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1.  Interfacial Protein-Protein Associations 
Biomacromolecules  2013;15(1):66-74.
While traditional models of protein adsorption focus primarily on direct protein-surface interactions, recent findings suggest that protein-protein interactions may play a central role. Using high-throughput intermolecular resonance energy transfer (RET) tracking, we directly observed dynamic, protein-protein associations of bovine serum albumin on poly(ethylene glycol) modified surfaces. The associations were heterogeneous and reversible, and associating molecules resided on the surface for longer times. The appearance of three distinct RET states suggested a spatially heterogeneous surface – with areas of high protein density (i.e. strongly-interacting clusters) coexisting with mobile monomers. Distinct association states exhibited characteristic behavior, i.e. partial-RET (monomer-monomer) associations were shorter-lived than complete-RET (protein-cluster) associations. While the fractional surface area covered by regions with high protein density (i.e. clusters) increased with increasing concentration, the distribution of contact times between monomers and clusters was independent of solution concentration, suggesting that associations were a local phenomenon, and independent of the global surface coverage.
PMCID: PMC3895929  PMID: 24274729
Protein adsorption; protein-protein interactions; single-molecule; total internal reflection fluorescence microscopy (TIRFM); solid-liquid interface; bovine serum albumin
2.  Phase-Contrast Optical Coherence Tomography: A New Technique for Non-Invasive Angiography 
Ophthalmology  2013;121(1):180-187.
Phase-contrast optical coherence tomography (PC-OCT) provides volumetric imaging of the retinal vasculature without the need for intravenous injection of a fluorophore. Here, we compare images from PC-OCT and fluorescein angiography (FA) for normal individuals and patients with age-related macular degeneration and diabetic retinopathy.
This is an evaluation of a diagnostic technology.
4 patients underwent comparative retinovascular imaging using FA and PC-OCT. Imaging was performed on 1 normal individual, 1 patient with dry age-related macular degeneration, 1 patient with exudative age-related macular degeneration and 1 patient with non-proliferative diabetic retinopathy.
FA imaging was performed using a Topcon (TRC-50IX) camera having resolution of 1280 (H) x 1024 (V) pixels. PC-OCT images were generated by software data processing of the entire cross-sectional image from consecutively acquired B-scans. Bulk axial motion was calculated and corrected for each transverse location, reducing the phase noise introduced from eye motion. Phase contrast was calculated through the variance of the motion-corrected phase changes acquired within multiple B-scans at the same position. Repeating these calculations over the entire volumetric scan produced a three-dimensional PC-OCT representation of the vasculature.
Main Outcome Measures
Feasibility of rendering retinal and choroidal microvasculature using PC-OCT was compared qualitatively to FA, the current gold standard for retinovascular imaging.
PC-OCT rendered a two-dimensional depth color-coded vasculature map of the retinal and choroidal vasculature non-invasively. The choriocapillaris was imaged with better resolution of microvascular detail using PC-OCT. Areas of geographic atrophy and choroidal neovascularization imaged by FA were depicted by PC-OCT. Regions of capillary non-perfusion from diabetic retinopathy were shown by both imaging techniques; there was not complete correspondence between microaneurysms shown on FA and PC-OCT images.
PC-OCT yields high resolution imaging of the retinal and choroidal microvasculature that compares favorably to FA.
PMCID: PMC4190463  PMID: 24156929
3.  Cardiac Failure after Liver Transplantation Requiring a Biventricular Assist Device 
Increased hepatic iron load in extrahepatic organs of cirrhotic patients with and without hereditary hemochromatosis portends a poorer long term prognosis after liver transplant. Hepatic as well as nonhepatic iron overload is associated with increased infectious and postoperative complications, including cardiac dysfunction. In this case report, we describe a cirrhotic patient with alpha 1 antitrypsin deficiency and nonhereditary hemochromatosis (non-HFE) that developed cardiogenic shock requiring mechanical circulatory support for twenty days after liver transplant. Upon further investigation, she was found to have significant iron deposition in both the liver and heart biopsies. Her heart regained complete and sustained recovery following ten days of mechanical biventricular support. This case highlights the importance of preoperatively recognizing extrahepatic iron deposition in patients referred for liver transplantation irrespective of etiology of liver disease as this may prevent postoperative complications.
PMCID: PMC4241562  PMID: 25431733
4.  Protocol to assess the neurophysiology associated with multi-segmental postural coordination 
Physiological measurement  2013;34(10):10.1088/0967-3334/34/10/N97.
Anticipatory postural adjustments (APAs) stabilize potential disturbances to posture caused by movement, impaired APAs are common with disease and injury. Brain functions associated with generating APAs remain uncertain due to a lack of paired tasks that require similar limb motion from similar postural orientations, but differ in eliciting an APA while also being compatible with brain imaging techniques (e.g., functional magnetic resonance imaging; fMRI). This study developed fMRI-compatible tasks differentiated by the presence or absence of APAs during leg movement. Eighteen healthy subjects performed two leg movement tasks, supported leg raise (SLR) and unsupported leg raise (ULR), to elicit isolated limb motion (no APA) versus multi-segmental coordination patterns (including APA), respectively. Ground reaction forces under the feet and electromyographic (EMG) activation amplitudes were assessed to determine the coordination strategy elicited for each task. Results demonstrated that the ULR task elicited a multi-segmental coordination that were either minimized or absent in the SLR task, indicating that it would serve as an adequate control task for fMRI protocols. A pilot study with a single subject performing each task in an MRI scanner demonstrated minimal head movement in both tasks and brain activation patterns consistent with an isolated limb movement for the SLR task versus multi-segmental postural coordination for the ULR task.
PMCID: PMC3884551  PMID: 24065623
postural coordination; MRI; EMG; cerebral cortex; multi-segmental
5.  The Effects of Excipients on Protein Aggregation During Agitation: An Interfacial Shear Rheology Study 
Journal of pharmaceutical sciences  2013;102(8):2460-2470.
We investigated the effects of excipients in solutions of keratinocyte growth factor 2 (KGF-2) on protein aggregation during agitation as well as on interfacial shear rheology at the air-water interface. Samples were incubated with or without agitation, and in the presence or absence of the excipients heparin, sucrose or polysorbate 80 (PS80). The effect of excipients on the extent of protein aggregation was determined by UV spectroscopy and microflow imaging (MFI). Interfacial shear rheology was used to detect the gelation time and strength of protein gels at the air-water interface. During incubation, protein particles of size ≥ 1 μm and insoluble aggregates formed faster for KGF-2 solutions subjected to agitation. Addition of either heparin or sucrose promoted protein aggregation during agitation. In contrast, PS 80 substantially inhibited agitation-induced KGF-2 aggregation but facilitated protein particulate formation in quiescent solutions. The combination of PS 80 and heparin or sucrose completely prevented protein aggregation during both non-agitated and agitated incubations. Interfacial rheological measurements showed that KGF-2 in buffer alone formed an interfacial gel within a few minutes. In the presence of heparin, KGF-2 interfacial gels formed too quickly for gelation time to be determined. KGF-2 formed gels in about 10 minutes in the presence of sucrose. The presence of PS80 in the formulation inhibited gelation of KGF-2. Furthermore, the interfacial gels formed by the protein in the absence of PS80 were reversible when PS80 was added to the samples after gelation. Therefore, there is a correspondence between formulations that exhibited interfacial gelation and formulations that exhibited agitation-induced aggregation.
PMCID: PMC4174554  PMID: 23712900
7.  DYX1C1 is required for axonemal dynein assembly and ciliary motility 
Nature genetics  2013;45(9):995-1003.
Dyx1c1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deletion of Dyx1c1 exons 2–4 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder characterized by chronic airway disease, laterality defects, and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1c.T2A start codon mutation recovered from an ENU mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also created laterality and ciliary motility defects. In humans, recessive loss-of-function DYX1C1 mutations were identified in twelve PCD individuals. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans revealed disruptions of outer and inner dynein arms (ODA/IDA). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA/IDA assembly factor DNAAF2/KTU. Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).
PMCID: PMC4000444  PMID: 23872636
8.  DNA Hairpin Stabilization on a Hydrophobic Surface 
DNA hybridization in the vicinity of surfaces is a fundamental process for self-assembled nanoarrays, nanocrystal superlattices, and biosensors. It is widely recognized that solid surfaces alter molecular forces governing hybridization relative to bulk solution, and these effects can either favor or disfavor the hybridized state depending on the specific sequence and surface. Results presented here provide new insights into the dynamics of DNA hairpin-coil conformational transitions in the vicinity of hydrophilic oligo(ethylene glycol) (OEG) and hydrophobic trimethylsilane (TMS) surfaces. Single-molecule methods are used to observe the forward and reverse hybridization hairpin-coil transition of adsorbed species while simultaneously measuring molecular surface diffusion in order to gain insight into surface interactions with individual DNA bases. At least 35,000 individual molecular trajectories are observed on each type of surface. We find that unfolding slows and the folding rate increases on TMS relative to OEG despite stronger attractions between TMS and unpaired nucleobases. These rate differences lead to nearly complete hairpin formation on hydrophobic TMS and significant unfolding on hydrophilic OEG, resulting in the surprising conclusion that hydrophobic surface coatings are preferable for nanotechnology applications that rely on DNA hybridization near surfaces.
PMCID: PMC3741999  PMID: 23184340
conformational change; molecular diffusion; poly(ethylene glycol); self-assembly; single-molecule tracking
9.  Effects of Molecular Size and Surface Hydrophobicity on Oligonucleotide Interfacial Dynamics 
Biomacromolecules  2012;13(12):4002-4011.
Single-molecule total internal reflection fluorescence microscopy was used to observe the dynamic behavior of (poly)-cytosine ssDNA (1–50 nucleotides long) at the interface between aqueous solution and hydrophilic (oligoethylene oxide-modified fused silica, OEG) and hydrophobic (octadecyltriethoxysilane-modified fused silica, OTES) solid surfaces. High throughput molecular tracking was used to determine >75,000 molecular trajectories for each molecular length, which were then used to calculate surface residence time and squared displacement (i.e. “step-size”) distributions. On hydrophilic OEG surfaces, the surface residence time increased systematically with ssDNA chain length, as expected due to increasing molecule-surface interactions. Interestingly, the residence time decreased with increasing ssDNA length on the hydrophobic OTES surface, particularly for longer chains. Similarly, the interfacial mobility of polynucleotides slowed with increasing chain length on OEG, but became faster on OTES. On OTES surfaces, the rates associated with desorption and surface diffusion exhibited the distinctive anomalous temperature dependence that is characteristic of hydrophobic interactions for short chain species but not for longer chains. These combined observations suggest that long oligonucleotides adopt conformations minimizing hydrophobic interactions, e.g. by internal sequestration of hydrophobic nucleobases.
PMCID: PMC3518566  PMID: 23127250
10.  Arthroscopic Posterior Bone Block Procedure: A New Technique Using Suture Anchor Fixation 
Arthroscopy Techniques  2013;2(4):e473-e477.
We present a novel all-arthroscopic technique of posterior shoulder stabilization that uses suture anchors for both bone block fixation and capsulolabral repair. The bone graft, introduced inside the glenohumeral joint through a cannula, is fixed with 2 suture anchors. The associated posteroinferior capsulolabral repair places the bone block in an extra-articular position. In this article we present the detailed arthroscopic technique performed in a consecutive series of 15 patients and report the early results. We also report the positioning, healing, and remodeling of the bone block using postoperative 3-dimensional computed tomography. The benefits of this new technique are as follows: (1) it is all arthroscopic, preserving the posterior deltoid and posterior rotator cuff muscles; (2) it is accurate, resulting in appropriate bone block positioning; (3) it is efficient, allowing for consistent bone graft healing; (4) it is anatomic, both restoring the glenoid bone stock and repairing the injured posterior labrum; and (5) it is safe, limiting hardware-related complications and eliminating the risk of injury to vital structures associated with drilling or screw insertion from posterior to anterior. We believe that this technique is advantageous because it does not use screws for fixation and may be safer for the patient.
PMCID: PMC4040011  PMID: 24892011
11.  Identifying Mechanisms of Interfacial Dynamics Using Single-Molecule Tracking 
The “soft” (i.e. non-covalent) interactions between molecules and surfaces are complex and highly-varied (e.g. hydrophobic, hydrogen bonding, ionic) often leading to heterogeneous interfacial behavior. Heterogeneity can arise either from spatial variation of the surface/interface itself or from molecular configurations (i.e. conformation, orientation, aggregation state, etc.). By observing adsorption, diffusion, and desorption of individual fluorescent molecules, single-molecule tracking can characterize these types of heterogeneous interfacial behavior in ways that are inaccessible to traditional ensemble-averaged methods. Moreover, the fluorescence intensity or emission wavelength (in resonance energy transfer experiments) can be used to simultaneously track molecular configuration and directly relate this to the resulting interfacial mobility or affinity. In this feature article, we review recent advances involving the use of single-molecule tracking to characterize heterogeneous molecule-surface interactions including: multiple modes of diffusion and desorption associated with both internal and external molecular configuration, Arrhenius activated interfacial transport, spatially dependent interactions, and many more.
PMCID: PMC3429661  PMID: 22716995
12.  Distinguishing Positional Uncertainty from True Mobility in Single-Molecule Trajectories That Exhibit Multiple Diffusive Modes 
Although imperfect spatial localization in single-molecule object tracking experiments has long been recognized to induce apparent motion in an immobile population of molecules, this effect is often ignored or incorrectly analyzed for mobile molecules. In particular, apparent motion due to positional uncertainty is often incorrectly assigned as a distinct diffusive mode. Here we show that, due to both static and dynamic contributions, positional uncertainty does not introduce a new apparent diffusive mode into trajectories, but instead causes a systematic shift of each measured diffusion coefficient. This shift is relatively simple: a factor of σ2/Δt is added to each diffusion coefficient, where σ is the positional uncertainty length scale and Δt is the time interval between observations. Therefore, by calculating the apparent diffusion coefficients as a function of Δt, it is straightforward to separate the true diffusion coefficients from the effective positional uncertainty. As a concrete demonstration, we apply this approach to the diffusion of the protein fibrinogen adsorbed to a hydrophobic surface, a system that exhibits three distinct modes of diffusion.
PMCID: PMC3410552  PMID: 22849801
diffusion; total internal reflection fluorescence microscopy (TIRFM); fibrinogen; static error; dynamic error; single molecule
13.  Microcystic macular oedema in multiple sclerosis is associated with disease severity 
Brain  2012;135(6):1786-1793.
Macular oedema typically results from blood–retinal barrier disruption. It has recently been reported that patients with multiple sclerosis treated with FTY-720 (fingolimod) may exhibit macular oedema. Multiple sclerosis is not otherwise thought to be associated with macular oedema except in the context of comorbid clinical uveitis. Despite a lack of myelin, the retina is a site of inflammation and microglial activation in multiple sclerosis and demonstrates significant neuronal and axonal loss. We unexpectedly observed microcystic macular oedema using spectral domain optical coherence tomography in patients with multiple sclerosis who did not have another reason for macular oedema. We therefore evaluated spectral domain optical coherence tomography images in consecutive patients with multiple sclerosis for microcystic macular oedema and examined correlations between macular oedema and visual and ambulatory disability in a cross-sectional analysis. Participants were excluded if there was a comorbidity that could account for the presence of macular oedema, such as uveitis, diabetes or other retinal disease. A microcystic pattern of macular oedema was observed on optical coherence tomography in 15 of 318 (4.7%) patients with multiple sclerosis. No macular oedema was identified in 52 healthy controls assessed over the same period. The microcystic oedema predominantly involved the inner nuclear layer of the retina and tended to occur in small, discrete patches. Patients with multiple sclerosis with microcystic macular oedema had significantly worse disability [median Expanded Disability Score Scale 4 (interquartile range 3–6)] than patients without macular oedema [median Expanded Disability Score Scale 2 (interquartile range 1.5–3.5)], P = 0.0002. Patients with multiple sclerosis with microcystic macular oedema also had higher Multiple Sclerosis Severity Scores, a measure of disease progression, than those without oedema [median of 6.47 (interquartile range 4.96–7.98) versus 3.65 (interquartile range 1.92–5.87), P = 0.0009]. Microcystic macular oedema occurred more commonly in eyes with prior optic neuritis than eyes without prior optic neuritis (50 versus 27%) and was associated with lower visual acuity (median logMAR acuity of 0.17 versus −0.1) and a thinner retinal nerve fibre layer. The presence of microcystic macular oedema in multiple sclerosis suggests that there may be breakdown of the blood–retinal barrier and tight junction integrity in a part of the nervous system that lacks myelin. Microcystic macular oedema may also contribute to visual dysfunction beyond that explained by nerve fibre layer loss. Microcystic changes need to be assessed, and potentially adjusted for, in clinical trials that evaluate macular volume as a marker of retinal ganglion cell survival. These findings also have implications for clinical monitoring in patients with multiple sclerosis on sphingosine 1-phosphate receptor modulating agents.
PMCID: PMC3359753  PMID: 22539259
multiple sclerosis; optical coherence tomography; retina; macular oedema
14.  Discounting of delayed rewards and executive dysfunction in individuals infected with hepatitis C 
Determine whether adults with hepatitis C, regardless of substance use disorder, are more likely to discount delayed rewards than adults without hepatitis C, and explore the relationship between delay discounting and neuropsychological functioning.
Procedures included clinical interviews, neuropsychological testing, and a delay discounting task.
Regardless of substance abuse history, adults with hepatitis C were significantly more likely to choose smaller immediate rewards over larger delayed rewards. Delay discounting correlated with performance on executive functioning tasks.
Increased discounting is associated with broad executive dysfunction, suggesting that HCV associated executive dysfunction may lead to altered decision making style.
PMCID: PMC3615977  PMID: 20694872
hepatitis C; neuropsychology; impulsive behavior; substance-related disorders; delay discounting
15.  Biomineralization and Size Control of Stable Calcium Phosphate Core Protein Shell Nanoparticles: Potential for Vaccine Applications 
Bioconjugate Chemistry  2012;23(3):610-617.
Calcium phosphate (CaP) polymorphs are nontoxic, biocompatible and hold promise in applications ranging from hard tissue regeneration to drug delivery and vaccine design. Yet, simple and robust routes for the synthesis of protein-coated CaP nanoparticles in the sub-100 nm size range remain elusive. Here, we used cell surface display to identify disulfide-constrained CaP binding peptides that, when inserted within the active site loop of E. coli Thioredoxin 1 (TrxA), readily and reproducibly drive the production of nanoparticles that are 50–70 nm in hydrodynamic diameter and consist of an approximately 25 nm amorphous calcium phosphate (ACP) core stabilized by the protein shell. Like bone and enamel proteins implicated in biological apatite formation, peptides supporting nanoparticle production were acidic. They also required presentation in a loop for high affinity ACP binding since elimination of the disulfide bridge caused a nearly 3-fold increase in hydrodynamic diameters. When compared to a commercial aluminum phosphate adjuvant, the small core-shell assemblies led to a 3-fold increase in mice anti-TrxA titers three weeks post-injection, suggesting that they might be useful vehicles for adjuvanted antigen delivery to dendritic cells.
PMCID: PMC3310268  PMID: 22263898
16.  Spontaneous epiretinal membrane separation 
Oman Journal of Ophthalmology  2013;6(1):56-57.
PMCID: PMC3678201  PMID: 23772129
17.  Connecting Rare DNA Conformations and Surface Dynamics using Single-Molecule Resonance Energy Transfer 
ACS nano  2011;5(12):9861-9869.
A mechanistic understanding of single-stranded DNA (ssDNA) behavior in the near-surface environment is critical to advancing DNA-directed self-assembled nanomaterials. A new approach is described that uses total internal reflection fluorescence microscopy to measure resonance energy transfer at the single-molecule level, providing a mechanistic understanding of the connection between molecular conformation and interfacial dynamics near amine-modified surfaces. Large numbers (>105) of ssDNA trajectories were observed, permitting dynamic correlation of molecular conformation with desorption and surface mobility. On the basis of dynamic behavior, molecules could be designated as members of the more common coiled population or a rare, weakly bound conformation. Molecules in the coiled state generally exhibited slow diffusion and conformational fluctuations that decreased with increasing average end-to-end distance. Lattice simulations of adsorbed self-avoiding polymers successfully predicted these trends. In contrast, the weakly bound conformation, observed in about 5% of molecules, had a large end-to-end distance but demonstrated conformational fluctuations that were much higher than predicted by simulations for adsorbed flexible chains. This conformation correlated positively with desorption events and led to fast diffusion, indicating weak surface associations. Understanding the role of the weakly bound conformation in DNA hybridization, and how solution conditions and surface properties may favor it, could lead to improved self-assembled nanomaterials.
PMCID: PMC3246573  PMID: 21942411
Single-molecule; resonance energy transfer; DNA; diffusion; adsorption; desorption; conformation
18.  Using Bacteria to Determine Protein Kinase Specificity and Predict Target Substrates 
PLoS ONE  2012;7(12):e52747.
The identification of protein kinase targets remains a significant bottleneck for our understanding of signal transduction in normal and diseased cellular states. Kinases recognize their substrates in part through sequence motifs on substrate proteins, which, to date, have most effectively been elucidated using combinatorial peptide library approaches. Here, we present and demonstrate the ProPeL method for easy and accurate discovery of kinase specificity motifs through the use of native bacterial proteomes that serve as in vivo libraries for thousands of simultaneous phosphorylation reactions. Using recombinant kinases expressed in E. coli followed by mass spectrometry, the approach accurately recapitulated the well-established motif preferences of human basophilic (Protein Kinase A) and acidophilic (Casein Kinase II) kinases. These motifs, derived for PKA and CK II using only bacterial sequence data, were then further validated by utilizing them in conjunction with the scan-x software program to computationally predict known human phosphorylation sites with high confidence.
PMCID: PMC3530509  PMID: 23300758
NeuroImage  2010;50(4):1392-1401.
Methamphetamine (MA) is associated with behavioral and cognitive deficits that may be related to macrostructural abnormalities. Quantitative anatomical comparisons between controls and methamphetamine-dependent individuals have produced conflicting results. We examined local and global differences in brain structure in 61 abstinent methamphetamine-dependent individuals and 44 controls with voxel-based morphometry and tissue segmentation. We related regional differences in gray matter density and whole brain segmentation volumes to performance on a behavioral measure of impulsivity and group membership using multiple linear regression. Within the MA group, we related cortical and subcortical gray matter density to MA use history, length of abstinence and age of first use. Controls had greater density relative to MA in bilateral insula and left middle frontal gyrus. Impulsivity was higher in the MA group and, within all subjects, impulsivity was positively correlated with gray matter density in posterior cingulate cortex and ventral striatum and negatively correlated in left superior frontal gyrus. Length of abstinence from MA was associated with greater amygdalar density. Earlier age of first use of MA (in subjects who initiated use before age 21) was associated with smaller intracranial volume. The findings are consistent with multiple possible mechanisms including neuroadaptations due to addictive behavior, neuroinflammation as well as dopaminergic and serotonergic neurotoxicity.
PMCID: PMC3478236  PMID: 20096794
20.  Hippocampal M1 receptor function associated with spatial learning and memory in aged female rhesus macaques 
Age  2010;33(3):309-320.
Of the acetylcholine muscarinic receptors, the type 1 (M1) and type 2 (M2) receptors are expressed at the highest levels in the prefrontal cortex (PFC) and hippocampus, brain regions important for cognition. As equivocal findings of age-related changes of M1 and M2 in the nonhuman primate brain have been reported, we first assessed age-related changes in M1 and M2 in the PFC and hippocampus using saturation binding assays. Maximum M1 receptor binding, but not affinity of M1 receptor binding, decreased with age. In contrast, the affinity of M2 receptor binding, but not maximum M2 receptor binding, increased with age. To determine if in the elderly cognitive performance is associated with M1 or M2 function, we assessed muscarinic function in elderly female rhesus macaques in vivo using a scopolamine challenge pharmacological magnetic resonance imaging and in vitro using saturation binding assays. Based on their performance in a spatial maze, the animals were classified as good spatial performers (GSP) or poor spatial performers (PSP). In the hippocampus, but not PFC, the GSP group showed a greater change in T2*-weighted signal intensity after scopolamine challenge than the PSP group. The maximum M1 receptor binding and receptor binding affinity was greater in the GSP than the PSP group, but no group difference was found in M2 receptor binding. Parameters of circadian activity positively correlated with the difference in T2*-weighted signal intensity before and after the challenge, the maximum M1 receptor binding, and the M1 receptor binding affinity. Thus, while in rhesus macaques, there are age-related decreases in M1 and M2 receptor binding, in aged females, hippocampal M1, but not M2, receptor function is associated with spatial learning and memory and circadian activity.
PMCID: PMC3168603  PMID: 20890730
M1 receptor; Scopolamine phMRI; Spatial maze
21.  Human Resistin: Found in Translation From Mouse to Man 
The discovery of resistin ten years ago as a fat cell-secreted factor that modulates insulin resistance suggested a link to the obesity-associated epidemics of diabetes and cardiovascular disease that are major human health concerns. While adipocyte-derived resistin is indisputably linked to insulin resistance in rodent models, the relevance of human resistin is complicated because human resistin is secreted by macrophages rather than adipocytes, and because of the descriptive nature of human epidemiology. Here we review the recent and growing evidence that human resistin is an inflammatory biomarker and potential mediator of diabetes and cardiovascular disease.
PMCID: PMC3130099  PMID: 21497511
22.  Noninvasive Imaging of the Foveal Avascular Zone with High-Speed, Phase-Variance Optical Coherence Tomography 
This study demonstrates two- and three-dimensional capillary networks of the human parafoveal region without use of any contrast agents or adaptive optics. Phase-variance optical coherence tomography provides precise measurement of the foveal avascular zone area from one single volumetric scan within 5-second acquisition time.
To demonstrate the application of phase-variance optical coherence tomography (pvOCT) for contrast agent–free in vivo imaging of volumetric retinal microcirculation in the human foveal region and for extraction of foveal avascular zone dimensions.
A custom-built, high-speed Fourier-domain OCT retinal imaging system was used to image retinas of two healthy subjects and eight diabetic patients. Through the acquisition of multiple B-scans for each scan location, phase differences between consecutive scans were extracted and used for phase-variance contrast, identifying motion signals from within blood vessels and capillaries. The en face projection view of the inner retinal layers segmented out from volumetric pvOCT data sets allowed visualization of a perfusion network with the foveal avascular zone (FAZ). In addition, the authors presented 2D retinal perfusion maps with pseudo color-coded depth positions of capillaries.
Retinal vascular imaging with pvOCT provides accurate measurements of the FAZ area and its morphology and a volumetric perfusion map of microcapillaries. In this study using two images from each fundus fluorescein angiography (FA) and pvOCT, the measured average areas of the FAZ from two healthy subjects were below 0.22 mm2, and each of eight diabetic patients had an enlarged FAZ area, larger than 0.22 mm2. Moreover, the FAZ areas demonstrated a significant correlation (r = 0.91) between measurements from FA and pvOCT.
The high-speed pvOCT allows contrast agent–free visualization of capillary networks in the human foveal region that is analogous to fundus FA imaging. This could allow for noninvasive diagnosis and progression monitoring of diabetic retinopathy in clinical settings.
PMCID: PMC3292386  PMID: 22125275
23.  Single-molecule resolution of interfacial fibrinogen behavior: Effects of oligomer populations and surface chemistry 
Using single-molecule total internal reflection fluorescence microscopy, the dynamic behavior of fibrinogen was observed at the interface between aqueous solution and various solid surfaces. Multiple populations of objects were observed, as characterized by surface residence times, interfacial diffusion, and fluorescence intensity. On all surfaces, populations exhibited direct links between surface residence time, rate of diffusion and fluorescence intensity. In particular longer-lived populations diffused more slowly and exhibited greater fluorescence intensity, leading to the conclusion that the objects represented fibrinogen monomers and discrete oligomer populations (dimers, trimers, etc.), and that these oligomer populations play an important role in the protein-surface interaction because of their long surface residence times. Two or three diffusive modes were observed for most populations, indicating that protein aggregates have multiple mechanisms for interaction with solid substrates. In addition, the fastest diffusive mode is believed to represent a hopping mode that often precedes desorption events. Surprisingly, a monolayer of PEG(5000) increased surface residence time and slowed diffusion of fibrinogen relative to bare fused silica or hydrophobically-modified fused silica, suggesting that the mechanism of PEG resistance to protein adhesion is more sophisticated than the simple repulsion of individual proteins.
PMCID: PMC3077424  PMID: 21391676
24.  Evaluation of deficiencies in current discharge summaries for dialysis patients in Canada 
Deficits in the transfer of information between inpatient and outpatient physicians are common and pose a patient safety risk. This is particularly the case for vulnerable populations such as patients with end-stage renal disease requiring dialysis. These patients have unique and complex health care needs that may not be effectively communicated on standard discharge summaries, which may result in potential medical errors and adverse events.
To evaluate Canadian dialysis center directors’ perceptions of deficiencies in the content and quality of hospital discharge summaries for dialysis patients.
A web-based, cross-sectional survey of Canadian dialysis center directors was performed between September and November 2010. The survey consisted of three parts. The first part was designed to assess dialysis center directors’ attitudes on the quality of discharge summaries they receive. The second part was designed to elicit respondents’ preferences for discharge summary content, and the third part consisted of questions regarding demographic and practice information.
Of 79 dialysis center directors, 21 (27%) completed the survey. Sixty-two percent felt that current discharge summaries inadequately communicate dialysis-specific information. Receipt of antibiotics for line sepsis or peritonitis, modifications to vascular access, and changes in target weight/dialysis prescription were rated as essential dialysis-specific information to include in discharge summaries by respondents.
Over three quarters of dialysis center directors find the current practice of transferring discharge information for hospitalized dialysis patients grossly inadequate. The inclusion of dialysis-specific information may improve the quality of discharge summaries for dialysis patients.
PMCID: PMC3333802  PMID: 22536078
information transfer; dialysis patients; discharge information

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