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Cannabidiol (CBD), a nonpsychoactive cannabinoid, has shown neuroprotective actions after neonatal hypoxia-ischemia (HI) in animals. We wanted to further explore the effects of CBD, alone and in conjunction with hypothermia, in a piglet model of global HI. Fifty-five anesthetized newborn piglets were randomized to either controls (n = 7) or HI (n = 48) by ventilation with 8% O2 until mean arterial blood pressure reached 20 mmHg and/or base excess reached −20 mmol/l. After resuscitation piglets were randomized to either: vehicle (VEH), CBD 1mg/kg, VEH+hypothermia (H) or CBD 1mg/kg+H (each n = 12). Piglets were euthanized 9.5 h after HI and plasma, urine, cerebrospinal fluid, and brain tissue were sampled for analysis. HI induced global damage with significantly increased neuropathology score, S100B in cerebrospinal fluid, hippocampal proton magnetic resonance spectroscopy biomarkers, plasma troponin-T, and urinary neutrophil gelatinase-associated lipocalin. CBD alone did not have any significant effects on these parameters while CBD+H reduced urinary neutrophil gelatinase-associated lipocalin compared with VEH+H (P < 0.05). Both hypothermic groups had significantly lower glutamate/N-acetylaspartate ratios (P < 0.01) and plasma troponin-T (P

In a consecutive hospital-based autopsy series, we examined the relationship between apolipoprotein E (apoE) and Alzheimer’s disease (AD) and investigated the clinicopathological relationship in AD. The study population included 99 patients (mean age 81 years) with AD-related neuropathological findings at death, of whom 83 were diagnosed with AD according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) classification, and a control group of patients without neurodegenerative disease (n = 1429). The patients were apoE genotyped and the density of β-amyloid senile plaques, neuritic plaques and neurofibrillary tangles was estimated in the cortex and hippocampus. The utility of immunohistochemical staining using an antibody directed against apoE4 in paraffin-embedded tissue was also evaluated. Among patients with “definite AD” according to CERAD, 65 % were e4 carriers, compared to 32 % among controls (p

Mice lacking glycosylated lysosomal membrane protein (Glmp gt/gt mice) have liver fibrosis as the predominant phenotype due to chronic liver injury. The Glmp gt/gt mice grow and reproduce at the same rate as their wild-type siblings. Life expectancy is around 18 months. Wild-type and Glmp gt/gt mice were studied between 1 week and 18 months of age. Livers were analyzed using histological, immunohistochemical, biochemical, and qPCR analyses. It was shown that Glmp gt/gt mice were not born with liver injury; however, it appeared shortly after birth as indicated by excess collagen expression, deposition of fibrous collagen in the periportal areas, and increased levels of hydroxyproline in Glmp gt/gt liver. Liver functional tests indicated a chronic, mild liver injury. Markers of inflammation, fibrosis, apoptosis, and modulation of extracellular matrix increased from an early age, peaking around 4 months of age and followed by attenuation of these signals. To compensate for loss of hepatocytes, the oval cell compartment was activated, with the highest activity of the oval cells detected at 3 months of age, suggesting insufficient hepatocyte proliferation in Glmp gt/gt mice around this age. Although constant proliferation of hepatocytes and oval cells maintained adequate hepatic function in Glmp gt/gt mice, it also resulted in a higher frequency of liver tumors in older animals. The Glmp gt/gt mouse is proposed as a model for slowly progressing liver fibrosis and possibly as a model for a yet undescribed human lysosomal disorder.

Mild therapeutic hypothermia (HT) reduces brain injury in survivors after perinatal asphyxia. Recent guidelines suggest that resuscitation of term infants should be started with air, but supplemental oxygen is still in use. It is not known whether supplemental oxygen during resuscitation affects the protection offered by subsequent HT.Wilcoxon median (95% confidence interval) hippocampal injury scores (range 0.0-4.0; 0 to ≥90% injury) were 21% O(2) normothermia (NT): 2.00 (1.25-2.50), 21% O(2) HT: 1.00 (0.50-1.50), 100% O(2) NT: 2.50 (1.50-3.25), and 100% O(2) HT: 2.00 (1.25-2.50). Although HT significantly reduced hippocampal injury (B = -0.721, SEM = 0.297, P = 0.018), reoxygenation with 100% O(2) increased injury (B = +0.647, SEM = 0.297, P = 0.033). Regression constant B = 1.896, SEM = 0.257 and normally distributed residuals.We confirm an ~50% neuroprotective effect of therapeutic HT in the neonatal rat. Reoxygenation with 100% O(2) increased injury and worsened reflex performance. HT was neuroprotective whether applied after reoxygenation with air or 100% O(2). However, HT after 100% O(2) gave no net neuroprotection.In an established neonatal rat model, hypoxia-ischemia (HI) was followed by 30-min reoxygenation in either 21% O(2) or 100% O(2) before 5 h of NT (37 °C) or HT (32 °C). The effects of HT and 100% O(2) on histopathologic injury in the hippocampus, basal ganglia, and cortex, and on postural reflex performance 7 d after the insult, were estimated by linear regression.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a clinically defined neurological condition after lack of oxygen and often associated with cardiac dysfunction in term infants. Therapeutic hypothermia (HT) after birth is neuroprotective in infants with HIE. However, it is not known whether HT is also cardioprotective. Four newborn pigs were used in the pilot study and a further 18 newborn pigs [randomly assigned to 72 h normothermia (NT) or 24 h HT followed by 48 h NT] were subjected to global HIE insults. Serum cTnI was measured before and post the HIE insult. Blood pressure, inotropic support, blood gases, and heart rate (HR) were recorded throughout. Cardiac pathology was assessed from histological sections. Cooling reduced serum cTnI levels significantly in HT pigs by 6 h (NT, 1.36 ± 0.67; HT, 0.34 ± 0.23 ng/mL; p = 0.0009). After rewarming, from 24 to 30 h postinsult, HR and cTnI increased in the HT group; from HR[24 h] = 117 ± 22 to HR[30 h] = 218 ± 32 beats/min (p = 0.0002) and from cTnI[24 h] = 0.23 ± 0.12 to cTnI[30 h] = 0.65 ± 0.53 ng/mL, (p = 0.05). There were fewer ischemic lesions on cardiac examination (37%) in the HT group compared with the NT group (70%). HT (24 h) pigs did not have the postinsult cTnI increase seen in NT-treated pigs. There was a trend that HT improved cardiac pathology in this 3-d survival model.

Three to 12 h of mild hypothermia (HT) starting after hypoxia-ischemia is neuroprotective in piglets that are anesthetized during HT. Newborn infants suffering from neonatal encephalopathy often ventilate spontaneously and are not necessarily sedated. We aimed to test whether mild posthypoxic HT lasting 24 h was neuroprotective if the animals were not sedated. Thirty-nine piglets (median weight 1.6 kg, range 0.8-2.2 kg; median age 24 h, range 7-48 h) were anesthetized and ventilated and subjected to a 45-min hypoxic (FiO(2) approximately 6%) global insult (n = 36) or sham hypoxia (n = 3). On reoxygenation, 18 were maintained normothermic (NT, 39.0 degrees C) for 72 h, and 21 were cooled from 39 (NT) to 35 degrees C (HT) for the first 24 h before NT was resumed (18 experimental, three sham hypoxia). Cardiovascular parameters and intermittent EEG were documented throughout. The brain was perfusion fixed for neuropathology and five main areas examined using light microscopy. The insult severity (duration in minutes of EEG amplitude < 7 microV) was similar in the NT and HT groups, mean +/- SD (28 +/- 7.2 versus 27 +/- 8.6 min), as was the mean FiO(2) (5.9 +/- 0.7 versus 5.8 +/- 0.8%) during the insult. Six NT and seven HT piglets developed posthypoxic seizures that lasted 29 and 30% of the time, respectively. The distribution and degree of injury (0.0-4.0, normal-maximal damage) within the brain (hippocampus, cortex/white matter, cerebellum, basal ganglia, thalamus) were similar in the NT and HT groups (overall score, mean +/- SD, 2.3 +/- 1.5 versus 2.4 +/- 1.3) as was the EEG background amplitude at 3 h (13 +/- 3.5 versus 10 +/- 3.3 microV). The HT animals shivered and were more active. The sham control group (n = 3) shivered but had normal physiology and neuropathology. Plasma cortisol was significantly higher in the HT group during the HT period, 766 +/- 277 versus 244 +/- 144 microM at 24 h. Mild postinsult HT for 24 h was not neuroprotective in unsedated piglets and did not reduce the number of animals that developed posthypoxic seizures. Cortisol reached 3 times the NT value at the end of HT. We speculate that the stress of shivering and feeling cold interfered with the previously shown neuroprotective effect of HT. Research on the appropriateness of sedation during clinical HT is urgent.

The aim of this study was to produce a neonatal piglet model which, avoiding vessel ligation, exposed the whole animal to hypoxia and produced dose-dependent clinical encephalopathy and neuropathologic damage similar to that seen after birth asphyxia. Twenty-three piglets were halothane-anesthetized. Hypoxia was induced in 19 piglets by reducing the fractional concentration of inspired oxygen (FiO2) to the maximum concentration at which the EEG amplitude was below 7 microV (low amplitude) for 17-55 min. There were transient increases in Fio2 to correct bradycardia and hypotension. Posthypoxia, the piglets were extubated when breathing was stable. Four were sham-treated controls. We aimed at 72-h survival; seven died prematurely due to posthypoxic complications. EEG and a videotaped itemized neurologic assessment were recorded regularly. We found that 95% of the animals showed neuropathologic damage. The duration of low amplitude EEG during the insult and the arterial pH at the end of the insult correlated with cortical/white matter damage; r = 0.75 and 0.81, respectively. Early postinsult EEG background amplitude (r = 0.86 at 3 h) and neurologic score (r = 0.79 at 8 h) correlated with neuropathology. Epileptic seizures in seven animals were always associated with severe neuropathologic damage. We conclude that EEG-controlled hypoxia and subsequent intensive care enabled the animals to survive with an encephalopathy which correlated with the cerebral hypoxic insult. The encephalopathy was clinically, electrophysiologically, and neuropathologically similar to that in the asphyxiated term infant. This model is suitable for examining mechanisms of damage and evaluation of potential protective therapies after birth asphyxia.

To study whether room air is as effective as 100% O2 in resuscitation after hypoxia, hypoxemia (PaO2 2.3-4.3 kPa) was induced in newborn pigs (2-5 d old) by ventilation with 8% O2 in nitrogen. When systolic blood pressure had fallen to 20 mm Hg, animals were randomly reoxygenated with either 21% O2 (group 1, n = 9) or 100% O2 (group 2, n = 11) for 20 min followed by 21% O2 in both groups. Controls (group 3, n = 5) were ventilated with 21% O2 throughout the experiment. Base deficit peaked at 31 +/- 5 mmol/L (mean +/- SD) for both hypoxic groups at 5 min of reoxygenation and then normalized over the following 3 h. There were no statistically significant differences between the two groups during reoxygenation concerning blood pressure, heart rate, base deficit, or plasma hypoxanthine. Hypoxanthine peaked at 165 +/- 40 and 143 +/- 42 mumol/L in group 1 and 2 (NS), respectively, and was eliminated monoexponentially in both groups with an initial half-life for excess hypoxanthine of 48 +/- 21 and 51 +/- 27 min (NS), respectively. Blinded pathologic examination of cerebral cortex, cerebellum, and hippocampus after 4 d showed no statistically significant differences with regard to brain damage. We conclude that 21% O2 is as effective as 100% O2 for normalizing blood pressure, heart rate, base deficit, and plasma hypoxanthine after severe neonatal hypoxemia in piglets and that the extent of the hypoxic brain damage is similar in the two groups.