Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.

The evolution of white matter microstructural changes after mild traumatic brain injury: A longitudinal DTI and NODDI study.

Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.

Developmental stability of the tonotopic organization of the chick's basilar papilla.

In the past, the damage patterns produced on the papilla of the chick by loud pure tones of different frequencies have been used to study the development of sound analysis by the hair cells of the basilar papilla. One conclusion from these data was that the best response frequency of individual hair cells changes substantially with age. However, this method has been criticized as unreliable. Now experiments have been performed in which single characterized nerve fibers were stained with horseradish peroxidase to permit the unequivocal localization of specific frequency responses in the papillae of chicks of different ages (2 and 21 days after hatching). There was no statistically significant change in the tonotopic organization of the papilla between the two groups of animals.

Utility of Repeat Head CT in Patients with Blunt Traumatic Brain Injury Presenting with Small Isolated Falcine or Tentorial Subdural Hematomas.

BACKGROUND AND PURPOSE: In blunt traumatic brain injury with isolated falcotentorial subdural hematoma not amenable to neurosurgical intervention, the routinely performed, nonvalidated practice of serial head CT scans frequently necessitates increased hospital resources and exposure to ionizing radiation. The study goal was to evaluate clinical and imaging features of isolated falcotentorial subdural hematoma at presentation and short-term follow-up. MATERIALS AND METHODS: We performed a retrospective analysis of patients presenting to a level 1 trauma center from January 2013 to March 2015 undergoing initial and short-term follow-up CT with initial findings positive for isolated subdural hematoma along the falx and/or tentorium. Patients with penetrating trauma, other sites of intracranial hemorrhage, or depressed skull fractures were excluded. Patient sex, age, Glasgow Coma Scale score, and anticoagulation history were obtained through review of the electronic medical records. RESULTS: Eighty patients met the inclusion criteria (53 males; 27 females; median age, 61 years). Of subdural hematomas, 57.1% were falcine, 33.8% were tentorial, and 9.1% were mixed. The mean initial Glasgow Coma Scale score was 14.2 (range, 6-15). Isolated falcotentorial subdural hematomas were small (mean, 2.8 mm; range, 1-8 mm) without mass effect and significant change on follow-up CT (mean, 2.7 mm; range, 0-8 mm; P = .06), with an average follow-up time of 10.3 hours (range, 3.9-192 hours). All repeat CTs demonstrated no change or decreased size of the initial subdural hematoma. No new intracranial hemorrhages were seen on follow-up CT. CONCLUSIONS: Isolated falcotentorial subdural hematomas in blunt traumatic brain injury average 2.8 mm in thickness and do not increase in size on short-term follow-up CT. Present data suggest that repeat CT in patients with mild traumatic brain injury with isolated falcotentorial subdural hematoma may not be necessary.

Multivariate Analysis of MRI Biomarkers for Predicting Neurologic Impairment in Cervical Spinal Cord Injury.

BACKGROUND AND PURPOSE: Acute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment. MATERIALS AND METHODS: We performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment. RESULTS: Nonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression. CONCLUSIONS: This study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging.

Phylogenetic development of the cochlea and its innervation.

Comparative studies of vertebrate hearing organs have enabled an integrated approach to difficult questions related to function. Recent evidence for the independent evolution of similar hearing-organ specializations, in particular hair-cell differentiation, has helped identify common problems of hearing receptors and put them in a new perspective. Evidence that cochlear amplification is an ancient phenomenon has widened the search for the motor mechanism involved. In this regard, different hypotheses are best examined by making optimal use of natural structural variations. Studies on the evolution of the efferent system have provided new routes to investigate its function.

Auditory processing in birds.

Over the past year, much progress has been achieved in the study of both the peripheral and the central auditory systems of birds. Significant advances have been made in the study of hair cells, including elucidation of the mechanisms of selectivity for sound frequency, functional differentiation, efferent innervation, and regeneration. Most of the studies of central auditory neurones have concerned the developmental and physiological correlates of vocal learning in songbirds and sound localisation in owls.

Increased seizure duration in mice lacking aquaporin-4 water channels.

Aquaporins are intrinsic membrane proteins involved in water transport in fluid-transporting tissues. In the brain, aquaporin-4 (AQP4) is expressed widely by glial cells, but its function is unclear. Extensive basic and clinical studies indicate that osmolarity affects seizure susceptibility, and in our previous studies we found that AQP4 -/- mice have an elevated seizure threshold in response to the chemoconvulsant pentylenetetrazol. In this study, we examined the seizure phenotype of AQP4 -/- mice in greater detail using in vivo electroencephalographic recording. AQP4 -/- mice were found to have dramatically longer stimulation-evoked seizures following hippocampal stimulation as well as a higher seizure threshold. These results implicate AQP4 in water and potassium regulation associated with neuronal activity and seizures.

The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes and remains without a treatment of proven benefit. Despite several existing outcome prediction models for ICH, there is no standard clinical grading scale for ICH analogous to those for traumatic brain injury, subarachnoid hemorrhage, or ischemic stroke. METHODS: Records of all patients with acute ICH presenting to the University of California, San Francisco during 1997-1998 were reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the ICH Score) was developed with weighting of independent predictors based on strength of association. RESULTS: Factors independently associated with 30-day mortality were Glasgow Coma Scale score (P<0.001), age >/=80 years (P=0.001), infratentorial origin of ICH (P=0.03), ICH volume (P=0.047), and presence of intraventricular hemorrhage (P=0.052). The ICH Score was the sum of individual points assigned as follows: GCS score 3 to 4 (=2 points), 5 to 12 (=1), 13 to 15 (=0); age >/=80 years yes (=1), no (=0); infratentorial origin yes (=1), no (=0); ICH volume >/=30 cm(3) (=1), <30 cm(3) (=0); and intraventricular hemorrhage yes (=1), no (=0). All 26 patients with an ICH Score of 0 survived, and all 6 patients with an ICH Score of 5 died. Thirty-day mortality increased steadily with ICH Score (P<0.005). CONCLUSIONS: The ICH Score is a simple clinical grading scale that allows risk stratification on presentation with ICH. The use of a scale such as the ICH Score could improve standardization of clinical treatment protocols and clinical research studies in ICH.

Specific inhibition of binding of antistasin and [A103,106,108] antistasin 93-119 to sulfatide (Gal(3-SO4)beta 1-1Cer) by glycosaminoglycans.

Leech-derived antistasin is a potent anticoagulant and antimetastatic protein that binds sulfatide (Gal(3-SO4)beta 1-1Cer) and sulfated polysaccharides. In this study, the synthetic fragment [A103,106,108] antistasin 93-119, which corresponds to the carboxyl terminus, showed specific and saturable binding to sulfatide. Binding was competitively blocked by glycosaminoglycans (GAGs) in the order: dextran sulfate 5000 congruent to dextran sulfate 500,000 greater than heparin greater than dermatan sulfate much greater than chondroitin sulfates A and C. This rank order of inhibitory potency was identical to that observed with whole antistasin. We suggest that residues 93-119 of antistasin represent a critical domain for binding GAGs and sulfated glycolipids.