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PubMed2006

Stochastic models of decisions about motion direction: behavior and physiology.

Roitman and Shadlen [Roitman J. D., & Shadlen M. N. (2002). Response of neurons in the lateral intraparietal area during a combined visual discrimination reaction time task. Journal of Neuroscience, 22, 9475-9489] have published a non-human primate study on visual decision making. They collected both behavioral and neurophysiological data and provided evidence that the data are qualitatively consistent with a mechanism based on accumulating sensory evidence up to a decision threshold. I have previously demonstrated that a time-variant diffusion model can account quite well quantitatively for both the behavioral and the neural data. In this manuscript I discuss how well the data constrains different components and parameters of the computational process. I also discuss the biological plausibility of the model parameters. I will demonstrate that a relatively large class of models, both with and without temporal integration and both stationary and time-variant could account for the behavioral data. Both the single cell recordings from the parietal cortex and previously published data from the extrastriate visual cortex provide additional constraints. Overall, the data favor a diffusion model with time-variant gain and leaky integrators. The integration time constant, however, turns out not to be well-constrained by the data.

Action Potentials↗
PubMed2001

Noninvasive vasectomy using a focused ultrasound clip: thermal measurements and simulations.

INTRODUCTION: Conventional surgical vasectomy may lead to complications including bleeding, infection, and scrotal pain. Noninvasive transcutaneous delivery of therapeutic focused ultrasound has previously been shown to thermally occlude the vas deferens. However, skin burns and inconsistent vas occlusion have presented complications. This study uses bio-heat transfer simulations and thermocouple measurements to determine the optimal ablation dosimetry for vas occlusion without skin burns. METHODS: A 2-rad ultrasound transducer mounted on a vasectomy-clip-delivered ultrasound energy at 4 MHz to the canine vas deferens co-located at the focus between the clip jaws. Chilled degassed water was circulated through an attached latex balloon, providing efficient ultrasound coupling into the tissue and active skin cooling to prevent skin burns. Thermocouples placed at the vas, intradermal, and skin surface locations recorded temperatures during ablation. Procedures were performed with transducer acoustic powers of 3-7 W and sonication times of 60-120 s on both the left and right vas deferens (n = 2) in a total of four dogs (precooling control, 3 W/120 s, 5 W/90 s, 7 W/60 s). Measurements were compared with bio-heat transfer simulations modeling the effects of variations in power and sonication time on tissue temperatures and coagulation zones. RESULTS: Active skin cooling produces a thermal gradient in the tissue during ablation, allowing sufficient thermal doses to be delivered to the vas without skin burns. However, low-power, long-duration heating produced excessive tissue necrosis due to thermal diffusion, while high power and short heating times reduced the therapeutic window and produced skin burns presumably due to direct ultrasound absorption. CONCLUSIONS: Both simulations and experiments suggest that a therapeutic window exists in which thermal occlusion of the vas may be achieved without the formation of skin burns in the canine model (power = 5-7 W, surface intensity = 1.4-1.9 W/cm2, time = 20-50 s). This range of ablation parameters will help guide future experiments to refine incisionless vasectomy using focused ultrasound.

Animals↗
PubMed1980

The measurement of rectal and testis temperature in conscious mice, with observations on the effect of direct heating.

The application of Newton's law of cooling to freshly killed mice was found not to measure accurately their rectal or testis temperature. Improvements in the fitting process gave satisfactory results for rectal temperature only. A diffusion model was applied to testis cooling but was of no avail. Finally a satisfactory correction factor was determined empirically. This method was applied to conscious mice whose hindquarters were immersed in a stirred oilbath at 34 to 42 degrees C for 1 h, and to controls. It was found that both rectal and testis temperatures increased with bath temperature, producing a graph with a slope of only 0.5, indicating a regulatory capacity. Conscious mice, but not anaesthetised, can maintain a testis temperature of 39 degrees C in a bath at 42 degrees C.

Animals↗
PubMed2004

Ion permeation through the alpha-hemolysin channel: theoretical studies based on Brownian dynamics and Poisson-Nernst-Plank electrodiffusion theory.

Identification of the molecular interaction governing ion conduction through biological pores is one of the most important goals of modern electrophysiology. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) and three-dimensional Poisson-Nernst-Plank (3d-PNP) electrodiffusion algorithms offer powerful and general approaches to study of ion permeation through wide molecular pores. A detailed analysis of ion flows through the staphylococcal alpha-hemolysin channel based on series of simulations at different concentrations and transmembrane potentials is presented. The position-dependent diffusion coefficient is approximated on the basis of a hydrodynamic model. The channel conductance calculated by GCMC/BD is approximately 10% higher than (electrophysiologically measured) experimental values, whereas results from 3d-PNP are always 30-50% larger. Both methods are able to capture all important electrostatic interactions in equilibrium conditions. The asymmetric conductance upon the polarity of the transmembrane potential observed experimentally is reproduced by GCMC/BD and 3d-PNP. The separation of geometrical and energetic influence of the channel on ion conduction reveals that such asymmetries arise from the permanent charge distribution inside the pore. The major determinant of the asymmetry is unbalanced charge in the triad of polar residues D127, D128, and K131. The GCMC/BD or 3d-PNP calculations reproduce also experimental reversal potentials and permeability rations in asymmetric ionic solutions. The weak anionic selectivity of the channel results from the presence of the salt bridge between E111 and K147 in the constriction zone. The calculations also reproduce the experimentally derived dependence of the reversible potential to the direction of the salt gradient. The origin of such effect arises from the asymmetrical distribution of energetic barriers along the channel axis, which modulates the preferential ion passage in different directions.

Bacterial Toxins↗
PubMed2004

Theoretical modeling and experimental evaluation of a microscale molecular mass sensor.

A theoretical model for a recently developed microscale molecular mass sensor (micro-MMS) is presented. The micro-MMS employs a widely applicable technique of measuring the refractive index gradient (RIG) in a microchannel created after two adjacent streams merge: a "sample stream" containing analyte(s) of interest in a host solvent and a "mobile-phase" stream containing only the host solvent. Because the flow in the microchannel is laminar, the analytes in the sample stream mix with the mobile-phase stream primarily by diffusion. The diffusion-induced RIG in the microchannel is measured by monitoring the deflection angle of a diode laser probe beam, which is orthogonal to both the direction of flow and the direction of analyte diffusion. The micro-MMS samples the RIG with probe beams at two positions along the direction of flow, and the ratio of the downstream to the upstream signal monitors the diffusion coefficient. Following calibration for a given class of compounds, the molecular mass of an analyte of interest can be determined. Along with the analyte diffusion coefficient, the theoretical model indicated three other specific parameters are important to interpret the micro-MMS output: the radius of the interrogating light probe beams, the time intervals between each of the detection positions, and the merge point relative to the detection positions. A series of experiments were conducted at different beam radii and flow rates to investigate these parameters, and the results are consistent with the model. The model shows that by using smaller beam radii and altering flow rates the molecular mass range of the micro-MMS can be, in principle, tuned from less than 10(2) g/mol to greater than 10(8) g/mol. The ratio data from the micro-MMS is also demonstrated to readily provide a "universal calibration", from which the determination of unknown diffusion coefficients can be readily obtained.

Journal Article↗
PubMed1985

Temperatures within comet nuclei.

We have performed a theoretical study of temperatures beneath the surface of a comet's nucleus. We solve the one-dimensional heat conduction equation for the outer portion of the comet. The upper boundary condition of the model is given by energy balance at the surface of the nucleus, including conduction of heat inward, radiation, insolation as modified by the coma, and sublimation. Our coma model assumes single scattering and includes attenuation of direct sunlight by dust grains, scattering of light onto the nucleus, and infrared radiation by dust grains. The lower boundary condition is zero net heat flux around an orbit. The thermal conductivity expression for the nucleus includes direct conduction at grain boundaries, radiative conduction, and Knudsen flow vapor diffusion. The thermal diffusivity of the nucleus and the resultant temperature profiles are shown to be strongly dependent on the physical properties of the material, including porosity, pore size, and compaction. The temperature profiles and the equilibrium temperature deep within the comet also depend on the functional relationship between thermal conductivity and temperature; the highest deep equilibrium temperatures are found for models where the thermal conductivity increases strongly with increasing temperature. The dependence of temperatures on the albedo and thermal emissivity of the nucleus is also calculated, as well as the variation of temperature with latitude for a variety of pole orientations. The effect of a dust mantle on subsurface temperatures is also investigated. All calculations are presented for short-period comets with orbits that make them accessible for exploration by spacecraft rendezvous. In situ measurements of the thermal profile in the upper meter of a comet nucleus can substantially constrain the thermal diffusivity of the material, which in turn can provide significant information about the physical properties of the nucleus.

Cosmic Dust↗
PubMed1995

Computer modeling of the effects of chewing sugar-free and sucrose-containing gums on the pH changes in dental plaque associated with a cariogenic challenge at different intra-oral sites.

Variation in salivary access to different intra-oral sites is an important factor in the site-dependence of dental caries. This study explored, theoretically, how access is modified by chewing sugar-free and sugar-containing gums. A finite difference computer model, described elsewhere, was used. This allowed for diffusion and/or reaction of substrate, acid product, salivary buffers, and fixed-acid groups. Site-dependent saliva/plaque exchange was modeled in terms of a 100-microns-thick salivary film covering the plaque (a) flowing directly from the salivary ducts, (b) flowing from the intra-oral salivary pool, or (c) exchanging with the pool. Computed flow-velocities or rates of exchange were based on previous intra-oral measurements. The model was also tested against an in vitro study conducted by two of the authors. In addition, the three proposed models of saliva/plaque interaction were compared, and the effect of salivary film thickness investigate. Results suggested that: (1) although sugar-free gum chewed during a cariogenic challenge causes a rapid rise in plaque pH, sucrose-containing gums cause the pH, after a temporary rise resulting from increased salivary flow, to stay low for an extended period; (2) the computer model reproduced in vitro tests reasonably well; (3) although the three models of the plaque/saliva interaction start from different assumptions, two lead to closely related predictions; and (4) increasing the assumed salivary film thickness by a large amount (e.g., from 50 to 200 microns) caused no change in modeled Stephan curves, as long as these changes were accompanied by appropriate reductions in film velocity, in accord, theoretically, with the practical clearance data.

Acids↗
PubMed1999

Ionic Diffusivity, Electrical Conductivity, Membrane and Thermoelectric Potentials in Colloids and Granular Porous Media: A Unified Model.

Ionic diffusivity, electrical conductivity, membrane and thermoelectric potentials in isotropic and homogeneous colloidal suspensions, and granular porous media saturated by a binary symmetric 1:1 electrolyte are four interrelated phenomena. The microstructure and the surface properties of the solid grains-water interface influence directly these properties. The ionic diffusivities (and the electrical conductivity, respectively) in colloids and porous media have contributions from diffusion (and electromigration, respectively) through the bulk solution occupying the pores, together with electromigration occurring at the grains-water interface in the electrical double layer. Surface diffusion in porous materials has no contribution from concentration gradients along the grains-water interface. Instead, surface diffusion is envisioned as a purely electromigration process due to the membrane potential. The tortuosities of the transport of anions and cations are equal to the bulk tortuosity of the pore space only at high ionic strength. As the ionic strength decreases, the dominant paths for transport of the ion corresponding to the counterion of the electrical double layer shift from the pore space to the solid grains-water interface. Because anions and cations do not move independently, the membrane potential created by the charge polarization alters the velocity of the anions and influences the mutual diffusivity coefficient of the salt in the porous material. An electric potential of thermal origin is also produced in nonisothermal conditions. The ionic contributions to the electrical conductivity are based on a differential effective medium approach. These ionic contributions to the electrical conductivity are used to derive the ionic diffusivities and the membrane and thermoelectric potentials. The influence of the temperature and the presence, in the pore space, of a second immiscible and nonwetting phase is also considered in this model. Porosity is shown to affect the membrane potential. Several predictions of the model are checked with success by comparing the model to a set of experimental data previously published. Copyright 1999 Academic Press.

Journal Article↗
PubMed2000

Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS.

Interleukin-1beta acts on the CNS to induce fever, neuroendocrine activation and behavioural depression. We have previously demonstrated that interleukin-1beta is synthesized in glial cells and macrophages of circumventricular organs and choroid plexus after intraperitoneal administration of bacterial lipopolysaccharide. Whether, and how, interleukin-1beta produced in glial cells affects neuronal functioning is unknown. Diffusion throughout the extracellular space is an important pathway by which factors produced by glial cells act on distant cells, a phenomenon coined "volume transmission". The present study assessed diffusion of recombinant rat interleukin-1beta, recombinant human interleukin-1 receptor antagonist and 10mol. wt dexran in the rat CNS after intracerebroventricular administration to model interleukin-1beta release from choroid plexus. Immunocytochemistry with specific antibodies directed against interleukin-1beta and interleukin-1 receptor antagonist revealed that these molecules rapidly penetrated into periventricular tissue and spread along white matter fibre bundles and blood vessels in the caudoputamen, hypothalamus and amygdala. The transcription factor nuclear factor kappa B and the immediate-early gene product Fos were detected immunocytochemically to reveal interleukin-1beta action. Intracerebroventricular infusion of interleukin-1beta induced nuclear factor kappa B translocation in choroid plexus, ependymal cells, basolateral amygdala, cerebral vasculature and meninges. Fos immunoreactivity was found in the supraoptic and paraventricular hypothalamus and central amygdala. We propose that intracerebroventricular injected interleukin-1beta can enter the brain parenchyma and act as a "volume transmission" signal in, for example, the basolateral amygdala where it might activate a neuronal projection to the central amygdala.

Animals↗
PubMed2005

Weak alignment NMR: a hawk-eyed view of biomolecular structure.

Imposing a very slight deviation from the isotropic random distribution of macromolecules in solution in an NMR sample tube permits the measurement of residual internuclear dipolar couplings (RDCs). Such interactions are very sensitive functions of the time-averaged orientation of the corresponding internuclear vectors and thereby offer highly precise structural information. In recent years, advances have been made both in the technology to measure RDCs and in the computational procedures that integrate this information in the structure determination process. The exceptional precision with which RDCs can be measured under weakly aligned conditions is also starting to reveal the mostly, but not universally, subtle effects of internal protein dynamics. Importantly, RDCs potentially can reveal motions taking place on a timescale slower than rotational diffusion and analysis is uniquely sensitive to the direction of motion, not just its amplitude.

Animals↗
PubMed2005

Principles of design and analyses for the calibration of accelerometry-based activity monitors.

The term "calibration" in accelerometry research has come to mean the conversion of counts into other established measurement units. In this article, two types of calibration research are described. Unit calibration (or interinstrument variability) is described as a reliability issue, whereas value calibration is described as more of a validity issue. Principles for design of accelerometry-based validation studies are described to provide a guide for future calibration research. The population must be representative of the intended population in terms of demographics and size, monitors must be representative of the population of monitors that would be available, and activities in the protocol must be representative of the types of activities performed by the intended population. It is also important to employ appropriate analytical strategies in this type of research. A case study employing the appropriate design principles is included to demonstrate how results can vary depending on the type of analyses that are used. Direct comparisons are made between a mixed model regression approach and an approach based on receiver operator characteristic curves.

Acceleration↗
PubMedDate not supplied

Nurse-managed centres: an innovative structure for nursing education and care.

The development of nursing centres in the USA began in the late 1800s with the concept of community-based nursing care provided by district and visiting nurses. Primary roles included health promotion and safeguarding hygiene in addition to caring for the sick. Established in 1893, the Henry Street Settlement in New York, a public health nursing system providing direct access to health care, became a model for other agencies in the USA.

Community Health Centers↗
PubMed1993

Peer coaching: building collegial support for using innovative health programs.

To ensure students achieve intended benefits from effective health programs, it is necessary to maximize program implementation and maintenance. Peer coaching provides a post-inservice staff development approach for health educators to strengthen teacher use of new health programs during implementation trials. While peer coaching positively influences teacher behavior and student outcomes, previous coaching programs have been limited in scope, have not been theoretically derived or adequately evaluated, and have not been systematically applied to health programs. This paper addresses teacher needs during trials, reviews peer coaching program features, and proposes a model to guide future planning, evaluation, and research. In this model, critical components of the coaching program include classroom assessments, coaching team cluster meetings, and administrative support. Strategies based on Social Learning Theory and Diffusion Theory are incorporated into the peer coaching program to influence teacher perceptions of their work roles, capability to implement a program, and commitment to the new instructional program. Interrelations among components are discussed and directions for future research and practice are suggested.

Curriculum↗
PubMed2003

Transabdominal near infrared oximetry of hypoxic stress in fetal sheep brain in utero.

The feasibility of transabdominal near-infrared (NIR) spectroscopy for detecting and quantifying fetal hypoxia in utero is demonstrated in a pregnant ewe model. A frequency domain NIR spectroscopy probe, consisting of two detectors and six sources operating at three wavelengths (675, 786, and 830 nm), was placed on the maternal abdomen directly above the fetal head. Fetal hypoxia was indirectly induced through occlusion of uterine blood flow for approximately 3 min. NIR photon diffusion measurements were made during a baseline period, during hypoxia of the fetus, and during recovery. Fetal blood samples were drawn from the fetal brachial artery and jugular veins at several time points during the cycle. Seven hypoxic cycles were induced in a total of five pregnant ewes. The NIR measurements were analyzed by using a two-layer diffusion model to deconvolve the fetal blood saturation from that of the pregnant ewe. Fetal hypoxia was detected. Good agreement was found between fetal blood saturation determined by the transabdominal NIR method and arterial and venous fetal blood saturation quantified from fetal blood samples by using a hemoximeter.

Abdomen↗
PubMed1978

Kinetics of D-histidine diffusion across rat intestine in vitro.

A five-compartment linear model for diffusion in vitro across rat jejunum has been proposed for the study of the kinetic constants of D-histidine transport. Once preliminary experiments using 2,4-dinitrophenol and L-methionine have proved that D-histidine gives rise to passive transport only, the validity of the model was tested and its parameters estimated through a best-fitting procedure by using experimental data concerning D-histidine transport. D-Histidine diffusion was studied in everted and unreverted loops mounted in an oxygenated bath system. Both mucosa to serosa and seroa to mucosa movements of D-histidine (3-30 mM) were evaluated by measuring chemically the amount of D-histidine transported into intestinal lumen every 5 min for 60 min. Results obtained proved that D-histidine transport in each direction (mucosa to seroa or seroa to mucosa) was dependent-concentration process. Nevertheless different values of gain and time constants were estimated for the transport in the two directions.

Animals↗
PubMed2004

A new approach for fluorescence correlation spectroscopy (FCS) based immunoassays.

Fluorescence correlation spectroscopy (FCS) is a powerful technique for measuring physicochemical properties, such as concentration and diffusion constant, of bio-molecules in complex mixtures. Although, as such, FCS is well suited for development of homogeneous immunoassays, a major obstacle lies in the relatively high molecular weight of antibodies. This is because in FCS discrimination between unbound fluorescently-labelled antibodies and the same antibodies bound to immune complexes is based on the difference of their respective diffusion coefficients. To overcome this limitation we here propose to use a fluorescently-labelled tag which has two crucial properties: (a) its molecular weight is significantly lower than that of an antibody and (b) it is capable to discriminate between free antibodies and immune complexes. We have evaluated the feasibility of this approach in a model system consisting of mouse monoclonal IgG directed against the Lewis X antigen, and Protein A as a low molecular weight tag.

Animals↗
PubMed2004

Theoretical simulation of K(+)-based mechanisms for regulation of capillary perfusion in skeletal muscle.

Muscle fibers release K(+) into the interstitial space upon recruitment. Increased local interstitial K(+) concentration ([K(+)]) can cause dilation of terminal arterioles, leading to perfusion of downstream capillaries. The possibility that capillary perfusion can be regulated by vascular responses to [K(+)] was examined using a theoretical model. The model takes into account the spatial relationship between functional units of muscle fiber recruitment and capillary perfusion. Diffusion of K(+) in the interstitial space was simulated. Two hypothetical mechanisms for vascular sensing of interstitial [K(+)] were considered: direct sensing by arterioles and sensing by capillaries with stimulation of feeding arterioles via conducted responses. Control by arteriolar sensing led to poor tissue oxygenation at high levels of muscle activation. With control by capillary sensing, increases in perfusion matched increases in oxygen demand. The time course of perfusion after sudden muscle activation was considered. Predicted capillary perfusion increased rapidly within the first 5 s of muscle fiber activation. The reuptake of K(+) by muscle fibers had a minor effect on the increase of interstitial [K(+)]. Uptake by perfused capillaries was primarily responsible for limiting the increase in [K(+)] in the interstitial space at the onset of fiber activation. Vascular responses to increasing interstitial [K(+)] may contribute to the rapid increase in blood flow that is observed to occur after the onset of muscle contraction.

Animals↗
PubMed1996

Cellular cholesterol efflux mediated by cyclodextrins. Demonstration Of kinetic pools and mechanism of efflux.

The efflux of cholesterol from cells in culture to cyclodextrin acceptors has been reported to be substantially more rapid than efflux induced by other known acceptors of cholesterol (Kilsdonk, E. P. C., Yancey, P., Stoudt, G., Bangerter, F. W., Johnson, W. J., Phillips, M. C., and Rothblat, G. H. (1995) J. Biol. Chem. 270, 17250-17256). In this study, we compared the kinetics of cholesterol efflux from cells with 2-hydroxypropyl-beta-cyclodextrins and with discoidal high density lipoprotein (HDL) particles to probe the mechanisms governing the remarkably rapid rates of cyclodextrin-mediated efflux. The rate of cholesterol efflux was enhanced by shaking cells growing in a monolayer and further enhanced by placing cells in suspension to achieve maximal efflux rates. The extent of efflux was dependent on cyclodextrin concentration, and maximal efflux was observed at concentrations >50 mM. For several cell types, biexponential kinetics of cellular cholesterol efflux were observed, indicating the existence of two kinetic pools of cholesterol: a fast pool (half-time (t1/2) approximately 19-23 s) and a slow pool with t1/2 of 15-30 min. Two distinct kinetic pools of cholesterol were also observed with model membranes (large unilamellar cholesterol-containing vesicles), implying that the cellular pools are in the plasma membrane. Cellular cholesterol content was altered by incubating cells with solutions of cyclodextrins complexed with increasing levels of cholesterol. The number of kinetic pools was unaffected by raising the cellular cholesterol content, but the size of the fast pool increased. After depleting cells of the fast pool of cholesterol, this pool was completely restored after a 40-min recovery period. The temperature dependence of cyclodextrin-mediated cholesterol efflux from cells and model membranes was compared; the activation energies were 7 kcal/mol and 2 kcal/mol, respectively. The equivalent activation energy observed with apo-HDL-phospholipid acceptor particles was 20 kcal/mol. It seems that cyclodextrin molecules are substantially more efficient than phospholipid acceptors, because cholesterol molecules desorbing from a membrane surface can diffuse directly into the hydrophobic core of a cyclodextrin molecule without having to desorb completely into the aqueous phase before being sequestered by the acceptor.

Animals↗