Saccular intracranial aneurysms (IAs) are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with IA in the combined data set, including intervals near RBBP8 on 18q11.2 (OR=1.22, P=1.1×10-12), STARD13/KL on 13q13.1 (OR=1.20, P=2.5×10-9) and a gene-rich region on 10q24.32 (OR=1.29, P=1.2×10-9). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR=1.28, P=1.3×10-12) and CDKN2A/B (9p21.3; OR=1.31, P=1.5×10-22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting proliferation and senescence of progenitor cell populations that are responsible for vascular formation and repair.

Cerebral water accumulation was studied during induction of brain edema in dystrophin-null transgenic mice (mdx-␤geo) and control mice. Immunofluorescence and immunoelectron microscopic analyses of dystrophin-null brains revealed a dramatic reduction of AQP4 (aquaporin-4) in astroglial end-feet surrounding capillaries (blood-brain barrier) and at the glia limitans (cerebrospinal fluidbrain interface). The AQP4 protein is mislocalized, because immunoblotting showed that the total AQP4 protein abundance was unaltered. Brain edema was induced by i.p. injection of distilled water and 8-deamino-arginine vasopressin. Changes in cerebral water compartments were assessed by diffusion-weighted MRI with determination of the apparent diffusion coefficient (ADC). In dystrophin-null mice and control mice, ADC gradually decreased by 5-6% from baseline levels during the first 35 min, indicating the initial phase of intracellular water accumulation is similar in the two groups. At this point, the control mice sustained an abrupt, rapid decline in ADC to 58% ؎ 2.2% of the baseline at 52.5 min, and all of the animals were dead by 56 min. After a consistent delay, the dystrophin-null mice sustained a similar decline in ADC to 55% ؎ 3.4% at 66.5 min, when all of the mice were dead. These results demonstrate that dystrophin is necessary for polarized distribution of AQP4 protein in brain where facilitated movements of water occur across the blood-brain barrier and cerebrospinal fluid-brain interface. Moreover, these results predict that interference with the subcellular localization of AQP4 may have therapeutic potential for delaying the onset of impending brain edema. Brain edema is associated with many intracranial neuropathological states, such as head trauma, ischemic brain injury, neoplasms, and metabolic diseases including systemic hyponatremia. Although much investigation has addressed the underlying molecular mechanisms and pathophysiology of brain edema, little is known about the regulation of water transport across the blood-brain barrier, the cerebrospinal fluid (CSF)-brain interface, and between extracellular and intracellular compartments in brain parenchyma.It is well recognized that the aquaporin family of water channel proteins is the major pathway by which water rapidly crosses cell membranes (1). Manley et al. recently reported that AQP4 (aquaporin-4; ref. 18) negatively influences the outcome from brain edema (2), and other recent studies also have suggested that AQP4 contributes to the development of brain edema (3, 4). These observations are consistent with the distribution of AQP4 in brain, because the protein is expressed abundantly in a highly polarized distribution in ependymal cells and astroglial membranes facing capillaries and forming the glia limitans (5).Decreased expression of AQP4 protein without changes in the AQP4 mRNA levels was reported recently in brains of Dmd mdx mice (C57BL10 ScSn mdx), a strain carrying a spontaneous mutation that prevents expression of the longest isoform of dystrophin (6)....

We conclude that only S-100B in severe traumatic brain injury has consistently demonstrated the ability to predict injury and outcome in adults. The number of studies with protein degradation products is insufficient especially in the pediatric care. Cohort studies with well-defined end points and further neuroproteomic search for biomarkers in mild injury should be triggered. After critically reviewing the study designs, we found that large homogenous patient populations, consistent injury, and outcome measures prospectively determined cutoff values, and a combined use of different predictors should be considered in future studies.

Outcome prediction following severe traumatic brain injury (sTBI) is a widely investigated field of research. A major breakthrough is represented by the IMPACT prognostic calculator based on admission data of more than 8500 patients. A growing body of scientific evidence has shown that clinically meaningful biomarkers, including glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and aII-spectrin breakdown product (SBDP145), could also contribute to outcome prediction. The present study was initiated to assess whether the addition of biomarkers to the IMPACT prognostic calculator could improve its predictive power. Forty-five sTBI patients (GCS score £ 8) from four different sites were investigated. We utilized the core model of the IMPACT calculator (age, GCS motor score, and reaction of pupils), and measured the level of GFAP, UCH-L1, and SBDP145 in serum and cerebrospinal fluid (CSF). The forecast and actual 6-month outcomes were compared by logistic regression analysis. The results of the core model itself, as well as serum values of GFAP and CSF levels of SBDP145, showed a significant correlation with the 6-month mortality using a univariate analysis. In the core model, the Nagelkerke R 2 value was 0.214. With multivariate analysis we were able to increase this predictive power with one additional biomarker (GFAP in CSF) to R 2 = 0.476, while the application of three biomarker levels (GFAP in CSF, GFAP in serum, and SBDP145 in CSF) increased the Nagelkerke R 2 to 0.700. Our preliminary results underline the importance of biomarkers in outcome prediction, and encourage further investigation to expand the predictive power of contemporary outcome calculators and prognostic models in TBI.