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PubMed1988

[Kidney medullary hypoxia: a key to understanding acute renal failure?].

The ability to produce a concentrated urine is imposed by a uniquely low ambient oxygen pressure in the renal medulla due to shunt diffusion within the vascular bundles. As the thick ascending limb of Henle's loop (TAL-segment) is able to glycolyse anaerobically, a phase of oxygen deficiency may be bridgespanned. It allows an exceptionally high oxygen extraction of 80% in this area. If oxygen capacity is reduced systematically, which can be effected in the isolated kidney model by using cell free perfusate, a typical pattern of lesions occur in TAL-segments. Segments near vascular bundles remain intact, as they take advantage from a radial oxygen diffusion originating from vascular bundles. The extent of lesions is increasing directed to the inner medulla due to the reduction of oxygen pressure, whereas lesions are not present in the inner medulla itself. Cells of TAL-segments are swelling during oxygen deficiency, when transport work surpasses the available energy necessary due to the luminal fluid inflow. Lesions could be prevented, when oxygen capacity was enhanced by adding erythrocytes or when transport was blocked by furosemide. Swollen cells in TAL-segments however are able to aggravate medullary hypoxia by an outflow block in vivo. Secondly, it can be demonstrated, that oxygen shunt diffusion is not only present in renal medulla but also within renal cortex especially as a preglomerular diffusion shunt for blood gases. Thus PCO2 has been measured to be 65 mmHg in the outermost cortical zone and thereby some 20 mmHg higher than renal venous blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

PubMed2006

Form versus disease: optimizing geometry during ventricular restoration.

OBJECTIVE: Dilated cardiomyopathy from many causes results in a change in ventricular geometry, whereby the elliptical chamber becomes more spherical. This may be the unifying geometric concept of heart failure, with similar alteration of spatial configuration in non-ischemic diffuse myocyte disease, ischemic cardiomyopathy with and without scar, and in valvular heart disease. METHODS: This change in architecture alters fiber direction and diminishes function, and has been related to alteration of the apical loop of the helical ventricular myocardial band model of cardiac shape. The underlying concept of rebuilding the ventricle by ventricular restoration is suggested to be reconstruction of form, rather than focusing on only the underlying disease. RESULTS: Examples are shown where the Surgical Anterior Ventricular Exclusion (SAVE) or Pacopexy procedure has been successfully applied to each of the above-mentioned diseases, and is suggested for dilated valvular cardiomyopathy. The interaction between rebuilding form and how this procedure restores more normal fiber orientation is discussed, and the possibility of a macroscopic/microscopic marriage between surgically altering the cardiac scaffold by restoration (macro) and cell biology to improve function in a new helical shape is suggested. CONCLUSIONS: The implication of these observations is that the surgical objective should become rebuilding ventricular form, rather than restricting restoration procedures to only addressing the disease.

Cardiomyopathy, Dilated↗

PubMed2005

Diffusion MR imaging characteristics of the developing primate brain.

Diffusion-based magnetic resonance imaging holds the potential to non-invasively demonstrate cellular-scale structural properties of brain. This method was applied to fixed baboon brains ranging from 90 to 185 days gestational age to characterize the changes in diffusion properties associated with brain development. Within each image voxel, a probability-theory-based approach was employed to choose, from a group of analytic equations, the one that best expressed water displacements. The resulting expressions contain eight or fewer adjustable parameters, indicating that relatively simple expressions are sufficient to obtain a complete description of the diffusion MRI signal in developing brain. The measured diffusion parameters changed systematically with gestational age, reflecting the rich underlying microstructural changes that take place during this developmental period. These changes closely parallel those of live, developing human brain. The information obtained from this primate model of cerebral microstructure is directly applicable to studies of human development.

Algorithms↗

PubMed2005

Hemoglobin and red blood cells as tools for studying peroxynitrite biochemistry.

Oxyhemoglobin represents a relevant intravascular sink of peroxynitrite. Indeed, peroxynitrite undergoes a fast isomerization (k = 1.7 x 10(4)M(-1)s(-1)) to nitrate in the presence of oxyhemoglobin; the reaction mechanism is complex and leads to methemoglobin and superoxide radical as additional products and a small amount (approximately 10%) of transient species, including ferrylhemoglobin, nitrogen dioxide, and globin-derived radicals. The mechanism of the reaction could be solved only after extensive quantitative analysis of reactants, intermediates, and products and setting up experimental conditions that favor direct reactions of peroxynitrite with hemoglobin versus peroxynitrite decay through proton- or carbon dioxide-catalyzed homolysis. Additionally, oxyhemoglobin has been used as a "reporter" molecule of peroxynitrite diffusion from extracellular to intracellular compartments, using red blood cells (RBCs) as a model system. In RBCs, peroxynitrite diffusion across the membrane is favored by the large abundance of anion channels, and average transit distances can vary as a function of cell density. Indeed, we have developed a mathematical model that incorporates competition between the extracellular consumption of peroxynitrite and the permeation to the erythrocytes as a function of the average diffusion distances. The RBC model presented herein serves to estimate biological diffusion distances of peroxynitrite in the presence of relevant molecular targets, and the theoretical approach can be successfully applied to study the diffusion of peroxynitrite in other cellular/tissue systems.

Erythrocytes↗

PubMed1956

Water flow through frog gastric mucosa.

The transport of water through biological membranes can be attributed to several causes. Gradients of chemical activity caused by the application of hydrostatic pressure or differences in solute concentration across the membrane may produce a net water flow, called passive transport (1). In the absence of such gradients a net flow may also occur which is defined as active transport, and is presumed to arise from metabolic processes occurring in the membrane. Pappenhehner, Renkin, and Borrero (2) and Koefoed-Johnsen and Ussing (3) have independently shown that passive flows can be interpreted to give a model of the membrane in terms of pore structure. In the present study two types of experiments have been performed on passive water transport across the isolated gastric mucosa of the frog. First, the unidirectional diffusion flow of water in either direction has been measured using tritiated water as a tracer. Second, an osmotic gradient has been applied across the membrane and a passive net flow has been measured. At the same time an active net flow in the same direction as HC1 secretion has also been observed. In addition to the water transport studies, separate measurements have been made of the restriction offered by the membrane to diffusion of various sized molecules. The combined results of these experiments are interpreted in terms of a polydisperse population of pores in the membrane.

Animals↗

PubMed2002

Optical and x-ray evidence of the "de Vries" Sm-A-Sm-C transition in a non-layer-shrinkage ferroelectric liquid crystal with very weak interlayer tilt correlation.

A non-layer-shrinkage fluorinated ferroelectric liquid crystal compound, 8422[2F3], has been characterized by means of optical, x-ray, and calorimetric methods. The orientational distribution within macroscopic volumes, determined through wide-angle x-ray scattering and birefringence measurements, was found to be identical in the Sm-A* and helical Sm-C* phases. Together with the absence of layer shrinkage, this constitutes strong evidence that the second-order Sm-A*-Sm-C* transition in this material is well described by the diffuse cone model of de Vries. The absolute values of the layer spacing show that the molecules aggregate to antiparallel pairs. The molecular interaction across the layer boundaries will then occur only between fluorine atoms, leading to unusually weak interlayer tilt direction correlation. This explains the experimental observations of a very easily disturbed Sm-C* helix and a peculiar surface-stabilized texture. Tilt angle and birefringence values as a function of field and temperature have been evaluated in the Sm-A* and Sm-C* phases and the results corroborate the conclusions from the x-ray investigations.

Journal Article↗

PubMed2002

Antiferroelectric liquid-crystal mixture without smectic layer shrinkage at the direct Sm-A-Sm-C()(a) transition.

We report results of x-ray, optic, electro-optic, and dielectric investigations on an antiferroelectric liquid-crystal mixture exhibiting a direct second-order phase transition between the Sm-A* and Sm-C(*)(a) phases with virtually no shrinkage in the smectic layer spacing. The birefringence measurements and texture observations suggest that the phase transition follows the diffuse cone model of Adrian de Vries, which explains the constant layer spacing. The antiferroelectric nature of the tilted phase is verified by the presence of twin polarization reversal peaks in the current response and by the absence of strong absorptions in the dielectric spectrum. The threshold for switching this phase to the synclinic, ferroelectric state is sharp and occurs at a very low voltage.

Journal Article↗

PubMed2004

Drifting diffusion on a circle as continuous limit of a multiurn Ehrenfest model.

We study the continuous limit of a multibox Erhenfest urn model proposed before by the authors. The evolution of the resulting continuous system is governed by a differential equation, which describes a diffusion process on a circle with a nonzero drifting velocity. The short time behavior of this diffusion process is obtained directly by solving the equation, while the long time behavior is derived using the Poisson summation formula. They reproduce the previous results in the large M (number of boxes) limit. We also discuss the connection between this diffusion equation and the Schrödinger equation of some quantum mechanical problems.

Journal Article↗

PubMed2003

Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization.

The mixed-lineage leukemia gene (MLL, ALL1, HRX) encodes a 3,969-amino-acid nuclear protein homologous to Drosophila trithorax and is required to maintain proper Hox gene expression. Chromosome translocations in human leukemia disrupt MLL (11q23), generating chimeric proteins between the N terminus of MLL and multiple translocation partners. Here we report that MLL is normally cleaved at two conserved sites (D/GADD and D/GVDD) and that mutation of these sites abolishes the proteolysis. MLL cleavage generates N-terminal p320 (N320) and C-terminal p180 (C180) fragments, which form a stable complex that localizes to a subnuclear compartment. The FYRN domain of N320 directly interacts with the FYRC and SET domains of C180. Disrupting the interaction between N320 and C180 leads to a marked decrease in the level of N320 and a redistribution of C180 to a diffuse nuclear pattern. These data suggest a model in which a dynamic post-cleavage association confers stability to N320 and correct nuclear sublocalization of the complex, to control the availability of N320 for target genes. This predicts that MLL fusion proteins of leukemia which would lose the ability to complex with C180 have their stability conferred instead by the fusion partners, thus providing one mechanism for altered target gene expression.

Amino Acid Motifs↗

PubMed1998

Position dependent control of cell fate in the Fucus embryo: role of intercellular communication.

The early embryo of the brown alga Fucus comprises two cell types, i. e. rhizoid and thallus which are morphogically and cytologically distinguishable. Previous work has pointed to the cell wall as a source of position-dependent information required for polarisation and fate determination in the zygote and 2-celled embryo. In this study we have analysed the mechanism(s) of cell fate control and pattern formation at later embryonic stages using a combination of laser microsurgery and microinjection. The results indicate that the cell wall is required for maintenance of pre-existing polarity in isolated intact cells. However, all cell types ultimately have the capacity to re-differentiate or regenerate rhizoid cells in response to ablation of neighbouring cells. This regeneration is regulated in a position-dependent manner and is strongly influenced by intercellular communication, probably involving transport or diffusion of inhibitory signals which appear to be essential for regulation of cell fate decisions. This type of cell-to-cell communication does not involve symplastic transport or direct cell-cell contact inhibition. Apoplastic diffusible gradients appear to be involved in pattern formation in the multicellular embryo.

Body Patterning↗

PubMed2002

New approaches to the treatment of myelodysplasia.

The therapeutic dilemma that confronts the management of patients with myelodysplastic syndromes (MDS) is illustrated by the absence of a Food and Drug Administration-approved agent with an indication for this disease. Clinical heterogeneity and inadequate understanding of the disease pathobiology have limited progress in the development of novel therapeutics. Preclinical investigations indicate that reciprocal interaction between the malignant clone and the microenvironment serve to create a hostile milieu that reinforces ineffective blood cell production. Ineffective hematopoiesis, the hallmark of MDS, arises from impaired progenitor responsiveness to normal trophic signals and excess local generation of inhibitory cytokines, which promote accelerated apoptotic loss of progenitors and their progeny. Evidence to support this model derives from cytokine neutralization studies and the direct relationship between plasma tumor necrosis factor-alpha concentration and DNA oxidation and glutathione depletion in malignant CD34+ progenitors. Recent investigations indicate that angiogenic molecules generated by malignant myelomonocytic precursors represent integral diffusable signals that reinforce leukemia progenitor self-renewal while promoting the generation of proapoptotic cytokines and medullary angiogenic response. The potential for leukemia evolution is compounded by epigenetic events including methylation silencing of the p15 proto-oncogene or activating ras point mutations. Delineation of such biologic features that are central to the pathobiology of MDS provides a reliable framework for the development of novel therapeutics. Antiangiogenic agents in clinical testing include vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, thalidomide and related analogues, and the recombinant VEGF neutralizing antibody, bevacizumab. Agents whose actions may restore differentiation programs, such as the DNA methyltransferase inhibitors or histone deacetylase inhibitors, offer the prospect to promote effective hematopoiesis while impacting the potential for leukemia evolution. RAS farnesyl transferase inhibitors have shown encouraging preliminary results in acute myeloid leukemia and are currently under investigation in advanced MDS and chronic myelomonocytic leukemia. Arsenic trioxide (ATO) interacts with a spectrum of biologic targets that may be uniquely suited to MDS. ATO is a potent inducer of apoptosis in thiol-depleted malignant progenitors and neovascular endothelium, while promoting differentiation through histone acetylation and inactivation of transcriptional corepressors. The identification of relevant biologic targets in MDS has raised expectations for the development of disease-specific therapies for MDS in the years that follow.

Amifostine↗

PubMed2002

Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream.

A portion of the lysosomal enzymes produced by cells is secreted, diffuses through extracellular spaces, and can be taken up by distal cells via mannose-6-phosphate receptor-mediated endocytosis. This provides the basis for treating lysosomal storage diseases, many of which affect the CNS. Normal enzyme secreted from a cluster of genetically corrected cells has been shown to reverse storage lesions in a zone of surrounding brain tissue in mouse disease models. However, low levels of enzyme activity and reduction of storage lesions also have been observed at sites in the brain that may not be explained by a contiguous gradient of secreted enzyme diffusing away from the genetically corrected cells. No direct evidence for alternative mechanisms of enzyme transport has been shown, and little is understood about the intracellular movement of lysosomal enzymes in neurons. We investigated whether axonal transport could occur, by expressing an eukaryotic lysosomal enzyme that can be visualized in tissue sections (beta-glucuronidase) in brain structures that have defined axonal connections to other structures. This resulted in the transfer of enzyme to, and a reversal of storage lesions in, neurons that project to the gene expression site, but not in nearby structures that would have been corrected if the effect had been mediated by diffusion. In addition, transduction of cells in the subventricular zone resulted in the uptake of beta-glucuronidase by cells entering the rostral migratory stream. Gene transfer to specific neuronal circuits or cells in migratory pathways may facilitate delivery to the global brain lesions found in these disorders.

Animals↗

PubMed2006

Modelling, fabrication and characterization of a polymeric micromixer based on sequential segmentation.

Effective and fast mixing is important for many microfluidic applications. In many cases, mixing is limited by molecular diffusion due to constrains of the laminar flow in the microscale regime. According to scaling law, decreasing the mixing path can shorten the mixing time and enhance mixing quality. One of the techniques for reducing mixing path is sequential segmentation. This technique divides solvent and solute into segments in axial direction. The so-called Taylor-Aris dispersion can improve axial transport by three orders of magnitudes. The mixing path can be controlled by the switching frequency and the mean velocity of the flow. Mixing ratio can be controlled by pulse width modulation of the switching signal. This paper first presents a simple time-dependent one-dimensional analytical model for sequential segmentation. The model considers an arbitrary mixing ratio between solute and solvent as well as the axial Taylor-Aris dispersion. Next, a micromixer was designed and fabricated based on polymeric micromachining. The micromixer was formed by laminating four polymer layers. The layers are micro machined by a CO(2) laser. Switching of the fluid flows was realized by two piezoelectric valves. Mixing experiments were evaluated optically. The concentration profile along the mixing channel agrees qualitatively well with the analytical model. Furthermore, mixing results at different switching frequencies were investigated. Due to the dynamic behavior of the valves and the fluidic system, mixing quality decreases with increasing switching frequency.

Complex Mixtures↗

PubMedDate not supplied

Experimental validation of a new coronary guide wire labeled with rubidium 81/krypton 81m for continuous assessment of myocardial blood flow.

BACKGROUND: The rubidium 81/krypton 81m method was suggested for assessment of myocardial blood flow (MBF) three decades ago. This study investigates the novel concept of using 81Rb-/81mKr-labeled coronary guide wires with wire-attached 81Rb activity and diffusable 81mKr gas for assessment of lesion-specific impairment of MBF by evaluation of the 81Rb/81mKr activity ratio. The feasibility of wire production is tested, and application of the method is investigated in the canine model. METHODS AND RESULTS: Conventional coronary guide wires for angioplasty (0.014 in) were labeled with radioactive 81Rb/81mKr by ion bombardment of the wire tip. A total of 16 of the 18 wires labeled in series showed successful 81Rb fixation in combination with free 81mKr gas diffusability during quality control measurements. The suitability of the wires to assess MBF in combination with an external gamma ray detector was investigated in open-chested dogs. Electromagnetic measurement of coronary blood flow (CBF) was used as reference, providing a signal that is directly linked to volumetric MBF. The 81Rb/81mKr ratio tracked changes in CBF reliably in all 6 dogs. The found linear dependence of measured 81Rb/81mKr count rates on measured CBF supports the modeling assumptions made to apply the theoretic basis of the 81Rb/81mKr technique to 81Rb-labeled coronary guide wires. CONCLUSION: 81Rb-/81mKr-labeled coronary guide wires provide a signal that indicates volumetric MBF directly. This unique capability may qualify the technique as a valuable tool for research purposes and as an attractive method for invasive cardiology at centers where the logistic arrangements for short-lived isotope supply are provided.

Animals↗

PubMed1987

Studies on the prevalence of paralysis agitans by tracer methodology.

The present study was motivated by the methodological issues revealed by a review of previous studies on Paralysis Agitans (PA) epidemiology. The study was given the following aims: To identify an easy available, inexpensive marker of PA frequency in populations; to develop, standardize and validate a model for measurement of PA prevalence by using that tracer; to study the geographical distribution of PA in Sweden, and to use the model in environmental risk analysis (ERA) for PA. Information on diagnoses and anti-parkinsonian drugs (APD) utilization from Swedish registers was analyzed, in order to select the group of APD which would best fulfill the prerequisites of specificity and preference of choice, and combined with prevalence data from direct surveys. Levodopa drugs were found to be the most suitable tracer for PA prevalence. A mathematical model was formulated to generate annual estimates for average age specific prevalences from total sales of levodopa, age specific population and figures for infant mortality rates. The following was required in order for the model to yield accurate estimates: high quality of the information to be used, good availability of levodopa drugs, a minimal size of the studied population of 100,000, an IMR lower than 28.8 per 1000 and that levodopa diffusion had reached the late adoption phase. Underdiagnosis was found to constitute an important cause of bias in classical surveys. Standardization for age and health services effectiveness by using infant mortality rates was shown to improve comparability of prevalence figures. The model was validated and showed internal consistency for age specific data on levodopa sales and on prevalence from Sweden and six Chinese towns, respectively. Estimates for prevalence for Iceland and Sardinia fitted historical data from direct surveys. The results of the ERA study showed that a high latitude and a low population density in 1900-20 were correlated with an increase in PA prevalence as measured by surveys or estimated by the use of the tracer method. Further analysis indicated that several so-called risk factors or concomitant diseases are associated with low population density. The geographical distribution of standardized PA prevalences in Swedish counties was studied for the period 1977-84. The findings were in accordance with the figures expected from the natural characteristics of the disease as determined by latitude and population density except in the county of Gävleborg which showed a significantly higher, and continuously increasing prevalence.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed2002

Validation of a kinetic model for the reactions in RIA.

The goal of this work was to check the validity of a model previously described for the study of kinetics of the processes taking place during the immuno-analytical measurement of insulin. The antibody was immobilized on the suface wall of the reaction tube. Tracer and insulin concentration, temperature, viscosity and ionic strength in the reaction medium were taken as independent variables. Biexponential kinetics depending on the concentration was observed. The results of the viscosity study show a clear negative influence of this parameter on the direct reaction velocity. Ionic strength had a slight effect, which suggests that the observed variation due to the addition of glycerol is not induced by the influence of the dielectric constant of the solution used. The effect of the temperature shows activation parameters similar to water flow-viscosity energy, which suggests a diffusion control for the reaction. The proposed model correctly interprets the influence of the studied variables.

Antibodies↗

PubMed1990

The development of handedness in left/right asymmetry.

The development of handed asymmetry requires a special mechanism for consistently specifying a difference between left and right sides. This is to be distinguished from both random asymmetry, and from those left/right differences that are mirror symmetrical. We propose a model for the development of handedness in bilateral animals, comprising three components. (i) A process termed conversion, in which a molecular handedness is converted into handedness at the cellular level. A specific model for this process is put forward, based on cell polarity and transport of cellular constituents by a handed molecule. (ii) A mechanism for random generation of asymmetry, which could involve a reaction-diffusion process, so that the concentration of a molecule is higher on one side than the other. The handedness generated by conversion could consistently bias this mechanism to one side. (iii) A tissue-specific interpretation process which responds to the difference between the two sides, and results in the development of different structures on the left and right. There could be direct genetic control of the direction of handedness in this model, most probably through the conversion process. Experimental evidence for the model is considered, particularly the iv mutation in the mouse, which appears to result in loss-of-function in biasing, and so asymmetry is random. The model can explain the abnormal development of handedness observed in bisected embryos of some mammalian, amphibian and sub-vertebrate species. Spiral asymmetry, as seen in spiral cleavage and in ciliates, involves only conversion of molecular asymmetry to the cellular and multicellular level, with no separate interpretation step.

Animals↗

PubMed2004

Modelling hydroenvironmental and health risk assessment parameters along the South Wales Coast.

This paper highlights the increasing concerns relating to hydroenvironmetal issues and cites recent examples of the challenges now being regularly faced by hydroenvironmetal scientists and engineers. The limitations and restrictions of both physical (or laboratory) and numerical (or computer based) hydraulic models used in the planning and management of aquatic basins are discussed. General details are given of numerical models used for flow and water quality concentration predictions in estuarine waters, with particular application to the challenges occurring along the South Wales coast. A highly accurate and non-diffusive finite difference scheme that solves the transport equation for predicting water quality indicators and suspended sediment concentration distributions is also discussed. In particular, details are outlined of the extension of the water quality indicators of faecal coliforms, as required to comply with the EU Bathing Water Directive, to predict health risk assessment, in the form of predicting the risk of gastroenteritis. Three example research projects along the South Wales coast are described; the projects involve the application of two-dimensional and three-dimensional hydroenvironmetal models to predict flow patterns and water quality indicator organism distributions in the coastal receiving waters. These studies include: (i) a curvilinear finite difference approach to modelling flows in the Bristol Channel, (ii) coastal health risk predictions in Swansea Bay using combined water quality and epidemiological models, and (iii) combined sewer overflow discharges into Cardiff Bay.

Computer Simulation↗