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PubMedDate not supplied

The blood-ocular barriers.

The introduction of the concept of blood-ocular barriers in the ophthalmic literature is briefly reviewed. Two main blood-ocular barriers are proposed: the blood-aqueous barrier and the blood-retinal barrier. The blood-aqueous barrier is formed by an epithelial barrier located in the nonpigmented layer of the ciliary epithelium and in the posterior iridial epithelium, and by the endothelium of the iridial vessels. Both these layers have tight junctions of the "leaky" type. The pereability of the blood-aqueous barrier shows a significant degree of pressure-dependent diffusion associated with transport activity, resembling the standing gradient osmotic flow model. The blood-retinal barrier is located at two levels, forming an outer barrier in the retinal pigment epithelium and an inner barrier in the endothelial membrane of the retinal vessels. Both these membranes have tight junctions of the "nonleaky" type. The permeability of the blood-retinal barrier resembles cellular permeability in general, diffusion being directly related to the predominant roles of lipid solubility and transport mechanisms. Finally, the clinical significance of the blood-ocular barrier is analyzed. The metabolism of cornea and lens and the regulation of intraocular fluids are directly influenced by the blood-aqueous barrier. Similarly, an alteration of the blood-retinal barrier appears to play an important role in the development of vascular retinopathies, pigment epitheliopathies, and retinal edema.

Animals↗
PubMed2005

Substrate binding to the molecular chaperone Hsp104 and its regulation by nucleotides.

The Hsp104 protein from Saccharomyces cerevisiae is a member of the Hsp100/Clp family of molecular chaperones. It mediates the solubilization of aggregated proteins in an ATP-dependent process assisted by the Hsp70/40 system. Although the principal function of Hsp104 is well established, the mechanistic details of this catalyzed disaggregation are poorly understood. In this work, we have investigated the interaction of Hsp104 with reduced, carboxymethylated alpha-lactalbumin (RCMLa), a permanently unfolded model substrate. Our results demonstrate that the affinity of Hsp104 toward polypeptides is regulated by nucleotides. In the presence of ATP or adenosine-5' -O-(3-thiotriphosphate), the chaperone formed complexes with RCMLa, whereas no binding was observed in the presence of ADP. In particular, the occupation of the N-terminally located nucleotide-binding domain with ATP seems to be crucial for substrate interaction. When ATP binding to this domain was impaired by mutation, Hsp104 lost its ability to interact with RCMLa. Our results also indicate that upon association with a polypeptide, a conformational change occurs within Hsp104 that strongly reduces the dynamics of nucleotide exchange and commits the bound polypeptide to ATP hydrolysis.

Adenosine Diphosphate↗
PubMed2006

Flow-enhanced adhesion regulated by a selectin interdomain hinge.

L-selectin requires a threshold shear to enable leukocytes to tether to and roll on vascular surfaces. Transport mechanisms govern flow-enhanced tethering, whereas force governs flow-enhanced rolling by prolonging the lifetimes of L-selectin-ligand complexes (catch bonds). Using selectin crystal structures, molecular dynamics simulations, site-directed mutagenesis, single-molecule force and kinetics experiments, Monte Carlo modeling, and flow chamber adhesion studies, we show that eliminating a hydrogen bond to increase the flexibility of an interdomain hinge in L-selectin reduced the shear threshold for adhesion via two mechanisms. One affects the on-rate by increasing tethering through greater rotational diffusion. The other affects the off-rate by strengthening rolling through augmented catch bonds with longer lifetimes at smaller forces. By forcing open the hinge angle, ligand may slide across its interface with L-selectin to promote rebinding, thereby providing a mechanism for catch bonds. Thus, allosteric changes remote from the ligand-binding interface regulate both bond formation and dissociation.

Cell Adhesion↗
PubMed2002

Simulation of methods for drug delivery to the cochlear fluids.

The inner ear fluids are remarkably 'unstirred' so that it cannot be assumed that applied drugs are dispersed throughout the fluid spaces. Calculation of the effective concentrations achieved when drugs are applied directly to the inner ear is made possible by simulations combining the physical processes involved in solute dispersal, which are diffusion, longitudinal fluid flow and clearances to other compartments. The approach has been validated in numerous experiments in which ion-selective electrodes were used to characterize the spread of marker substances in the cochlear fluids. The model incorporates the known size and geometry of cochlear fluid spaces for 6 species, including the guinea pig and the human. The simulator allows the dispersal of drugs or other substances to be approximated with knowledge of relatively few parameters. The simulation program is available on the Internet at http://oto.wustl.edu/cochlea/.

Animals↗
PubMed1991

Informational masking and auditory attention.

Informational masking is broadly defined as a degradation of auditory detection or discrimination of a signal embedded in a context of other similar sounds; it is not related to energetic masking caused by physical interactions between signal and masker. In this paper, we report a systematic release from informational masking of a target tone in a nine-tone rapid auditory sequence as the target is increasingly isolated in frequency or intensity from the remaining sequence components. Improved target-tone frequency difference limens as isolation increases are interpreted as a reflection of increasingly focused auditory attention. The change from diffuse to highly focused attention is gradual over the frequency and intensity ranges examined, with each 1-dB increment in target intensity relative to the remaining components producing performance improvements equivalent to those produced by a 2% increase in frequency isolation. The results are modeled as bands of attention in the frequency and intensity domains. For attention directed by frequency isolation, there is a strong correspondence with auditory filters predicted by the power spectrum model of masking. These data also support the existence of an attention band of intensity, with a bandwidth of about 5-7 dB at the moderate levels used in this experiment.

Adult↗
PubMed1985

Persuasive communication and medical technology assessment.

Assessments of medical technologies with respect to their efficacy, safety, and cost-effectiveness are expected to influence clinical practice, but they are often lost in an avalanche of medical information. We developed a conceptual model that may aid understanding of the potential impact on clinical practice of new medical information in general and assessment information in particular. The model identifies aspects of medical communication that may influence an assessment's subsequent impact, including sources, messages, channels, audiences, and settings. We reviewed the literature on how medical information diffuses to physicians and highlighted those factors likely to heighten physicians' awareness and decisions to incorporate recommended medical advances. We outlined implications for educational interventions and promising research directions.

Humans↗
PubMed1994

Modelling the spread of foot-and-mouth disease virus.

Foot-and-mouth disease is an economically important viral disease in animals. It is shown that airborne diffusion is one of the main sources of contamination between animals and between herds. Epidemiological data linked to viral particle excretion can thus be used in a predictive model, added to meteorological data related to the few days before the slaughter of animals. The model computes, on a 10 km radius around the outbreak and in every space direction, the quantity of viral particles that a sensitive animal could have breathed. The aim is to define a risk area, and, according to the number and size of farms in the surrounding, to give arguments for the best sanitary decision within the emergency plan.

Air Microbiology↗
PubMed1998

[Effect of A1 adenosine receptor blockade on postischemic damage to the coronary microcirculation].

Recent studies suggest that A1 adenosine receptor antagonists may prevent reperfusion injury in the lung and heart. The pathophysiology of this protective effect is unclear; a possible inhibition of superoxide anion release from neutrophils, or leukocyte activation and platelet aggregation are reported. We tested the hypothesis of a blood-independent cardioprotection following A1 adenosine receptor antagonism with 1,3 dipropyl,8-cyclopentylxanthine (DPCPX). Isolated working rat hearts were submitted to 10 and 20 min global ischemia in order to assess functional alterations, necrosis enzyme and purine release in coronary effluent, arrhythmias, heart weight, ultrastructural morphometry and microvascular permeability by FITC-albumin diffusion technique. DPCPX (100 nM) was administered to the perfusion buffer before ischemia. In untreated hearts we detected a significant impairment of function, associated with a significant enzyme and purine release, myocardial edema and ultrastructural damage. In DPCPX-treated hearts functional and histological damage was significantly reduced compared to controls. Moreover, a significant reduction in postischemic endothelial permeability (FITC-albumin diffusion, p < 0.02) and ultrastructural damage was observed. Our data suggest that A1 adenosine receptor antagonism with DPCPX significantly reduces ischemia-reperfusion damage in isolated, crystalloid perfused rat heart by a direct reduction of endothelium damage, fluid diffusion within the interstitium and improvement of coronary microcirculation.

Adenosine↗
PubMed1997

Origin of the photoacoustic signal in cytochrome P-450cam: role of the Arg186-Asp251-Lys178 bifurcated salt bridge.

The origin of the photoacoustic signal in ferrous CO-camphor-cytochrome P-450cam was investigated. Recently, the Arg186-Asp251-Lys178 bifurcated salt bridge, located above the heme pocket, has been shown to play a key role in the control of the diffusion step of camphor binding [Deprez, E., Gerber, N. C., Di Primo, C., Douzou, P., Sligar, S. G., & Hui Bon Hoa, G. (1994) Biochemistry 33, 14464-14468]. We considered the hypothesis that electrostriction resulting from the transient exposure of these charged residues to the solvent could be responsible for part of the photoacoustic signal. We thus examined the effects of a site-directed mutation of these linkages and ionic strength increases. Upon replacement of the Asp251 residue by an asparagine residue, the overall enthalpy and volume change of the CO dissociation reaction decrease from -5 to -24 kcal/mol and from 11 to 5.4 mL/mol, respectively. The mutation has the same effect on the thermodynamic parameters as increasing the ionic strength of the medium over a range of potassium or sodium concentrations from 0 to 500 mM. For the D251N mutant, the overall enthalpy of the reaction does not change with the ionic strength whereas a small effect is observed on the volume change. The results indicate that electrostriction around the bifurcated salt bridge contributes to the photoacoustic signal and suggest a scheme in which, following photodissociation of CO and diffusion of the molecule through the protein matrix, the structure relaxes and the bifurcated salt bridge desolvates.

Camphor↗
PubMedDate not supplied

Use of heating rate and specific absorption rate in the hyperthermia clinic.

The specific absorption rate (SAR), which is the mass-normalized rate of energy absorption by a biological body, has been used by hyperthermia researchers to characterize energy deposition and heating patterns in tissues and in biological models. Before thermal diffusion and blood flow alter the temperature distribution, energy deposition and heating rate (HR) are related by constants. Therefore SAR is usually calculated from the initial rate of temperature rise measured during heating. SAR is an appropriate parameter for theoretical calculations or electric field measurement in tissue. However, the ultimate parameter in hyperthermia is temperature. Instead of computing the temperature rise from SAR (W/kg) and specific heat (kcal/kg.degree C) which were originally obtained from temperature measurements, it is simpler and more convenient to use HR (degree C/W-min) directly, especially when heterogeneous tissues are involved. The advantages of using HR instead of SAR in hyperthermia clinics are discussed.

Body Temperature↗
PubMed2004

Implementing evidence-based practice: walking the talk.

Russworm and Larrabee's (1999) six-step model for evidence-based practice (EBP) was used by 10 nursing teams to seek answers to clinical questions. These teams, primarily composed of staff nurses, participated in a health region-wide EBP program over 1 year. Overall, the model served as a useful mechanism for examining practice-derived questions. However, additional strategies needed to be incorporated by the project teams. These included making decisions about change/no change at an earlier stage than was suggested by the model; seeking additional evidence including survey data to benchmark "best" practices; and ensuring colleagues' and managers' input, support, and involvement. Four project teams (three of which addressed nursing procedural questions) found insufficient empirical evidence on which to base change; the outlook for directing evidence-based practice was promising for the remaining six projects. The EBP program was judged to be highly satisfactory to participants and their managers.

Alberta↗
PubMed2003

Population-based study of non-Hodgkin lymphoma, histology, and medical history among human immunodeficiency virus-negative participants in San Francisco.

A population-based case-control study of non-Hodgkin lymphoma was conducted in the San Francisco Bay Area of California from 1988 to 1995. The study used Working Formulation histologic subtypes of non-Hodgkin lymphoma. Diffuse and immunoblastic large-cell lymphomas and all follicular lymphomas were combined to reflect two Revised European-American Lymphoma (REAL) classifications. Results were obtained from age- and sex-adjusted polytomous multivariable logistic models for 1,304 cases and 2,402 controls who were negative for human immunodeficiency virus. Statistically significant odds ratios for REAL large-cell lymphoma were decreased for receipt of five or more different vaccines (odds ratio (OR) = 0.65), use of calcium channel blockers (OR = 0.35), mononucleosis (OR = 0.55), plant allergies (OR = 0.72), and animal allergies (OR = 0.40). Odds ratios for REAL follicular lymphoma were decreased for use of nonsteroidal antiinflammatory drugs (OR = 0.67), hepatitis (OR = 0.36), and having had three or more bee or wasp stings (OR = 0.79) and were increased for heart disease (OR = 1.5). Similar elevated odds ratios for heart disease and Bacillus Calmette-Guérin vaccine and decreased odds ratios for nonsteroidal antiinflammatory drugs, plant allergies, and three or more bee or wasp stings were found for small lymphocytic lymphoma. These data provide direction for further investigation of immune function and genetic characteristics of subtypes of non-Hodgkin lymphoma in lymphomagenesis and warrant analyses in large pooled data sets.

Case-Control Studies↗
PubMed2005

A continuous damage random thresholds model for simulating the fracture behavior of nacre.

This study investigates the fracture properties of nacre using a discrete lattice model based on continuous damage random threshold fuse network. The discrete lattice topology of the model is based on nacre's unique brick and mortar microarchitecture. The mechanical behavior of each of the bonds in the discrete lattice model is governed by the characteristic modular damage evolution of the organic matrix and the mineral bridges between the aragonite platelets. The numerical results obtained using this simple discrete lattice model are in very good agreement with the previously obtained experimental results, such as nacre's stiffness, tensile strength, and work of fracture. The analysis indicates that nacre's superior toughness is a direct consequence of ductility (maximum shear strain) of the organic matrix in terms of repeated unfolding of protein molecules, and its fracture strength is a result of its ordered brick and mortar architecture with significant overlap of the platelets, and shear strength of the organic matrix.

Biocompatible Materials↗
PubMed2005

Hemoglobin mediated nitrite activation of soluble guanylyl cyclase.

Nitrite has long been known to be vasoactive when present at large concentrations but it was thought to be inactive under physiological conditions. Surprisingly, we have recently shown that supraphysiological and near physiological concentrations of nitrite cause vasodilation in the human circulation. These effects appeared to result from reduction of nitrite by deoxygenated hemoglobin. Thus, nitrite was proposed to play a role in hypoxic vasodilation. We now discuss these results in the context of nitrite reacting with hemoglobin and effecting vasodilation and present new data modeling the nitric oxide (NO) export from the red blood cell and measurements of soluble guanylate cyclase (sGC) activation. We conclude that NO generated within the interior of the red blood cell is not likely to be effectively exported directly as nitric oxide. Thus, an intermediate species must be formed by the nitrite/deoxyhemoglobin reaction that escapes the red cell and effects vasodilation.

Animals↗
PubMed2003

Two-state folding over a weak free-energy barrier.

We present a Monte Carlo study of a model protein with 54 amino acids that folds directly to its native three-helix-bundle state without forming any well-defined intermediate state. The free-energy barrier separating the native and unfolded states of this protein is found to be weak, even at the folding temperature. Nevertheless, we find that melting curves to a good approximation can be described in terms of a simple two-state system, and that the relaxation behavior is close to single exponential. The motion along individual reaction coordinates is roughly diffusive on timescales beyond the reconfiguration time for a single helix. A simple estimate based on diffusion in a square-well potential predicts the relaxation time within a factor of two.

Amino Acids↗
PubMed1994

Simulation of reduced band broadening during single-stranded DNA pulsed field electrophoresis in polyacrylamide gels.

Using a computer simulation algorithm based on the reptation model, we investigated the effects of pulsed field gel electrophoresis on the separation of single-stranded DNA molecules in denaturing polyacrylamide gels. Pulsed fields that combine two different field intensities were found to affect the orientation of the reptation tube as well as the electrophoretic velocity, the rate of band broadening, the plate height and the molecular length for which the minimum of mobility was found, in agreement with available experimental results. Due to "memory" effects, pulses alternating between the forward and backward directions can reduce the diffusion constant by many orders of magnitude. Pulses of identical polarity but different intensities reduce the diffusion because stretches of less-oriented DNA segments are conserved during the migration. We suggest that, for DNA sequencing, pulsed fields of fixed polarity should be used to reduce band broadening and not to overcome band inversion or suppress molecular orientation. We conclude that, using a low intensity, constant electric field will lead to smaller band widths than any pulsed field regime, in a similar length of experimental time, but with less complications.

Algorithms↗
PubMed2005

Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model.

Accumulation and aggregation of amyloid beta peptide 1-42 (Abeta42) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of Abeta42 versus Abeta40 or total Abeta is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-Abeta42 mAb, an anti-Abeta40 mAb, and multiple Abeta(1-16) mAbs. We established in vivo binding selectivity of the anti-Abeta42 and anti-Abeta40 mAbs using novel TgBRI-Abeta mice. We then conducted a prevention study in which the anti-Abeta mAbs were administered to young Tg2576 mice, which have no significant Abeta deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting Abeta deposits. Anti-Abeta42, anti-Abeta40, and anti-Abeta(1-16) mAbs attenuated plaque deposition in the prevention study. In contrast, anti-Abeta42 and anti-Abeta40 mAbs were less effective in attenuating Abeta deposition in the therapeutic studies and were not effective in clearing diffuse plaques following direct injection into the cortex. These data suggest that selective targeting of Abeta42 or Abeta40 may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting.

Alzheimer Disease↗
PubMed1978

Experimental stroke in gerbils: effect on translation and transcription.

The effect of cerebral ischemia on polypeptide synthesis with isolated microsomes and DNA-dependent RNA polymerase activity with isolated nuclei was investigated by occlusion of right common carotid artery of gerbils. There was a prompt decline of microsomal polypeptide synthesis already at 30 min after occlusion of the artery, and at 4--5 h the specific radioactivity (dpm per microgram protein) was 50% of the control value. At 24 h, when the animals were only slightly responsive to external stimuli, the specific radioactivity of ischemic brain was only 20% of the control value. DNA-dependent RNA polymerase activity was unaffected for 1 h, and clear suppression did not appear until 3 h after occlusion. However, the extent of suppression was similar between polypeptide synthesis and RNA polymerase activity beyond 3 h after occlusion. Although more selective vulnerability of polypeptide synthesis thus exists in cerebral ischemia, the difference between two biochemical processes was not as striking as seen in cerebral anoxia. Focal progression of cerebral ischemia to diffuse infarction in gerbils was suggested as a possible explanation for the disparity in comparison to the diffuse effect in cerebral anoxia along with the difference in the magnitude of acidosis and depletion of energy reserve.

Animals↗