess the compliance rate of children and adolescents with GH treatment in New Zealand. METHODS: This was a national survey of GH compliance, in which all children receiving government-funded GH for a four-month interval were included. Compliance was defined as ≥ 85% adherence (no more than one missed dose a week on average) to prescribed treatment. Compliance was determined based on two parameters: either the number of GH vials requested (GHreq) by the family or the number of empty GH vials returned (GHret). Data are presented as mean ± SEM. FINDINGS: 177 patients were receiving GH in the study period, aged 12.1 ± 0.6 years. The rate of returned vials, but not number of vials requested, was positively associated with HVSDS (p < 0.05), such that patients with good compliance had significantly greater linear growth over the study period (p