Aquaporin-4 gene variant independently associated with oedema after intracerebral haemorrhage.

INTRODUCTION: Aquaporin-4 (AQP4) is the prominent water-channel protein in the brain playing a critical role in controlling cell water content. After intracerebral haemorrhage (ICH), perihematomal oedema (PHE) formation leads to a rapid increase in intracranial pressure (ICP) after the initial bleed. We sought to investigate the effect of a common genomic variant in the AQP4 gene on PHE formation after ICH. METHODS: We reviewed the literature and identified a candidate polymorphism in AQP4 genes previously reported in Genome Wide Association Studies (GWAS). Between February 2009 and March 2011, 128 patients consented to genetic testing and were genotyped for single nucleotide polymorphism (SNP) on the AQP4 gene. Genomic DNA was extracted from buccal swabs using MasterAmp extraction kits (Epicentre, Madison, WI, USA). DNA extracted from buffy coats of whole blood samples was amplified via PCR. Linear regression with log-transformed ICH + PHE volume as the response variable was used to determine the association of SNP controlled for admission variables age, GCS, infratentorial location, hypertension, systolic blood pressure (SBP), blood urea nitrogen (BUN), glucose and alkaline phosphatase. RESULTS: Nine of 128 patients had the minor allele for SNP rs1058427. Presence of the minor allele was significant in the model (P = 0.021), and associated with an increase of 88% in ICH + PHE volume (ß = 0.632, exp(ß) = 1.88) after controlling for admission variables. The only other significant variables included in the model was GCS (P < 0.001). CONCLUSION: The establishment of an independent association between rs1054827 and ICH + PHE volume provides evidence implicating the AQP4 gene in haematoma and oedema formation after ICH. Further investigation is needed to characterise this link.

Inflammation, negative nitrogen balance, and outcome after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To analyze the impact of inflammation and negative nitrogen balance (NBAL) on nutritional status and outcomes after subarachnoid hemorrhage (SAH). METHODS: This was a prospective observational study of SAH patients admitted between May 2008 and June 2012. Measurements of C-reactive protein (CRP), transthyretin (TTR), resting energy expenditure (REE), and NBAL (g/day) were performed over 4 preset time periods during the first 14 postbleed days (PBD) in addition to daily caloric intake. Factors associated with REE and NBAL were analyzed with multivariable linear regression. Hospital-acquired infections (HAI) were tracked daily for time-to-event analyses. Poor outcome at 3 months was defined as a modified Rankin Scale score ≥ 4 and assessed by multivariable logistic regression. RESULTS: There were 229 patients with an average age of 55 ± 15 years. Higher REE was associated with younger age (p = 0.02), male sex (p < 0.001), higher Hunt Hess grade (p = 0.001), and higher modified Fisher score (p = 0.01). Negative NBAL was associated with lower caloric intake (p < 0.001), higher body mass index (p < 0.001), aneurysm clipping (p = 0.03), and higher CRP:TTR ratio (p = 0.03). HAIs developed in 53 (23%) patients on mean PBD 8 ± 3. Older age (p = 0.002), higher Hunt Hess (p < 0.001), lower caloric intake (p = 0.001), and negative NBAL (p = 0.04) predicted time to first HAI. Poor outcome at 3 months was associated with higher Hunt Hess grade (p < 0.001), older age (p < 0.001), negative NBAL (p = 0.01), HAI (p = 0.03), higher CRP:TTR ratio (p = 0.04), higher body mass index (p = 0.03), and delayed cerebral ischemia (p = 0.04). CONCLUSIONS: Negative NBAL after SAH is influenced by inflammation and associated with an increased risk of HAI and poor outcome. Underfeeding and systemic inflammation are potential modifiable risk factors for negative NBAL and poor outcome after SAH.

von Willebrand factor genetic variant associated with hematoma expansion after intracerebral hemorrhage.

BACKGROUND: Hematoma expansion, the leading cause of neurologic deterioration after intracerebral hemorrhage (ICH), remains one of the few modifiable risk factors for poor outcome. In the present study, we explored whether common genetic variants within the hemostasis pathway were related to hematoma expansion during the acute period after ICH. METHODS: Patients with spontaneous ICH who were admitted to the institutional Neuro-ICU between 2009 and 2011 were enrolled in the study, and clinical data were collected prospectively. Hematoma size was measured in patients admitted on or before postbleed day 2. Baseline models for hematoma growth were constructed using backwards stepwise logistic regression. Genotyping of single-nucleotide polymorphisms for 13 genes involved in hemostasis was performed, and the results were individually included in the above baseline models to test for independent association of hematoma expansion. RESULTS: During the study period, 82 patients were enrolled in the study and had complete data. The mean age was 65.9 ± 14.9 years, and 38% were female. Only von Willebrand factor was associated with absolute and relative hematoma growth in univariate analysis (P < .001 and P = .007, respectively); von Willebrand factor genotype was independently predictive of relative hematoma growth but only approached significance for absolute hematoma growth (P = .002 and P = .097, respectively). CONCLUSIONS: Our genomic analysis of various hemostatic factors identified von Willebrand factor as a potential predictor of hematoma expansion in patients with ICH. The identification of von Willebrand factor single-nucleotide polymorphisms may allow us to better identify patients who are at risk for hematoma enlargement and will benefit the most from treatment. The relationship of von Willebrand factor with regard to hematoma enlargement in a larger population warrants further study.

Functional outcome prediction following intracerebral hemorrhage.

The ICH score is a validated method of assessing the risk of mortality and morbidity after intracerebral hemorrhage (ICH). We sought to compare the ability of the ICH score to predict outcome assessed with three of the most widely used scales: the Barthel Index (BI), modified Rankin Scale (mRS), and Glasgow Outcome Score (GOS). All patients with ICH treated at our institution between February 2009 and March 2011 were followed-up at three months using the mRS, GOS, and BI. The ICH score was highly correlated with the three-month mRS (ρ=0.59, p<0.001), BI (ρ=-0.57, p<0.001) and GOS (ρ=0.61, p<0.001). The ICH score also predicted dependency for each measure well, with areas under the curve falling between 0.826 and 0.833. Our results suggest that future clinical studies that use the ICH score to stratify patients may employ any of the three outcome scales and expect good discrimination of disability.

Variation in a locus linked to platelet aggregation phenotype predicts intraparenchymal hemorrhagic volume.

OBJECTIVE: Alteration in platelet aggregation has been shown to promote bleeding and affect outcome after intracerebral hemorrhage (ICH).We investigated the influence of genetic variants of platelet aggregation, and their effects on admission ICH volume and clinical outcome. METHODS: Our prospective study analyzed selected candidate single-nucleotide polymorphisms (SNPs) previously associated with platelet aggregation phenotype in previous genome-wide association studies, with regards to outcome and ICH volume. Patients were assessed at the Columbia University Medical Center Neuro-Intensive Care Unit. Exclusion criteria included age <18 years, ICH following trauma, hemorrhagic transformation, or tumor, no consent for genetic analysis, or incomplete data. Radiological variables (location and volume of acute ICH, presence of intraventricular extension, midline shift, and hydrocephalus) and clinical variables (mortality and modified Rankin score at discharge) were prospectively recorded. RESULTS: One hundred and twenty-two patients with spontaneous ICH between February 2009 and May 2011 diagnosed via clinical assessment and admission computed tomography scan were included. The median admission Glasgow coma scale score (GCS) was 11·5. Univariate predictors of mortality at discharge included systolic blood pressure, presence of intraventricular hemorrhage, anticoagulant use, and GCS, the only independent predictor of discharge mortality (P<0·001). Age, intraventricular hemorrhage, and GCS were associated with poor functional outcome; age (P = 0·001) and GCS (P<0·001) were significant in the multivariate model. Admission GCS (P<0·01), antiplatelet use, and rs342286 (PIK3CG; P = 0·04; R(2) = 0·247) had univariate associations with hematoma volume. DISCUSSION: We identified SNP rs342286 as an independent predictor of admission hematoma volume. Our findings suggest that PIK3CG function, which is previously linked to this SNP and affects platelet aggregation, impacts the severity of the intraparenchymal bleed.

Osteochondroses: a clinical review for the pediatrician.

The purpose of this article is to provide the pediatrician with a thorough review of the variety of osteochondroses that affect children and adolescents. These conditions present in all different parts of the body in a wide range of patients: from the sedentary to athletic, the toddler to the pre-teen.The osteochondroses often are self-limiting and resolve with nonoperative management, but there are a few circumstances when operative treatment may be required. Recent literature confirms the heterogeneity of these conditions with respect to the clinical presentations and musculoskeletal manifestations.We think this article will heighten awareness of these disorders in the pediatric community, so that prompt intervention may be rendered.