Angiogenesis induced by prenatal ischemia predisposes to periventricular hemorrhage during postnatal mechanical ventilation.

BACKGROUND: Three risk factors are associated with hemorrhagic forms of encephalopathy of prematurity (EP): (i) prematurity, (ii) in utero ischemia (IUI) or perinatal ischemia, and (iii) mechanical ventilation. We hypothesized that IUI would induce an angiogenic response marked by activation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), the latter degrading vascular basement membrane and increasing vulnerability to raised intravenous pressure during positive pressure mechanical ventilation. METHODS: We studied a rat model of hemorrhagic-EP characterized by periventricular hemorrhages in which a 20-min episode of IUI is induced at E19, pups are born naturally at E21-22, and on P0, are subjected to a 20-min episode of positive pressure mechanical ventilation. Tissues were studied by H&E staining, immunolabeling, immunoblot, and zymography. RESULTS: Mechanical ventilation of rat pups 2-3 d after 20-min IUI caused widespread hemorrhages in periventricular tissues. IUI resulted in upregulation of VEGF and MMP-9. Zymography confirmed significantly elevated gelatinase activity. MMP-9 activation was accompanied by severe loss of MMP-9 substrates, collagen IV and laminin, in microvessels in periventricular areas. CONCLUSION: Our findings are consistent with the hypothesis that positive pressure mechanical ventilation of the newborn in the context of recent prenatal ischemia/hypoxia can predispose to periventricular hemorrhages.

Complications Associated with Decompressive Craniectomy: A Systematic Review.

Decompressive craniectomy (DC) has been used for many years in the management of patients with elevated intracranial pressure and cerebral edema. Ongoing clinical trials are investigating the clinical and cost effectiveness of DC in trauma and stroke. While DC has demonstrable efficacy in saving life, it is accompanied by a myriad of non-trivial complications that have been inadequately highlighted in prospective clinical trials. Missing from our current understanding is a comprehensive analysis of all potential complications associated with DC. Here, we review the available literature, we tabulate all reported complications, and we calculate their frequency for specific indications. Of over 1500 records initially identified, a final total of 142 eligible records were included in our comprehensive analysis. We identified numerous complications related to DC that have not been systematically reviewed. Complications were of three major types: (1) Hemorrhagic (2) Infectious/Inflammatory, and (3) Disturbances of the CSF compartment. Complications associated with cranioplasty fell under similar major types, with additional complications relating to the bone flap. Overall, one of every ten patients undergoing DC may suffer a complication necessitating additional medical and/or neurosurgical intervention. While DC has received increased attention as a potential therapeutic option in a variety of situations, like any surgical procedure, DC is not without risk. Neurologists and neurosurgeons must be aware of all the potential complications of DC in order to properly advise their patients.

Increased small conductance calcium-activated potassium type 2 channel-mediated negative feedback on N-methyl-D-aspartate receptors impairs synaptic plasticity following context-dependent sensitization to morphine.

BACKGROUND: Hippocampal long-term potentiation (LTP) is impaired following repeated morphine administration paired with a novel context. This procedure produces locomotor sensitization that can be abolished by blocking calcium (Ca(2+))-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in the hippocampus. However, the mechanisms underlying LTP impairment remain unclear. Here, we investigate the role of N-methyl-D-aspartate receptors (NMDARs), AMPARs, and small conductance Ca(2+)-activated potassium type 2 (SK2) channels in LTP induction after context-dependent sensitization to morphine. METHODS: Mice were treated with saline or escalating doses of morphine (5, 8, 10, and 15 mg/kg) every 12 hours in a locomotor activity chamber and a challenge dose of 5 mg/kg morphine was given 1 week later. After the challenge, the hippocampi were removed to assay phosphatase 2A (PP2A) activity, NMDAR, and SK2 channel synaptic expression or to perform electrophysiological recordings. RESULTS: Impaired hippocampal LTP, which accompanied morphine-induced context-dependent sensitization, could not be restored by blocking Ca(2+)-permeable AMPARs. Context-dependent sensitization to morphine altered hippocampal NMDAR subunit composition and enhanced the SK2 channel-mediated negative feedback on NMDAR. Increased PP2A activity observed following context-dependent sensitization suggests that the potentiated SK2 channel effect on NMDAR was mediated by increased SK2 sensitivity to Ca(2+). Finally, inhibition of SK2 channel or PP2A activity restored LTP. CONCLUSIONS: Our studies demonstrate that the SK2 channel-NMDAR feedback loop plays a role in opiate-induced impairment of hippocampal plasticity and that the positive modulation of SK2 channels occurs via increases in PP2A activity. This provides further evidence that small conductance Ca(2+)-activated potassium channels play a role in drug-induced plasticity.