Meniere's disease. A neuropsychological study

A neuro-psychological study is described comprising 19 patients with Meniere's Disease who were participating in an experimental lithium therapy programme. The patients evidenced an organic dysfunction which is not entirely periphearl. The interpretation of the results are not incompatible with an attempt to reconcile neuro-psychological and psycho-somatic viewpoints regarding etiological aspects of Meniere's Disease. An evaluation of the lithium effect was performed.     

General strategy for biosensor design and construction employing multifunctional surface-tethered components

Biosensors function by reversibly linking bioreceptor-target analyte binding with closely integrated signal generation and can either continuously monitor analyte concentrations or be returned to baseline readout values by removal of analyte. We present an approach for producing fully reversible, reagentless, self-assembling biosensors on surfaces. In the prototype biosensor, quencher-dye-labeled biotin-linked E. coli maltose binding protein (MBP) bound in a specific orientation to a NeutrAvidin-coated surface is employed as a bioreceptor. To complete sensor formation, a modular tether arm consisting of a flexible biotinylated DNA oligonucleotide, a fluorescence resonance energy-transfer (FRET) donor dye, and a distal beta-cyclodextrin (beta-CD) analyte analogue is bound in an equimolar amount to the same surface by means of DNA-directed immobilization. After self-assembly, a baseline level of FRET quenching is observed due to specific interaction between the beta-CD of the flexible tether arm and the sugar binding site of MBP, which brings the two dyes into proximity. Addition of the target analyte, the nutrient maltose, displaces the linked beta-CD-dye of the DNA-based tether arm, and a concentration-dependent change in FRET results. Biosensor sensitivity and dynamic range can be controlled by either using MBP variants having different binding constants or by binding of modulator DNA oligonucleotides that are complementary to the flexible DNA tether. The sensor can be regenerated and returned to baseline quenching levels by washing away analyte. A complex set of interactions apparently exists on the sensing surface that may contribute to sensor behavior and range. This approach may represent a general way to assemble a wide range of useful biosensors.     

Multiplexed toxin analysis using four colors of quantum dot fluororeagents

Quantum dots (QDs) have the potential to simplify the performance of multiplexed analysis. In this work, we prepared bioinorganic conjugates made with highly luminescent semiconductor nanocrystals (CdSe-ZnS core-shell QDs) and antibodies to perform multiplexed fluoroimmunoassays. Sandwich immunoassays for the detection of cholera toxin, ricin, shiga-like toxin 1, and staphylococcal enterotoxin B were performed simultaneously in single wells of a microtiter plate. Initially the assay performance for the detection of each toxin was examined. We then demonstrated the simultaneous detection of the four toxins from a single sample probed with a mixture of all four QD-antibody reagents. Using a simple linear equation-based algorithm, it was possible to deconvolute the signal from mixed toxin samples, which allowed quantitation of all four toxins simultaneously.     

Self-assembled nanoscale biosensors based on quantum dot FRET donors

The potential of luminescent semiconductor quantum dots (QDs) to enable development of hybrid inorganic-bioreceptor sensing materials has remained largely unrealized. We report the design, formation and testing of QD-protein assemblies that function as chemical sensors. In these assemblies, multiple copies of Escherichia coli maltose-binding protein (MBP) coordinate to each QD by a C-terminal oligohistidine segment and function as sugar receptors. Sensors are self-assembled in solution in a controllable manner. In one configuration, a beta-cyclodextrin-QSY9 dark quencher conjugate bound in the MBP saccharide binding site results in fluorescence resonance energy-transfer (FRET) quenching of QD photoluminescence. Added maltose displaces the beta-cyclodextrin-QSY9, and QD photoluminescence increases in a systematic manner. A second maltose sensor assembly consists of QDs coupled with Cy3-labelled MBP bound to beta-cyclodextrin-Cy3.5. In this case, the QD donor drives sensor function through a two-step FRET mechanism that overcomes inherent QD donor-acceptor distance limitations. Quantum dot-biomolecule assemblies constructed using these methods may facilitate development of new hybrid sensing materials.     

Multiple-Instance Learning of Real-Valued Geometric Patterns

Recently there has been significant research in multiple-instance learning, yet most of this work has only considered this model when there are Boolean labels. However, in many of the application areas for which the multiple-instance model fits, real-valued labels are more appropriate than Boolean labels. We define and study a real-valued multiple-instance model in which each multiple-instance example (bag) is given a real-valued label in [0, 1] that indicates the degree to which the bag satisfies the target concept. To provide additional structure to the learning problem, we associate a real-valued label with each point in the bag. These values are then combined using a real-valued aggregation operator to obtain the label for the bag. We then present on-line agnostic algorithms for learning real-valued multiple-instance geometric concepts defined by axis-aligned boxes in constant-dimensional space and describe several possible applications of these algorithms. We obtain our learning algorithms by reducing the problem to one in which the exponentiated gradient or gradient descent algorithm can be used. We also give a novel application of the virtual weights technique. In typical applications of the virtual weights technique, all of the concepts in a group have the same weight and prediction, allowing a single representative concept from each group to be tracked. However, in our application there are an exponential number of different weights and possible predictions. Hence, boxes in each group have different weights and predictions, making the computation of the contribution of a group significantly more involved. However, we are able to both keep the number of groups polynomial in the number of trials and efficiently compute the overall prediction.     

Role of blood shear stress in the regulation of vascular smooth muscle cell migration

Smooth muscle cell (SMC) migration from the media to the intima of blood vessels contributes to neointimal formation and atherogenesis. Here, we demonstrate how blood shear stress regulates vascular SMC migration in the encapsulating tissue of a micro-cylinder implanted in the center of the rat vena cava with the micro-cylinder perpendicular to blood flow. In this model, the micro-cylinder was exposed to a laminar flow with a known shear stress field in the leading region and a vortex flow in the trailing region. After surgery, the micro-cylinder was encapsulated by a thrombus-like tissue within one day, followed by SMC migration from the vena cava to the encapsulating tissue from day 3 to 20. SMC migration was time-dependent with a peak migration speed at day 5. At each given time (excluding day 1), blood shear stress exerts an inhibitory effect on SMC migration with significantly suppressed SMC migration in the laminar flow region than in the stagnation, separation, and vortex flow regions. SMCs were relatively parallel to the shear stress direction in high shear stress regions, whereas perpendicular to the shear stress direction in low shear stress regions. These results suggest that blood shear stress plays a role in regulating SMC migration and orientation in this model.