Influences of luminance and accommodation stimuli on pupil size and pupil center location

PURPOSE. To investigate effects of luminance and accommodation stimuli on pupil size and pupil center location and their implications for progressive addition lens wear. METHODS. Participants were young and older adult groups (n=20, 22±2 years, age range 18-25 years; n=19, 49±4 years, 45-58 years). A wave aberrometer included a relay system to allow a 12.5°x11° background for the internal fixation target. Participants viewed the target under a matrix of conditions with luminance levels 0.01, 3.7, 120 and 6100 cd/m² and with accommodation stimuli up to 6 diopters in 2 diopter steps. Pupil sizes and their centers, relative to limbus centers, were determined from anterior eye images. RESULTS. With luminance increase, reduction in pupil size was accentuated by increase in accommodation stimulus in the young, but not in the older, group. As luminance increased, pupil center location altered. This was nasally in both groups with an average shift of approximately 0.12mm. Relative to the lowest stimulus condition, the mean of the maximum absolute pupil center shifts was 0.26±0.08mm for both groups with individual shifts up to 0.5mm, findings consistent with previous studies. There was no significant effect of accommodation on pupil center locations for either age group, or evidence that location was influenced by the combination of luminance and accommodation stimulus that resulted in any particular pupil size. CONCLUSIONS. Variations in luminance and accommodation influence pupil size, but only the former affects pupil center location significantly. Pupil center shifts are too small to be of concern in fitting progressive addition lenses.

The short-term accommodation response to aniso-accommodative stimuli in isometropia

Purpose There have been only a limited number of studies examining the accommodative response that occurs when the two eyes are provided with disparate accommodative stimuli, and the results from these studies to date have been equivocal. In this study, we therefore aimed to examine the capacity of the visual system to aniso-accommodate by objectively measuring the interocular difference in the accommodation response between fellow dominant and non-dominant eyes under controlled monocular and binocular viewing conditions during short-term exposure to aniso-accommodative stimuli. Methods The accommodative response of each eye of sixteen young isometropic adults (mean age 22 ± 2 years) with normal binocular vision was measured using an open-field autorefractor during a range of testing conditions; monocularly (accommodative demands ranging from 1.32 to 4.55 D) and binocularly while altering the accommodation demand for each eye (aniso-accommodative stimuli ranging from 0.24 to 2.05 D). Results Under monocular viewing conditions, the dominant and non-dominant eyes displayed a highly symmetric accommodative response; mean interocular difference in spherical equivalent 0.01 ± 0.06 D (relative) and 0.22 ± 0.06 D (absolute) (p>0.05). During binocular viewing, the dominant eye displayed a greater accommodative response (0.11 ± 0.34 D relative and 0.24 ± 0.26 D absolute) irrespective of whether the demand of the dominant or non-dominant eye was altered (p = 0.01). Astigmatic power vectors J0 and J45 did not vary between eyes or with increasing accommodation demands under monocular or binocular viewing conditions (p>0.05). Conclusion The dominant and non-dominant eyes of young isometropic individuals display a similar consensual lag of accommodation under both monocular and binocular viewing conditions, with the dominant eye showing a small but significantly greater (by 0.12 to 0.25 D) accommodative response. Evidence of short-term aniso-accommodation in response to asymmetric accommodation demands was not observed.

Photochemical design of stimuli-responsive nanoparticles prepared by supramolecular host–guest chemistry

We introduce the design of a thermoresponsive nanoparticle via sacrificial micelle formation based on supramolecular host–guest chemistry. Reversible addition–fragmentation chain transfer (RAFT) polymerization was employed to synthesize well-defined polymer blocks of poly(N,N-dimethylacrylamide) (poly(DMAAm)) (Mn,SEC = 10 700 g mol–1, Đ = 1.3) and poly(N-isopropylacrylamide) (poly(NiPAAm)) (Mn,SEC = 39 700 g mol–1, Đ = 1.2), carrying supramolecular recognition units at the chain termini. Further, 2-methoxy-6-methylbenzaldehyde moieties (photoenols, PE) were statistically incorporated into the backbone of the poly(NiPAAm) block as photoactive cross-linking units. Host–guest interactions of adamantane (Ada) (at the terminus of the poly(NiPAAm/PE) chain) and β-cyclodextrin (CD) (attached to the poly(DMAAm chain end) result in a supramolecular diblock copolymer. In aqueous solution, the diblock copolymer undergoes micellization when heated above the lower critical solution temperature (LCST) of the thermoresponsive poly(NiPAAm/PE) chain, forming the core of the micelle. Via the addition of a 4-arm maleimide cross-linker and irradiation with UV light, the micelle is cross-linked in its core via the photoinduced Diels–Alder reaction of maleimide and PE units. The adamantyl–cyclodextrin linkage is subsequently cleaved by the destruction of the β-CD, affording narrowly distributed thermoresponsive nanoparticles with a trigger temperature close to 30 °C. Polymer chain analysis was performed via size exclusion chromatography (SEC), nuclear magnetic resonance (NMR) spectroscopy, and dynamic light scattering (DLS). The size and thermoresponsive behavior of the micelles and nanoparticles were investigated via DLS as well as atomic force microscopy (AFM).

Proinflammatory cytokines regulate cementogenic differentiation of periodontal ligament cells by Wnt/Ca2+ signaling pathway

Periodontal inflammation can inhibit cell differentiation of periodontal ligament cells (PDLCs), resulting in decreased bone/cementum regeneration ability. The Wnt signaling pathway, including canonical Wnt/β-catenin signaling and noncanonical Wnt/Ca2+ signaling, plays essential roles in cell proliferation and differentiation during tooth development. However, little is still known whether noncanonical Wnt/Ca2+ signaling cascade could regulate cementogenic/osteogenic differentiation capability of PDLCs within an inflammatory environment. Therefore, in this study, human PDLCs (hPDLCs) and their cementogenic differentiation potential were investigated in the presence of cytokines. The data demonstrated that both cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) inhibited cell proliferation, relative alkaline phosphatase activity, bone/cementum-related gene/protein expression, and canonical Wnt pathway-related gene/protein expression in hPDLCs. Interestingly, both cytokines upregulated the noncanonical Wnt/Ca2+ signaling-related gene and protein expression in hPDLCs. When the Wnt/Ca2+ pathway was blocked by Ca2+/calmodulin-dependent protein kinase II inhibitor KN93, even in the presence of IL-6 and TNF-α, cementogenesis could be stimulated in hPDLCs. Our data indicate that the Wnt/Ca2+ pathway plays an inhibitory role on PDLC cementogenic differentiation in inflammatory microenvironments. Therefore, targeting the Wnt/Ca2+ pathway may provide a novel therapeutic approach to improve periodontal regeneration for periodontal diseases.

Innate immunity and its control in the pathogenesis of inflammatory rheumatic diseases

The pathogenesis of inflammatory rheumatic diseases, including rheumatoid arthritis (RA) and spondyloarthropathies (SpAs) such as reactive arthritis (ReA), is incompletely understood. ReA is a sterile joint inflammation, which may follow a distal infection caused by Gram-negative bacteria that have lipopolysaccharide (LPS) in their outer membrane. The functions of innate immunity that may affect the pathogenesis, prognosis and treatment of these diseases were studied in this thesis. When compared with healthy controls, whole blood monocytes of healthy subjects with previous ReA showed enhanced capacity to produce TNF, an essential proinflammatory cytokine, in response to adherent conditions (mimicking vascular endothelium made adherent by inflammatory signals) and non-specific protein kinase C stimulation. Also, blood neutrophils of these subjects showed high levels of CD11b, an important adhesion molecule, in response to adherence or LPS. Thus, high responsiveness of monocytes and neutrophils when encountering inflammatory stimuli may play a role in the pathogenesis of ReA. The results also suggested that the known risk allele for SpAs, HLA-B27, may be an additive contributor to the observed differences. The promoter polymorphisms TNF 308A and CD14 (gene for an LPS receptor component) 159T were found not to increase the risk of acute arthritis. However, all female patients who developed chronic SpA had 159T and none of them had 308A, possibly reflecting an interplay between hormonal and inflammatory signals in the development of chronic SpA. Among subjects with early RA, those having the polymorphic TLR4 +896G allele (causing the Asp299Gly change in TLR4, another component of LPS receptor) required a combination of disease-modifying antirheumatic drugs to achieve remission. It is known that rapid treatment response is essential in order to maintain the patients work ability. Hence, +896G might be a candidate marker for identifying the patients who need combination treatment. The production of vascular endothelial growth factor (VEGF), which strongly promotes vascular permeability and angiogenesis that takes place e.g. early in rheumatic joints, was induced by LPS and inhibited by interferon (IFN)-alpha in peripheral blood mononuclear cells. These long-living cells might provide a source of VEGF when stimulated by LPS and migrating to inflamed joints, and the effect of IFN-alpha may contribute to the clinical efficacy of this cytokine in inhibiting joint inflammation.

The mast cell as a regulator of atherosclerotic plaque stability

Atherosclerosis is an inflammatory disease progressing over years via the accumulation of cholesterol in arterial intima with subsequent formation of atherosclerotic plaques. The stability of a plaque is determined by the size of its cholesterol-rich necrotic lipid core and the thickness of the fibrous cap covering it. The strength and thickness of the cap are maintained by smooth muscle cells and the extracellular matrix produced by them. A plaque with a large lipid core and a thin cap is vulnerable to rupture that may lead to acute atherothrombotic events, such as myocardial infarction and stroke. In addition, endothelial erosion, possibly induced by apoptosis of endothelial cells, may lead to such clinical events. One of the major causes of plaque destabilization is inflammation induced by accumulated and modified lipoproteins, and exacerbated by local aberrant shear stress conditions. Macrophages, T-lymphocytes and mast cells infiltrate particularly into the plaque’s shoulder regions prone to atherothrombotic events, and they are present at the actual sites of plaque rupture and erosion. Two major mechanisms of plaque destabilization induced by inflammation are extracellular matrix remodeling and apoptosis. Mast cells are bone marrow-derived inflammatory cells that as progenitors upon chemotactic stimuli infiltrate the target tissues, such as the arterial wall, differentiate in the target tissues and mediate their effects via the release of various mediators, typically in a process called degranulation. The released preformed mast cell granules contain proteases such as tryptase, chymase and cathepsin G bound to heparin and chondroitin sulfate proteoglycans. In addition, various soluble mediators such as histamine and TNF-alpha are released. Mast cells also synthesize many mediators such as cytokines and lipid mediators upon activation. Mast cells are capable of increasing the level of LDL cholesterol in the arterial intima by increasing accumulation and retention of LDL and by decreasing removal of cholesterol by HDL in vitro. In addition, by secreting proinflammatory mediators and proteases, mast cells may induce plaque destabilization by inducing apoptosis of smooth muscle and endothelial cells. Also in vivo data from apoE-/- and ldlr-/- mice suggest a role for mast cells in the progression of atherosclerosis. Furthermore, mast cell-deficient mice have become powerful tools to study the effects of mast cells in vivo. In this study, evidence suggesting a role for mast cells in the regulation of plaque stability is presented. In a mouse model genetically susceptible to atherosclerosis, mast cell deficiency (ldlr-/-/KitW-sh/W-sh mice) was associated with a less atherogenic lipid profile, a decreased level of lipid accumulation in the aortic arterial wall and a decreased level of vascular inflammation as compared to mast-cell competent littermates. In vitro, mast cell chymase-induced smooth muscle cell apoptosis was mediated by inhibition of NF-kappaB activity, followed by downregulation of bcl-2, release of cytochrome c, and activation of caspase-8, -9 and -3. Mast cell-induced endothelial cell apoptosis was mediated by chymase and TNF-alpha, and involved chymase-mediated degradation of fibronectin and vitronectin, and inactivation of FAK- and Akt-mediated survival signaling. Subsequently, mast cells induced inhibition of NF-kappaB activity and activation of caspase-8 and -9. In addition, possible mast cell protease-mediated mechanisms of endothelial erosion may include degradation of fibronectin and VE-cadherin. Thus, the present results suggest a role for mast cells in destabilization of atherosclerotic plaques.

Investigating online reading with eye tracking and EEG : The influence of text format, reading task and parafoveal stimuli on reading processes

Research on reading has been successful in revealing how attention guides eye movements when people read single sentences or text paragraphs in simplified and strictly controlled experimental conditions. However, less is known about reading processes in more naturalistic and applied settings, such as reading Web pages. This thesis investigates online reading processes by recording participants eye movements. The thesis consists of four experimental studies that examine how location of stimuli presented outside the currently fixated region (Study I and III), text format (Study II), animation and abrupt onset of online advertisements (Study III), and phase of an online information search task (Study IV) affect written language processing. Furthermore, the studies investigate how the goal of the reading task affects attention allocation during reading by comparing reading for comprehension with free browsing, and by varying the difficulty of an information search task. The results show that text format affects the reading process, that is, vertical text (word/line) is read at a slower rate than a standard horizontal text, and the mean fixation durations are longer for vertical text than for horizontal text. Furthermore, animated online ads and abrupt ad onsets capture online readers attention and direct their gaze toward the ads, and distract the reading process. Compared to a reading-for-comprehension task, online ads are attended to more in a free browsing task. Moreover, in both tasks abrupt ad onsets result in rather immediate fixations toward the ads. This effect is enhanced when the ad is presented in the proximity of the text being read. In addition, the reading processes vary when Web users proceed in online information search tasks, for example when they are searching for a specific keyword, looking for an answer to a question, or trying to find a subjectively most interesting topic. A scanning type of behavior is typical at the beginning of the tasks, after which participants tend to switch to a more careful reading state before finishing the tasks in the states referred to as decision states. Furthermore, the results also provided evidence that left-to-right readers extract more parafoveal information to the right of the fixated word than to the left, suggesting that learning biases attentional orienting towards the reading direction.

Intermittent electrical stimuli for guidance of human mesenchymal stem cell lineage commitment towards neural-like cells on electroconductive substrates

In the context of the role of multiple physical factors in dictating stem cell fate, the present paper demonstrates the effectiveness of the intermittently delivered external electric field stimulation towards switching the stem cell fate to specific lineage, when cultured in the absence of biochemical growth factors. In particular, our findings present the ability of human mesenchymal stem cells (hMSCs) to respond to the electric stimuli by adopting extended neural-like morphology on conducting polymeric substrates. Polyaniline (PANI) is selected as the model system to demonstrate this effect, as the electrical conductivity of the polymeric substrates can be systematically tailored over a broad range (10(-9) to 10 S/cm) from highly insulating to conducting by doping with varying concentrations (10(-5) to 1 M) of HCl. On the basis of the culture protocol involving the systematic delivery of intermittent electric field (dc) stimulation, the parametric window of substrate conductivity and electric field strength was established to promote significant morphological extensions, with minimal cellular damage. A time dependent morphological change in hMSCs with significant filopodial elongation was observed after 7 days of electrically stimulated culture. Concomitant with morphological changes, a commensurate increase in the expression of neural lineage commitment markers such as nestin and PI tubulin was recorded from hMSCs grown on highly conducting substrates, as revealed from the mRNA expression analysis using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) as well as by immune-fluorescence imaging. Therefore, the present work establishes the key role of intermittent and systematic delivery of electric stimuli as guidance cues in promoting neural-like differentiation of hMSCs, when grown on electroconductive substrates. (C) 2014 Elsevier Ltd. All rights reserved.

Charge Transfer Induces Formation of Stimuli-Responsive, Chiral, Cohesive Vesicles-on-a-String that Eventually Turn into a Hydrogel

A charge transfer (CT) mediated two-component, multistimuli responsive supergelation involving a L-histidine-appended pyrenyl derivative (PyHisOMe) as a donor and an asymmetric bolaamphiphilic naphthalene-diimide (Asym-NDI) derivative as an acceptor in a 2: 1 mixture of H2O/MeOH was investigated. Asym-NDI alone self-assembled into pH-responsive vesicular nanostructures in water. Excellent selectivity in CT gel formation was achieved in terms of choosing amino acid appended pyrenyl donor scaffolds. Circular di-chroism and morphological studies suggested formation of chiral, interconnected vesicular assemblies resembling ``pearls-on-a-string'' from these CT mixed stacks. XRD studies revealed the formation of monolayer lipid membranes from these CT mixed stacks that eventually led to the formation of individual vesicles. Strong cohesive forces among the interconnected vesicles originate from the protrusion of the oxyethylene chains from the surfaces of the chiral vesicles.

Differential viability response of prokaryotes and eukaryotes to high strength pulsed magnetic stimuli

The present study examines the efficacy of a high strength pulsed magnetic field (PMF) towards bacterial inactivation in vitro, without compromising eukaryotic cell viability. The differential response of prokaryotes Staphylococcus aureus (MESA), Staphylococcus epidermidis, and Escherichia coli], and eukaryotes C2C12 mouse myoblasts and human mesenchymal stem cells, hMSCs] upon exposure to varying PMF stimuli (1-4 T, 30 pulses, 40 ms pulse duration) is investigated. Among the prokaryotes, similar to 60% and similar to 70% reduction was recorded in the survival of staphylococcal species and E. coli, respectively at 4 T PMF as evaluated by colony forming unit (CPU) analysis and flow cytometry. A 2-5 fold increase in intracellular ROS (reactive oxygen species) levels suggests oxidative stress as the key mediator in PMF induced bacterial death/injury. The 4 T PMF treated staphylococci also exhibited longer doubling times. Both TEM and fluorescence microscopy revealed compromised membranes of PMF exposed bacteria. Under similar PMF exposure conditions, no immediate cytotoxicity was recorded in C2C12 mouse myoblasts and hMSCs, which can be attributed to the robust resistance towards oxidative stress. The ion interference of iron containing bacterial proteins is invoked to analytically explain the PMF induced ROS accumulation in prokaryotes. Overall, this study establishes the potential of PMF as a bactericidal method without affecting eukaryotic viability. This non-invasive stimulation protocol coupled with antimicrobial agents can be integrated as a potential methodology for the localized treatment of prosthetic infections. (C) 2015 Elsevier B.V. All rights reserved.

Stimuli-responsive weak polyelectrolyte multilayer films: A thin film platform for self triggered multi-drug delivery

Polyelectrolyte multilayer (PEM) thin film composed of weak polyelectrolytes was designed by layer-by-layer (LbL) assembly of poly(allylamine hydrochloride) (PAH) and poly(methacrylic acid) (PMA) for multi-drug delivery applications. Environmental stimuli such as pH and ionic strength showed significant influence in changing the film morphology from pore-free smooth structure to porous structure and favored triggered release of loaded molecules. The film was successfully loaded with bovine serum albumin (BSA) and ciprofloxacin hydrochloride (CH) by modulating the porous polymeric network of the film. Release studies showed that the amount of release could be easily controlled by changing the environmental conditions such as pH and ionic strength. Sustained release of loaded molecules was observed up to 8 h. The fabricated films were found to be biocompatible with epithelial cells during in-vitro cell culture studies. PEM film reported here not only has the potential to be used as self-responding thin film platform for transdermal drug delivery, but also has the potential for further development in antimicrobial or anti-inflammatory coatings on implants and drug-releasing coatings for stents. (C) 2015 Elsevier B.V. All rights reserved.

Stimuli-responsive protamine-based biodegradable nanocapsules for enhanced bioavailability and intracellular delivery of anticancer agents

Enzyme-and pH-responsive polyelectrolyte nanocapsules having diameters in the range of 200 +/- 20 nm were fabricated by means of Layer-by-Layer assembly of biopolymers, protamine, and heparin, and then loaded with anticancer drug doxorubicin. The incorporation of the FDA-approved peptide drug protamine as a wall component rendered the capsules responsive to enzyme stimuli. The stimuli-responsive drug release from these nanocapsules was evaluated, and further modulation of capsule permeability to avoid premature release was demonstrated by crosslinking the wall components. The interaction of the nanocapsules with cancer cells was studied using MCF-7 breast cancer cells. These capsules were readily internalized and disintegrated inside the cells, culminating in the release of the loaded doxorubicin and subsequent cell death as observed by confocal microscopy and MTT Assay. The bioavailability studies performed using BALB/c mice revealed that the encapsulated doxorubicin exhibited enhanced bioavailability compared to free doxorubicin. Our results indicate that this stimuli-responsive system fabricated from clinically used FDA-approved molecules and exhibiting minimal premature release has great potential for drug-delivery applications.

Stimuli-responsive protamine-based biodegradable nanocapsules for enhanced bioavailability and intracellular delivery of anticancer agents

Enzyme-and pH-responsive polyelectrolyte nanocapsules having diameters in the range of 200 +/- 20 nm were fabricated by means of Layer-by-Layer assembly of biopolymers, protamine, and heparin, and then loaded with anticancer drug doxorubicin. The incorporation of the FDA-approved peptide drug protamine as a wall component rendered the capsules responsive to enzyme stimuli. The stimuli-responsive drug release from these nanocapsules was evaluated, and further modulation of capsule permeability to avoid premature release was demonstrated by crosslinking the wall components. The interaction of the nanocapsules with cancer cells was studied using MCF-7 breast cancer cells. These capsules were readily internalized and disintegrated inside the cells, culminating in the release of the loaded doxorubicin and subsequent cell death as observed by confocal microscopy and MTT Assay. The bioavailability studies performed using BALB/c mice revealed that the encapsulated doxorubicin exhibited enhanced bioavailability compared to free doxorubicin. Our results indicate that this stimuli-responsive system fabricated from clinically used FDA-approved molecules and exhibiting minimal premature release has great potential for drug-delivery applications.