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• 1. Another small step toward neural repair
• 2. Even short period of controlled mechanical ventilation results in atrophy of the diaphragm
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1. Another small step toward neural repair 

Neural transplantation with the hope of treating diverse conditions such as Parkinson's disease or stroke has been tried in animal models and occasionally in patients for decades. However, these attempts have not been successful—despite occasional reports of clinical improvement, overall neural repair in the central nervous system has remained experimental. We should not be surprised—nobody would expect an arm to regrow after injection of some mesenchymal stem cells into the stump, so why should we expect miraculous successes with injection of cells into the brain? Spurred by the initial failures, the leading research teams are focusing on a better understanding of the complex processes of neural stem cell differentiation and the interaction between the cells, other cells and their environment. A recent article by Teng et al [3] examined the interaction between neural progenitor cells and endothelial cells. Neural progenitor cells from the subventricular zone of the adult rat were cocultured with cerebral endothelial cells isolated from the stroke boundary. The neural progenitors demonstrated increased proliferation and shifted from astrocytic to neuronal differentiation. In another experiment, medium was collected from neural progenitor cell–promoted capillary tube formation of normal endothelial cells. Both effects were suppressed by blockage of vascular endothelial growth factor receptor 2.

This is a nice demonstration of the interaction between developing neural and vascular progenitors and another step toward the understanding of the conditions for real neural repair. However, even a perfect understanding of the control of neural differentiation and excellent coordination with revascularization may not be enough. It is not clear how any new neurons will integrate into the brain and work with the existing mechanisms for brain plasticity especially in the injured or ischemic brain. It is possible that ischemia changes the efficacy of synaptic transmission via the induction of a postischemic long-term potentiation (i-LTP) [1], which may deeply influence the plastic reorganization of cortical representational maps occurring after cerebral ischemia, inducing a functional connection of previously noninteracting neurons. The same i-LTP may exert a detrimental effect in the periinfarct area, facilitating excitotoxic processes via the sustained, long-term enhancement of glutamate-mediated neurotransmission [1]. The road to clinical neural repair is long, but the study by Teng et al [3] demonstrates a fruitful approach that may lead to real progress.

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2. Even short period of controlled mechanical ventilation results in atrophy of the diaphragm 

Many critically ill patients require ventilator support, which may last for days, and sometimes much longer. Disuse atrophy is well known in all muscles, and a new study by Levine et al [2] looked at the degree of diaphragm atrophy in humans after mechanical ventilation. The authors collected diaphragm biopsy specimens taken from brain-dead subjects who were ventilated for 18 to 69 hours. Controls were specimens taken from patients who had surgery for benign or malignant lesions near the diaphragm; those operations lasted for 2 to 3 hours. The researchers performed histologic, biochemical, and gene expression studies. Compared with controls, the study specimens demonstrated a more than 50% decrease in the cross-sectional area of the muscle fibers. Increased activation of the proteolytic pathway was seen.

The degree and rapid onset of atrophy are surprising and a cause for concern. The subjects were brain-dead, and the ventilation was entirely mechanical. It is possible that modes that require some work by the diaphragm, such as assist-control, or synchronized intermittent mandatory ventilation with pressure support, will not result in the same severe atrophy. However, this has to be tested. The study demonstrates the need to wean ventilation rapidly and reminds us of the risks of sedation and paralysis of intensive care patients.

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References 

1. Di Filippo M, Tozzi A, Costa C, Belcastro V, Tantucci M, Picconi B, et al. Plasticity and repair in the post-ischemic brain. Neuropharmacology. 2008;[Electronic publication ahead of print]
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2. Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327–1335
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3. Teng H, Zhang ZG, Wang L, Zhang RL, Zhang L, Morris D, et al. Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke. J Cereb Blood Flow Metab. 2008;28(4):764–771
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