Retinal thickness estimation from SD-OCT macular scans

Glaucoma, a leading cause of blindness worldwide, can be detected using retinal thicknesses from spectral-domain optical coherence tomography (SD-OCT) scans of the macula. We calculate the desired thickness maps as the distance between the inner-limiting membrane (ILM) and retinal pigmented epithelium (RPE) of the retina. To delineate these two layers, we use a set of two deformable open surfaces that are driven by intensity contrast, while preserving their shape and topology properties, i.e. local surface smoothness and inter-surface distance smoothness. To evaluate our method, qualified graders manually segmented 30 random sections from 20 OCT image stacks, in triplicate; we make comparisons with obtained ground-truth and the clinically tested Heidelberg Spectralis segmentation. We show the superiority of our method with respect to accuracy and average execution time (~7 secs), validating it as a clinical tool

Non-genomic effects of nuclear receptors: insights from the anucleate platelet

Nuclear receptors have the ability to elicit two different kinds of responses, genomic and non-genomic. While genomic responses control gene expression by influencing the rate of transcription, non-genomic effects occur rapidly and independently of transcriptional regulation. Due to their anucleate nature and mechanistically well-characterised and rapid responses, platelets provide a model system for the study of any non-genomic effects of the nuclear receptors. Several nuclear receptors have been found to be expressed in human platelets, and multiple nuclear receptor agonists have been shown to elicit anti-platelet effects by a variety of mechanisms. The non-genomic functions of NRs vary, including the regulation of kinase and phosphatase activity, ion channel function, intracellular calcium levels and production of second messengers. Recently, the characterisation of mechanisms and identification of novel binding partners of nuclear receptors have further strengthened the prospects of developing their ligands into potential therapeutics that offer cardio-protective properties in addition to their other defined genomic effects

Alternative Splicing in the Differentiation of Human Embryonic Stem Cells into Cardiac Precursors

The role of alternative splicing in self-renewal, pluripotency and tissue lineage specification of human embryonic stem cells (hESCs) is largely unknown. To better define these regulatory cues, we modified the H9 hESC line to allow selection of pluripotent hESCs by neomycin resistance and cardiac progenitors by puromycin resistance. Exon-level microarray expression data from undifferentiated hESCs and cardiac and neural precursors were used to identify splice isoforms with cardiac-restricted or common cardiac/neural differentiation expression patterns. Splice events for these groups corresponded to the pathways of cytoskeletal remodeling, RNA splicing, muscle specification, and cell cycle checkpoint control as well as genes with serine/threonine kinase and helicase activity. Using a new program named AltAnalyze (http://www.AltAnalyze.org), we identified novel changes in protein domain and microRNA binding site architecture that were predicted to affect protein function and expression. These included an enrichment of splice isoforms that oppose cell-cycle arrest in hESCs and that promote calcium signaling and cardiac development in cardiac precursors. By combining genome-wide predictions of alternative splicing with new functional annotations, our data suggest potential mechanisms that may influence lineage commitment and hESC maintenance at the level of specific splice isoforms and microRNA regulation

Selectivity and Mechanism of Hydrogen Atom Transfer by an Isolable Imidoiron(III) Complex

This article discusses a mechanistic study of hydrogen atom transfer by an isolable iron (III) imido complex, LᴹᵉFeNAd (Lᴹᵉ = bulky β-diketiminate ligand, 2,4-bis(2,6-diisopropylphenylimido)pentyl; Ad = 1-adamantyl)

Segmentation of human retinal layers from optical coherence tomography scans

An algorithm was developed in to efficiently segment the inner-limiting membrane (ILM) and retinal pigmented epithelium (RPE) from spectral domain-optical coherence tomography image volumes. A deformable model framework is described and implemented in which free-form deformations (FFD) are used to direct two deformable sheets to the two high-contrast layers of interest. Improved accuracy in determining retinal thickness (the distance between the ILM and the RPE) is demonstrated against the commercial state-of-the-art Spectralis OCT native segmentation software. A novel adaptation of the highest confidence first (HCF) algorithm is utilized to improve upon the initial results. The proposed adaptation of HCF provides distance-based clique potentials and an efficient solution to layer-based segmentation, reducing a 3D problem to 2D inference

Computational modeling of the cephalic arch predicts hemodynamic profiles in patients with brachiocephalic fistula access receiving hemodialysis

Background: The most common configuration for arteriovenous fistula is brachiocephalic which often develop cephalic arch stenosis leading to the need for numerous procedures to maintain access patency. The hemodynamics that contributes to the development of cephalic arch stenosis is incompletely understood given the inability to accurately determine shear stress in the cephalic arch. In the current investigation our aim was to determine pressure, velocity and wall shear stress profiles in the cephalic arch in 3D using computational modeling as tools to understand stenosis. Methods: Five subjects with brachiocephalic fistula access had protocol labs, Doppler, venogram and intravascular ultrasound imaging performed at 3 and 12 months. 3D reconstructions of the cephalic arch were generated by combining intravascular ultrasounds and venograms. Standard finite element analysis software was used to simulate time dependent blood flow in the cephalic arch with velocity, pressure and wall shear stress profiles generated. Results: Our models generated from imaging and flow measurements at 3 and 12 months offer snapshots of the patient’s cephalic arch at a precise time point, although the remodeling of the vessel downstream of an arteriovenous fistula in patients undergoing regular dialysis is a dynamic process that persists over long periods of time (~ 5 years). The velocity and pressure increase at the cephalic bend cause abnormal hemodynamics most prominent along the inner wall of the terminal cephalic arch. The topology of the cephalic arch is highly variable between subjects and predictive of pathologic stenosis at later time points. Conclusions: Low flow velocity and wall pressure along the inner wall of the bend may provide possible nidus of endothelial activation that leads to stenosis and thrombosis. In addition, 3D modelling of the arch can indicate areas of stenosis that may be missed by venograms alone. Computational modeling reconstructed from 3D radiologic imaging and Doppler flow provides important insights into the hemodynamics of blood flow in arteriovenous fistula. This technique could be used in future studies to determine optimal flow to prevent endothelial damage for patients with arteriovenous fistula access.</p

Dual Orexin Receptor Antagonist Attenuates Increases in IOP, ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats

Purpose: Intraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures. Methods: Sprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI). Results: Administration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8-40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R2 = 0.18, P = 0.04). The ICP responses during the peak response period (4-16 minutes) versus DORA dose were also linear (R2 = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015). Conclusions: DORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation

The "metabolic memory": is more than just tight glucose control necessary to prevent diabetic complications?

Context: The concept of a "metabolic memory," that is of diabetic vascular stresses persisting after glucose normalization, has been supported both in the laboratory and in the clinic and in both type 1 and type 2 diabetes. Evidence Acquisition: Using PubMed, we searched for publications on diabetic micro- and macrovascular complications using terms such as persistence, prolongation, sustained, and "memory" and focusing on the mechanistic basis behind this metabolic memory. Evidence Synthesis: We found that as early as the mid-1980s this memory phenomenon was described in diabetic animals and isolated cells exposed to high glucose followed by normalized glucose and then, beginning around 2002, in results from large clinical trials such as the Diabetes Complications and Control Trial-Epidemiology of Diabetes Interventions and Complications and the United Kingdom Prospective Diabetes Study. Furthermore, mechanisms for propagating this memory appear focused on the nonenzymatic glycation of cellular proteins and lipids and on an excess of cellular reactive oxygen and nitrogen species, in particular originating at the level of glycated mitochondrial proteins and perhaps acting in concert with one another to maintain stress signaling independent of glucose levels. Conclusions: The emergence of this metabolic memory suggests the need for early aggressive treatment aiming to "normalize" metabolic control together perhaps with the addition of agents which reduce cellular reactive species and glycation in order to minimize long-term diabetic complications. (J Clin Endocrinol Metab 94: 410-415, 2009