Classifying visual field loss in glaucoma through baseline matching of stable reference sequences

Glaucoma is a common disease of the eye that often results in partial blindness. The main symptom of glaucoma is progressive loss of sight in the visual field over time. The clinical management of glaucoma involves monitoring the progress of the disease using a sequence of regular visual field tests. However, there is currently no universally accepted standard method for classifying changes in the visual field test data. Sequence matching techniques typically rely on similarity measures. However, visual field measurements are very noisy, particularly in people with glaucoma. It is therefore difficult to establish a reference data set including both stable and progressive visual fields. This paper proposes a method that uses a "baseline" computed from a query sequence, to match stable sequences in a database of visual field measurements collected from volunteers. The purpose of the new method is to classify a given query sequence as being stable or progressive. The results suggest that the new method gives a significant improvement in accuracy for identifying progressive sequences, though there is a small penalty for stable sequences

The CXCL12/CXCR4 Axis Plays a Critical Role in Coronary Artery Development

The chemokine CXCL12 and its receptor CXCR4 have many functions during embryonic and post-natal life. We used murine models to investigate the role of CXCL12/CXCR4 signaling in cardiac development and found that embryonic Cxcl12-null hearts lacked intra-ventricular coronary arteries (CAs) and exhibited absent or misplaced CA stems. We traced the origin of this phenotype to defects in the early stages of CA stem formation. CA stems derive from the peritruncal plexus, an encircling capillary network that invades the wall of the developing aorta. We showed that CXCL12 is present at high levels in the outflow tract, while peritruncal endothelial cells (ECs) express CXCR4. In the absence of CXCL12, ECs were abnormally localized and impaired in their ability to anastomose with the aortic lumen. We propose that CXCL12 is required for connection of peritruncal plexus ECs to the aortic endothelium and thus plays a vital role in CA formation

Analysis of Coronary Vessels in Cleared Embryonic Hearts

Whole mount visualization of the embryonic coronary plexus from which the capillary and arterial networks will form is rendered problematic using standard microscopy techniques, due to the scattering of imaging light by the thick heart tissue, as these vessels are localized deep within the walls of the developing heart. As optical clearing of tissues using organic solvents such as BABB (1 part benzyl alcohol to 2 parts benzyl benzoate) has been shown to greatly improve the optical penetration depth that can be achieved, we combined clearance of whole, PECAM1-immunostained hearts, with laser-scanning confocal microscopy, in order to obtain high-resolution images of vessels throughout the entire heart. BABB clearance of embryonic hearts takes place rapidly and also acts to preserve the fluorescent signal for several weeks; in addition, samples can be imaged multiple times without loss of signal. This straightforward method is also applicable to imaging other types of blood vessels in whole embryos

Effect of Obesity on Acute Ozone-Induced Changes in Airway Function, Reactivity, and Inflammation in Adult Females

We previously observed greater ozone-induced lung function decrements in obese than non-obese women. Animal models suggest that obesity enhances ozone-induced airway reactivity and inflammation. In a controlled exposure study, we compared the acute effect of randomized 0.4ppm ozone and air exposures (2 h with intermittent light exercise) in obese (N = 20) (30<BMI<40Kg/m2) vs. non-obese (N = 20) (BMI<25Kg/m2) non-smoking 18–35 year old women. We measured spirometry and bronchial reactivity to inhaled methacholine (3h post-exposure). Inflammation and obesity markers were assessed in the blood (pre, 4h post, and 20h post exposures) and induced-sputum (4h post-exposures and on 24h pre-exposure training day, no exercise): measures of C reactive protein (CRP) (blood only), leptin (blood only), adiponectin, interleukins IL-6, IL-1b, and IL-8, and tumor necrosis factor alpha, and sputum cell differential cell counts. The pre- to post-exposure decrease in forced vital capacity after ozone (adjusted for the change after air exposure) was significantly greater in the obese group (12.5+/-7.5 vs. 8.0+/-5.8%, p<0.05). Post ozone exposure, 6 obese and 6 non-obese subjects responded to methacholine at ≤ 10mg/ml (the maximum dose); the degree of hyperresponsiveness was similar for the two groups. Both BMI groups showed similar and significant ozone-induced increases in sputum neutrophils. Plasma IL-6 was increased by exercise (4 hr post air exposure vs. pre) only in the obese but returned to pre-air exposure levels at 20hr post-exposure. Plasma IL-6 was significantly increased at 4hr post ozone exposure in both groups and returned to pre-exposure levels by 20h post-exposure. These results confirm our previous findings of greater post-ozone spirometric decrements in obese young women. However, acute ozone-induced airway reactivity to methacholine and airway inflammation did not differ by obesity at the exposure and exercise levels used

Observation-Driven Estimation of the Spatial Variability of 20th Century Sea Level Rise

Over the past two decades, sea level measurements made by satellites have given clear indications of both global and regional sea level rise. Numerous studies have sought to leverage the modern satellite record and available historic sea level data provided by tide gauges to estimate past sea level rise, leading to several estimates for the 20th century trend in global mean sea level in the range between 1 and 2 mm/yr. On regional scales, few attempts have been made to estimate trends over the same time period. This is due largely to the inhomogeneity and quality of the tide gauge network through the 20th century, which render commonly used reconstruction techniques inadequate. Here, a new approach is adopted, integrating data from a select set of tide gauges with prior estimates of spatial structure based on historical sea level forcing information from the major contributing processes over the past century. The resulting map of 20th century regional sea level rise is optimized to agree with the tide gauge-measured trends, and provides an indication of the likely contributions of different sources to regional patterns. Of equal importance, this study demonstrates the sensitivities of this regional trend map to current knowledge and uncertainty of the contributing processes

Dual role for CXCL12 signaling in semilunar valve development

Summary: Cxcl12-null embryos have dysplastic, misaligned, and hyperplastic semilunar valves (SLVs). In this study, we show that CXCL12 signaling via its receptor CXCR4 fulfills distinct roles at different stages of SLV development, acting initially as a guidance cue to pattern cellular distribution within the valve primordia during the endocardial-to-mesenchymal transition (endoMT) phase and later regulating mesenchymal cell proliferation during SLV remodeling. Transient, anteriorly localized puncta of internalized CXCR4 are observed in cells undergoing endoMT. In vitro, CXCR4+ cell orientation in response to CXCL12 requires phosphatidylinositol 3-kinase (PI3K) signaling and is inhibited by suppression of endocytosis. This dynamic intracellular localization of CXCR4 during SLV development is related to CXCL12 availability, potentially enabling activation of divergent downstream signaling pathways at key developmental stages. Importantly, Cxcr7-/- mutants display evidence of excessive CXCL12 signaling, indicating a likely role for atypical chemokine receptor CXCR7 in regulating ligand bioavailability and thus CXCR4 signaling output during SLV morphogenesis

Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

Argonne National Laboratory Report ANL-76-9

Progress report describing the research and management efforts of Argonne National Laboratory's program on high-performance lithium/metal sulfide batteries during the period July-December 1975. The batteries are being developed for two applications: off-peak energy storage in electric utility networks and electric-vehicle propulsion. The battery designs for the two applications differ, particularly in cell configuration and electrode design because of the differing performance requirements

NEMO oligomerization and its ubiquitin-binding properties

The IKK [IκB (inhibitory κB) kinase] complex is a key regulatory component of NF-κB (nuclear factor κB) activation and is responsible for mediating the degradation of IκB, thereby allowing nuclear translocation of NF-κB and transcription of target genes. NEMO (NF-κB essential modulator), the regulatory subunit of the IKK complex, plays a pivotal role in this process by integrating upstream signals, in particular the recognition of polyubiquitin chains, and relaying these to the activation of IKKα and IKKβ, the catalytic subunits of the IKK complex. The oligomeric state of NEMO is controversial and the mechanism by which it regulates activation of the IKK complex is poorly understood. Using a combination of hydrodynamic techniques we now show that apo-NEMO is a highly elongated, dimeric protein that is in weak equilibrium with a tetrameric assembly. Interaction with peptides derived from IKKβ disrupts formation of the tetrameric NEMO complex, indicating that interaction with IKKα and IKKβ and tetramerization are mutually exclusive. Furthermore, we show that NEMO binds to linear di-ubiquitin with a stoichiometry of one molecule of di-ubiquitin per NEMO dimer. This stoichiometry is preserved in a construct comprising the second coiled-coil region and the leucine zipper and in one that essentially spans the full-length protein. However, our data show that at high di-ubiquitin concentrations a second weaker binding site becomes apparent, implying that two different NEMO–di-ubiquitin complexes are formed during the IKK activation process. We propose that the role of these two complexes is to provide a threshold for activation, thereby ensuring sufficient specificity during NF-κB signalling

Age and African-American race impact the validity and reliability of the asthma control test in persistent asthmatics

Abstract Background The Asthma Control Test (ACT) is widely used to assess asthma control, yet the validity and reliability of the test have not been specifically evaluated in adolescents or African-Americans. We conducted a prospective psychometric study of the ACT in African-American (AA) and non-African-American (nAA) adolescents with persistent asthma, with emphasis on the clinical utility of the test for medical decision making. Methods Participants completed the ACT and performed spirometry. A physician conducted a guidelines-based assessment of asthma control, blinded to the ACT score. Study procedures were repeated 6–8 weeks later. The ACT-based asthma control assessment was compared to physician assessment. Results For baseline and follow-up visits, internal consistency, as measured using Cronbach’s alpha, was 0.80 and 0.81 in AA teens and 0.80 and 0.83 in nAA teens. Intraclass correlation coefficients were 0.59 and 0.76 in AA and nAA teens, respectively, with stable asthma control over time. Agreement between ACT and physician assessment was moderate in AA teens and fair in nAA teens. An ACT score of ≤19 showed reduced sensitivity for not well controlled asthma in both groups, while a score of ≤21 had the greatest area under the ROC curve. ACT scores were marginally responsive to change in control status. Conclusions Concerns for the ACT’s ability to detect uncontrolled asthma in adolescents emphasizes the need for a more comprehensive evaluation of asthma control in clinical settings. A higher threshold ACT score to define not well controlled asthma may be needed if the ACT is to be used for medical decision making. Trial registration ClinicalTrials.gov: NCT02671643 , NCT02662413