The glymphatic pathway expedites clearance of waste, including soluble amyloid ␤ (A␤) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of A␤, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and A␤ clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans.

No abstract

Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose–treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied by attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt, epidermal growth factor receptor (EGFR), and Sirt1 activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted epithelial wound healing, recovery of corneal sensation, improvement of mitochondrial function, and reactivation of Akt, EGFR, and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose–treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a neurokinin-1 (NK-1) receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 receptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.

Aim-To study the use of penetrating keratoplasty (PKP) for the treatment of severe fungal keratitis that could not be cured by antifungal medication. Methods-A retrospective analysis of 108 cases of severe fungal keratitis in which PKP was performed served as the basis for this study. Fungal keratitis was diagnosed by KOH staining of corneal scrapings or by confocal microscopic imaging of the cornea. All patients received a combination of topical and oral antifungal medicines without steroids as the first course of therapy. Patients whose corneal infection was not cured or in whom the infection progressed during antifungal treatment were given a PKP. After surgery, the patients continued to receive antifungal therapy with gradual tapering of the dose over a 1-2 month period. Cyclosporine was used to prevent graft rejection beginning 2 weeks after PKP. Topical steroid only was administered to the patient whose donor graft was over 8.5 mm and with a heavy iris inflammation 2 weeks after PKP. The surgical specimens were used for microbiological evaluation and examined histopathologically. The patients were followed for 6-24 months after PKP. Graft rejection, clarity of the graft, visual acuity, and surgical complications were recorded. Results-Corneal grafts in 86 eyes (79.6%) remained clear during follow up. There was no recurrence of fungal infection and the visual acuity ranged from 40/200 to 20/20. Complications in some patients included recurrent fungal infection in eight eyes (7.4%), corneal graft rejection in 32 eyes (29.6%), secondary glaucoma in two eyes (1.9%), and five eyes (4.6%) developed cataracts. 98 of 108 of the recipient corneas had PAS positive fungal hyphae in tissue sections; 97 of 108 were culture positive for various fungi, including Fusarium (63), Aspergillus (14), Candida (9), Penicillium (4), and seven cases in which septate hyphae were seen but identification of the organism was not conclusive. Conclusions-PKP is an eVective treatment for fungal keratitis that does not respond to antifungal medication. Early surgical intervention before the disease becomes advanced is recommended. It is critical that the surgical procedure remove the infected tissue in its entirety in order to eVect a cure.