Epidemiology and Outcomes of Vertebral Artery Injury in 16 582 Cervical Spine Surgery Patients: An AOSpine North America Multicenter Study.

STUDY DESIGN: A multicenter retrospective case series was compiled involving 21 medical institutions. Inclusion criteria included patients who underwent cervical spine surgery between 2005 and 2011 and who sustained a vertebral artery injury (VAI). OBJECTIVE: To report the frequency, risk factors, outcomes, and management goals of VAI in patients who have undergone cervical spine surgery. METHODS: Patients were evaluated on the basis of condition-specific functional status using the Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA) score, the Nurick scale, and the 36-Item Short-Form Health Survey (SF-36). RESULTS: VAIs were identified in a total of 14 of 16 582 patients screened (8.4 per 10 000). The mean age of patients with VAI was 59 years (±10) with a female predominance (78.6%). Patient diagnoses included myelopathy, radiculopathy, cervical instability, and metastatic disease. VAI was associated with substantial blood loss (770 mL), although only 3 cases required transfusion. Of the 14 cases, 7 occurred with an anterior-only approach, 3 cases with posterior-only approach, and 4 during circumferential approach. Fifty percent of cases of VAI with available preoperative imaging revealed anomalous vessel anatomy during postoperative review. Average length of hospital stay was 10 days (±8). Notably, 13 of the 14 (92.86%) cases resolved without residual deficits. Compared to preoperative baseline NDI, Nurick, mJOA, and SF-36 scores for these patients, there were no observed changes after surgery (P = .20-.94). CONCLUSIONS: Vertebral artery injuries are potentially catastrophic complications that can be sustained from anterior or posterior cervical spine approaches. The data from this study suggest that with proper steps to ensure hemostasis, patients recover function at a high rate and do not exhibit residual deficits

Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch

Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.Comment: 14 pages, 4 figure

Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis

Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure.</p

Characterisation of the Fibroblast Growth Factor Dependent Transcriptome in Early Development

BACKGROUND: FGF signaling has multiple roles in regulating processes in animal development, including the specification and patterning of the mesoderm. In addition, FGF signaling supports self renewal of human embryonic stem cells and is required for differentiation of murine embryonic stem cells into a number of lineages. METHODOLOGY/PRINCIPAL FINDINGS: Given the importance of FGF signaling in regulating development and stem cell behaviour, we aimed to identify the transcriptional targets of FGF signalling during early development in the vertebrate model Xenopus laevis. We analysed the effects on gene expression in embryos in which FGF signaling was inhibited by dominant negative FGF receptors. 67 genes positively regulated by FGF signaling and 16 genes negatively regulated by FGF signaling were identified. FGF target genes are expressed in distinct waves during the late blastula to early gastrula phase. Many of these genes are expressed in the early mesoderm and dorsal ectoderm. A widespread requirement for FGF in regulating genes expressed in the Spemann organizer is revealed. The FGF targets MKP1 and DUSP5 are shown to be negative regulators of FGF signaling in early Xenopus tissues. FoxD3 and Lin28, which are involved in regulating pluripotency in ES cells are shown to be down regulated when FGF signaling is blocked. CONCLUSIONS: We have undertaken a detailed analysis of FGF target genes which has generated a robust, well validated data set. We have found a widespread role for FGF signaling in regulating the expression of genes mediating the function of the Spemann organizer. In addition, we have found that the FGF targets MKP1 and DUSP5 are likely to contribute to the complex feedback loops involved in modulating responses to FGF signaling. We also find a link between FGF signaling and the expression of known regulators of pluripotency

The Effects of Nitrogen on the Interface State Density Near the Conduction Band Edge in 4H and 6H-SiC

Results are reported for the passivation of interface states near the conduction band edge in SiO{sub 2}/SiC MOS capacitors using post-oxidation anneals in nitric oxide, ammonia and forming gas (N{sub 2}5%H{sub 2}). Anneals in nitric oxide and ammonia reduce the interface state density significantly for 4H-SiC, while forming gas anneals are largely ineffective. Results suggest that interface states in SiO{sub 2}/SiC and SiO{sub 2}/SiC have different origins, and a model is described for interface state passivation by nitrogen in the SiO{sub 2}/SiC system. The peak inversion channel mobility measured for lateral 4H-SiC MOSFETs increases following NO passivation

Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis

Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure

A theory of motivation and ontological enhancement: the role of disability policy in student empowerment and institutional change

As debate continues around the nature and values of education, it is important to ask the question of what factors motivate a student to engage with the ends of an educational institution. In this paper, a broad, holistic view of learner motivation, derived from Aristotelian ethics, is used to provide a model to drive institutional change. Focussing on the approach of one Higher Education institution to the particular accommodations required for students with disabilities, the paper identifies three factors which motivate students, a failure to engage with the aims and ends of the educational project, a failure to see that a particular learning aim is worth attaining, and a simple lack of will‐power to attain it. To each of these failures a social cause is identified, and a change in both the institutional culture and the individual learner's approach to their education is suggested

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Eight Americas: Investigating Mortality Disparities across Races, Counties, and Race-Counties in the United States

BACKGROUND: The gap between the highest and lowest life expectancies for race-county combinations in the United States is over 35 y. We divided the race-county combinations of the US population into eight distinct groups, referred to as the “eight Americas,” to explore the causes of the disparities that can inform specific public health intervention policies and programs. METHODS AND FINDINGS: The eight Americas were defined based on race, location of the county of residence, population density, race-specific county-level per capita income, and cumulative homicide rate. Data sources for population and mortality figures were the Bureau of the Census and the National Center for Health Statistics. We estimated life expectancy, the risk of mortality from specific diseases, health insurance, and health-care utilization for the eight Americas. The life expectancy gap between the 3.4 million high-risk urban black males and the 5.6 million Asian females was 20.7 y in 2001. Within the sexes, the life expectancy gap between the best-off and the worst-off groups was 15.4 y for males (Asians versus high-risk urban blacks) and 12.8 y for females (Asians versus low-income southern rural blacks). Mortality disparities among the eight Americas were largest for young (15–44 y) and middle-aged (45–59 y) adults, especially for men. The disparities were caused primarily by a number of chronic diseases and injuries with well-established risk factors. Between 1982 and 2001, the ordering of life expectancy among the eight Americas and the absolute difference between the advantaged and disadvantaged groups remained largely unchanged. Self-reported health plan coverage was lowest for western Native Americans and low-income southern rural blacks. Crude self-reported health-care utilization, however, was slightly higher for the more disadvantaged populations. CONCLUSIONS: Disparities in mortality across the eight Americas, each consisting of millions or tens of millions of Americans, are enormous by all international standards. The observed disparities in life expectancy cannot be explained by race, income, or basic health-care access and utilization alone. Because policies aimed at reducing fundamental socioeconomic inequalities are currently practically absent in the US, health disparities will have to be at least partly addressed through public health strategies that reduce risk factors for chronic diseases and injuries

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events