Person:

Du, Rose

Background: With the recent development of microarray technologies, the comparability of gene expression data obtained from different platforms poses an important problem. We evaluated two widely used platforms, Affymetrix U133 Plus 2.0 and the Illumina HumanRef-8 v2 Expression Bead Chips, for comparability in a biological system in which changes may be subtle, namely fetal lung tissue as a function of gestational age. Results: We performed the comparison via sequence-based probe matching between the two platforms. "Significance grouping" was defined as a measure of comparability. Using both expression correlation and significance grouping as measures of comparability, we demonstrated that despite overall cross-platform differences at the single gene level, increased correlation between the two platforms was found in genes with higher expression level, higher probe overlap, and lower p-value. We also demonstrated that biological function as determined via KEGG pathways or GO categories is more consistent across platforms than single gene analysis. Conclusion: We conclude that while the comparability of the platforms at the single gene level may be increased by increasing sample size, they are highly comparable ontologically even for subtle differences in a relatively small sample size. Biologically relevant inference should therefore be reproducible across laboratories using different platforms.

Background and Purpose: Pilot study to examine the use of T1-, T2-, and T2*-weighted images for evaluating hematoma size and extent of edema in mouse brain at high field. Methods: Following collagenase-induced intracerebral hemorrhage, nine mice were imaged at 4.7 T using T1-, T2-, and T2*-weighted images for hematoma and edema quantitation on days 1, 3, 10, and 21 after surgery. Values were compared with morphometric analysis of cryosections at the time of final MR imaging. Results: For hematoma quantitation, the Spearman correlation coefficient (r) between T1 signal change and histology was 0.70 (P < 0.04) compared with r = 0.61 (P < 0.09) for T2*. The extent of perihematomal edema formation on cryosections was well reflected on T2 with r = 0.73 (P < 0.03). Conclusions: Within the limits of our pilot study, MR imaging on 4.7 T appears to approximate the temporal changes in hematoma and edema sizes in murine ICH well, thus laying the groundwork for longitudinal studies on hematoma resorption and edema formation.

Brain temperature, as an independent therapeutic target variable, has received increasingly intense clinical attention. To date, brain hypothermia represents the most potent neuroprotectant in laboratory studies. Although the impact of brain temperature is prevalent in a number of common human diseases including: head trauma, stroke, multiple sclerosis, epilepsy, mood disorders, headaches, and neurodegenerative disorders, it is evident and well recognized that the therapeutic application of induced hypothermia is limited to a few highly selected clinical conditions such as cardiac arrest and hypoxic ischemic neonatal encephalopathy. Efforts to understand the fundamental aspects of brain temperature regulation are therefore critical for the development of safe, effective, and pragmatic clinical treatments for patients with brain injuries. Although centrally-mediated mechanisms to maintain a stable body temperature are relatively well established, very little is clinically known about brain temperature's spatial and temporal distribution, its physiological and pathological fluctuations, and the mechanism underlying brain thermal homeostasis. The human brain, a metabolically “expensive” organ with intense heat production, is sensitive to fluctuations in temperature with regards to its functional activity and energy efficiency. In this review, we discuss several critical aspects concerning the fundamental properties of brain temperature from a clinical perspective.

Since the initial publication of the International Study of Unruptured Intracranial Aneurysms (ISUIA), management of unruptured intracranial aneurysms has been mainly based on the size of the aneurysm. The contribution of morphological characteristics to treatment decisions of unruptured aneurysms has not been well studied in a systematic and location specific manner. We present a large sample of basilar artery tip aneurysms (BTA) that were assessed using a diverse array of morphological variables to determine the parameters associated with ruptured aneurysms. Demographic and clinical risk factors of aneurysm rupture were obtained from chart review. CT angiograms (CTA) were evaluated with Slicer, an open source visualization and image analysis software, to generate 3-D models of the aneurysms and surrounding vascular architecture. Morphological parameters examined in each model included aneurysm volume, aspect ratio, size ratio, aneurysm angle, basilar vessel angle, basilar flow angle, and vessel to vessel angles. Univariate and multivariate analyses were performed to determine statistical significance. From 2008–2013, 54 patients with BTA aneurysms were evaluated in a single institution, and CTAs from 33 patients (15 ruptured, 18 unruptured) were available and analyzed. Aneurysms that underwent reoperation, that were associated with arteriovenous malformations, or that lacked preoperative CTA were excluded. Multivariate logistic regression revealed that a larger angle between the posterior cerebral arteries (P1-P1 angle, p = 0.037) was most strongly associated with aneurysm rupture after adjusting for other morphological variables. In this location specific study of BTA aneurysms, the larger the angle formed between posterior cerebral arteries was found to be a new morphological parameter significantly associated with ruptured BTA aneurysms. This is a physically intuitive parameter that can be measured easily and readily applied in the clinical setting.

Prior research has suggested that regional weather patterns impact the risk of rupture of cerebral aneurysms, but the findings in the literature have been inconsistent. Furthermore, no nationwide analysis to date has examined the association between meteorological factors and the post-procedural outcomes of patients after the treatment for ruptured cerebral aneurysms. The purpose of this study was to use a nationwide sample to analyze the association between specific meteorological parameters—temperature, precipitation, sunlight, and humidity—and hospital admission rate for and outcome after aneurysmal subarachnoid hemorrhage. Patients were identified using the Nationwide Inpatient Sample (2001–2010): Those with an ICD-9 diagnosis code for subarachnoid hemorrhage and a procedural code for aneurysm repair were included. Climate data were obtained from the State of the Climate Report 2010 released by the National Climatic Data Center. Multivariate regression models were constructed to analyze the association between average state monthly temperature, precipitation, and percent possible sunlight, as well as relative morning humidity and both monthly hospital admission rate, adjusted for annual state population in millions, and in-hospital mortality. 16,970 admissions were included from 723 hospitals across 41 states. Decreased daily sunlight and lower relative humidity were associated with an increased rate of admission for ruptured cerebral aneurysms (p<0.001), but had no association with differential inpatient mortality. No significant changes in these observed associations were seen when multivariate analyses were constructed. This is the first nationwide study to suggest that decreased sunlight and lower relative humidity are associated with admission for ruptured cerebral aneurysms. While it has been postulated that external atmospheric factors may cause hormonal and homeostatic changes that impact the risk of rupture of cerebral aneurysms, additional research is needed to confirm and further understand these relationships.

Investigation into the association of insurance status with the outcomes of patients undergoing neurosurgical intervention has been limited: this is the first nationwide study to analyze the impact of primary payer on the outcomes of patients with aneurysmal subarachnoid hemorrhage who underwent endovascular coiling or microsurgical clipping. The Nationwide Inpatient Sample (2001–2010) was utilized to identify patients; those with both an ICD-9 diagnosis codes for subarachnoid hemorrhage and a procedure code for aneurysm repair (either via an endovascular or surgical approach) were included. Hierarchical multivariate regression analyses were utilized to evaluate the impact of primary payer on in-hospital mortality, hospital discharge disposition, and length of hospital stay with hospital as the random effects variable. Models were adjusted for patient age, sex, race, comorbidities, socioeconomic status, hospital region, location (urban versus rural), and teaching status, procedural volume, year of admission, and the proportion of patients who underwent ventriculostomy. Subsequent models were also adjusted for time to aneurysm repair and time to ventriculostomy; subgroup analyses evaluated for those who underwent endovascular and surgical procedures separately. 15,557 hospitalizations were included. In the initial model, the adjusted odds of in-hospital mortality were higher for Medicare (OR 1.23, p<0.001), Medicaid (OR 1.23, p<0.001), and uninsured patients (OR 1.49, p<0.001) compared to those with private insurance. After also adjusting for timing of intervention, Medicaid and uninsured patients had a reduced odds of non-routine discharge (OR 0.75, p<0.001 and OR 0.42, p<0.001) despite longer hospital stays (by 8.35 days, p<0.001 and 2.45 days, p = 0.005). Variations in outcomes by primary payer–including in-hospital post-procedural mortality–were more pronounced for patients of all insurance types who underwent microsurgical clipping. The observed differences by primary payer are likely multifactorial, attributable to varied socioeconomic factors and the complexities of the American healthcare delivery system.

In contrast to size, the association of morphological characteristics of intracranial aneurysms with rupture has not been established in a systematic manner. We present an analysis of the morphological variables that are associated with rupture in anterior communicating artery aneurysms to determine site-specific risk variables. One hundred and twenty-four anterior communicating artery aneurysms were treated in a single institution from 2005 to 2010, and CT angiograms (CTAs) or rotational angiography from 79 patients (42 ruptured, 37 unruptured) were analyzed. Vascular imaging was evaluated with 3D Slicer© to generate models of the aneurysms and surrounding vasculature. Morphological parameters were examined using univariate and multivariate analysis and included aneurysm volume, aspect ratio, size ratio, distance to bifurcation, aneurysm angle, vessel angle, flow angle, and parent-daughter angle. Multivariate logistic regression revealed that size ratio, flow angle, and parent-daughter angle were associated with aneurysm rupture after adjustment for age, sex, smoking history, and other clinical risk factors. Simple morphological parameters such as size ratio, flow angle, and parent-daughter angle may thus aid in the evaluation of rupture risk of anterior communicating artery aneurysms.

The rupture risk of unruptured intracranial aneurysms is known to be dependent on the size of the aneurysm. However, the association of morphological characteristics with ruptured aneurysms has not been established in a systematic and location specific manner for the most common aneurysm locations. We evaluated posterior communicating artery (PCoA) aneurysms for morphological parameters associated with aneurysm rupture in that location. CT angiograms were evaluated to generate 3-D models of the aneurysms and surrounding vasculature. Univariate and multivariate analyses were performed to evaluate morphological parameters including aneurysm volume, aspect ratio, size ratio, distance to ICA bifurcation, aneurysm angle, vessel angles, flow angles, and vessel-to-vessel angles. From 2005–2012, 148 PCoA aneurysms were treated in a single institution. Preoperative CTAs from 63 patients (40 ruptured, 23 unruptured) were available and analyzed. Multivariate logistic regression revealed that smaller volume (p = 0.011), larger aneurysm neck diameter (0.048), and shorter ICA bifurcation to aneurysm distance (p = 0.005) were the most strongly associated with aneurysm rupture after adjusting for all other clinical and morphological variables. Multivariate subgroup analysis for patients with visualized PCoA demonstrated that larger neck diameter (p = 0.018) and shorter ICA bifurcation to aneurysm distance (p = 0.011) were significantly associated with rupture. Intracerebral hemorrhage was associated with smaller volume, larger maximum height, and smaller aneurysm angle, in addition to lateral projection, male sex, and lack of hypertension. We found that shorter ICA bifurcation to aneurysm distance is significantly associated with PCoA aneurysm rupture. This is a new physically intuitive parameter that can be measured easily and therefore be readily applied in clinical practice to aid in the evaluation of patients with PCoA aneurysms.

Background— It has recently been shown that vitamin D deficiency can increase asthma development and severity and that variations in vitamin D receptor genes are associated with asthma susceptibility. Objective— We sought to find genetic factors that might interact with vitamin D levels to affect the risk of asthma exacerbation. Methods: We conducted a genome-wide study of gene–vitamin D interaction on asthma exacerbations using population-based and family-based approaches on 403 subjects and trios from the Childhood Asthma Management Program. Twenty-three polymorphisms with significant interactions were studied in a replication analysis in 584 children from a Costa Rican cohort. Results: We identified 3 common variants in the class I MHC– restricted T cell–associated molecule gene (CRTAM) that were associated with an increased rate of asthma exacerbations based on the presence of a low circulating vitamin D level. These results were replicated in a second independent population (unadjusted combined interaction, P =.00028–. 00097; combined odds ratio, 3.28–5.38). One variant, rs2272094, is a nonsynonymous coding polymorphism of CRTAM. Functional studies on cell lines confirmed the interaction of vitamin D and rs2272094 on CRTAM expression. CRTAM is highly expressed in activated human CD8 + and natural killer T cells, both of which have been implicated in asthmatic patients. Conclusion— The findings highlight an important gene-environment interaction that elucidates the role of vitamin D and CD8 + and natural killer T cells in asthma exacerbation in a genome-wide gene-environment interaction study that has been replicated in an independent population. The results suggest the potential importance of maintaining adequate vitamin D levels in subsets of high-risk asthmatic patients.

S100 calcium binding protein B (S100B), a well-studied marker for neurologic injury, has been suggested as a candidate for predicting outcome after subarachnoid hemorrhage. We performed a pooled analysis summarizing the associations between S100B protein in serum and cerebrospinal fluid (CSF) with radiographic vasospasm, delayed ischemic neurologic deficit (DIND), delayed cerebral infarction, and Glasgow Outcome Scale (GOS) outcome. A literature search using PubMed, the Cochrane Library, and the EMBASE databases was performed to identify relevant studies published up to May 2015. The weighted Stouffer’s Z method was used to perform a pooled analysis of outcome measures with greater than three studies. A total of 13 studies were included in this review. Higher serum S100B level was found to be associated with cerebral infarction as diagnosed by CT (padj = 3.1 x 10−4) and worse GOS outcome (padj = 5.5 x 10−11). There was no association found between serum and CSF S100B with radiographic vasospasm or DIND. S100B is a potential prognostic marker for aSAH outcome.