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PubMed1992

A unified neural network [corrected] model of spatiotemporal processing in X and Y retinal ganglion cells. I. Analytical results.

This work presents unified analyses of spatial and temporal visual information processing in a feed-forward network of neurons that obey membrane, or shunting equations. The feed-forward shunting network possesses properties that make it well suited for processing of static, spatial information. However, it is shown here that those same properties of the shunting network that lead to good spatial processing imply poor temporal processing characteristics. This article presents an extension of the feed-forward shunting network model that solves this problem by means of preprocessing layers. The anatomical interpretation of the resulting model is structurally analogous to recently discovered data on a retinal circuit connecting cones to retinal ganglion cells through pairs of push-pull bipolar cells. Mathematical analysis of the lumped model leads to the hypothesis that X and Y retinal ganglion cells may consist of a single mechanism acting in different parameter ranges. This hypothesis is confirmed in the companion article, wherein the model--in conjunction with a nonlinear temporal adaptation mechanism--is used to reproduce experimental data of both X and Y cells by simple changes in morphological and physiological parameters.

Mathematics↗

PubMed1987

Determination of "active" cytochrome P-450 from relaxation kinetics of product formation.

We estimate the "active" part of cytochrome P-450, which is involved in a special substrate transformation, by measuring the initial change of the production rate as a function of the relaxation transitions between two different steady states of the reaction cycle of cytochrome P-450 using the light-reversibility of the carbon monoxide inhibition. The kinetic data of such relaxations are interpreted within a model cycle, which reduces the reaction cycle to three steps. The estimation of the rate constant of the first reduction step, derived from model simulation of the production rate, is confirmed by independent experimental study of the reduction kinetics. An application of our model to the O-deethylation of 7-ethoxycoumarin reveals that--in a time average--10%-15% of the spectroscopically detectable cytochrome P-450 is involved in that transformation.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1986

The adsorption and reaction of adenine nucleotides on montmorillonite.

The binding of AMP to Zn(2+)-montmorillonite was investigated in the presence of buffers and salts. Good's buffers, piperazine-N,N'-bis(2-ethanesulfonate) [PIPES] and morpholine-N-2-ethanesulfonate [MES], perturbed the exchangeable cations to a lesser extent (only 9% of Zn2+ displaced by 0.2 M buffer) than was observed with imidazole and lutidine buffers or NaCl and KCl salts (up to 80% of Zn2+ displaced). AMP adsorption isotherms measured in the presence of 0.2 M PIPES, MES, or Na2SO4 exhibited normal Langmuir-type behavior. The adsorption coefficient, KL, is 3-fold greater in the presence of HEPES or PIPES than it is in the absence of buffers. Basal spacings measured by X-ray diffraction for Zn(2+)-montmorillonite are 13 and 15 angstroms in the presence of PIPES, while a value of 12.8 angstroms was determined in the absence of PIPES. These data are interpreted in a model in which the adsorption of AMP is mediated by a Zn2+ complex of PIPES in different orientations in the interlamellar region of the montmorillonite. The type of exchangeable cation does not affect the ability of the lattice-bound Fe3+ in the montmorillonite to oxidize diaminomaleonitrile (DAMN). Exchangeable Cu2+ oxidizes DAMN, but exchangeable Fe3+ is nearly ineffective as an oxidant. The addition of DISN to 3'-AMP bound to Zn(2+)-montmorillonite in the presence of 0.2 M PIPES resulted in a higher yield of 2',3'-cAMP than is observed with a comparable concentration of Zn2+, a result which inplicates surface catalysis by the montmorillonite.

Adenine Nucleotides↗

PubMed1980

Action of glucosamine on acetylcholine-sensitive channels.

The action of glucosamine was studied on voltage clamped neurones of Aplysia, presenting an excitatory response to acetylcholine. Noise and relaxation experiments show that glucosamine increases the mean channel open time and reduces the amplitude of the elementary current associated with the acetylcholine response. Both effects are enhanced by hyperpolarization of the cell membrane. The results are interpreted by a model assuming glucosamine binding to open channels. This binding impedes the flow of permeant ions and decreases the closing rate of the channels.

Acetylcholine↗

PubMed1990

Mechanism of action of H2-antagonists on histamine- or dimaprit-stimulated H2-receptors of spontaneously beating guinea-pig atrium.

Cimetidine, ranitidine and famotidine are antagonists of the histamine H2-receptors on the spontaneously beating right atrium of the guinea pig. When analyzed by the classical Schild method their pA2-values are respectively: 6.3, 6.8 and 7.7 with dimaprit as agonist and 5.8, 6.5 and 7.7 with histamine as agonist. Radioligand-displacement studies with [3H]-tiotidine as radioligand resulted in pKd values for cimetidine, ranitidine and famotidine of 6.3; 6.9 and 8.2 respectively. In dimaprit-stimulated atria all antagonists added at concentrations above their Kd values depressed the maximal increase in frequency. In the presence of histamine this effect was much less pronounced and only visible at concentrations of ranitidine and famotidine around 10.Kd. The rightward shift of the curves as well as the decrease in Emax are reversible but the dissociation constants of the antagonists are small (less than 10(-3) s-1). The spontaneously beating right atrium showed receptor reserve for histamine and virtually no receptor reserve for dimaprit. The results have been interpreted in a model in which H2-antagonists act mainly by competing with the agonist for the histamine receptor site but have in addition a distinct affinity for a secondary site on the receptor. Occupation of this site by the antagonist prevents building up of the stimulus elicited by the agonist and thus decreases the Emax. In systems with receptor reserve (histamine) the effect of antagonist binding to the secondary binding site is seen only at high concentration of antagonist while in absence of receptor reserve (dimaprit) the depression of Emax is directly visible. Simulations of the model show that the affinity of this secondary binding site is 50-(famotidine) to 100-(cimetidine and ranitidine) fold lower than for the agonist binding site.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

Clozapine acts as a 5-HT2 antagonist by attenuating DOI-induced inhibition of male rat sexual behaviour.

Evidence has been reported that clozapine may derive part of its therapeutic effects in treatment-resistant schizophrenic patients by interacting with the serotonin system. Among the few behavioural models available to test the hypothesis of an interaction of clozapine with 5-HT2 receptors, male rat sexual behaviour is particularly useful, since in this behaviour 5-HT1A and 5-HT2 receptors have opposite functions. Stimulation of 5-HT1A receptors facilitates ejaculatory behaviour and stimulation of 5-HT2 receptors inhibit ejaculation. In the present study, male rat sexual behaviour was depressed by treatment with DOI (1.0 mg/kg), a selective 5-HT2 receptor agonist. The depressive effect of DOI was attenuated by the administration of clozapine (0.1-1.0 mg/kg) in doses that by themselves did not significantly affect sexual behaviour. It was concluded that clozapine in the male rat sexual behaviour model may be interpreted as serving as a 5-HT2 antagonist.

Animals↗

PubMed1998

Geography and mental health: a review.

In our current health care context, characterized by fiscal restraint and decentralization of accountability for health to regional authorities, geographic inequities in need, access to care, utilization, and health outcomes will come under increasing scrutiny. Knowledge gained from ecological studies about geographic disparities in mental health are likely to have important implications for policy, program planning, and resource allocations. In light of the growing relevance of the geography of mental health, this paper will review (1) selected contributions of geographic studies to the field of mental health, (2) common ecologic study approaches used in most geographic studies, (3) key conceptual and methodological challenges related to the application and interpretation of ecologic models in mental health, and (4) the wider potential of this technique for resource equity. Given the importance of geography for needs assessment and service planning, it is surprising that geographic study designs, which use ecological data, have not received greater attention as an important and viable method of assessing population mental health.

Diagnosis-Related Groups↗

PubMed2000

Sonographic assessment of renal length in the first year of life: the problem of "spurious nephromegaly".

PURPOSE: Interest in the potential diagnostic or prognostic implications of nephromegaly as evidence for compensatory renal hypertrophy has recently been emphasized in a variety of clinical settings. This project was designed to compare the results of linear and nonlinear sonographic models in the interpretation of renal size and growth during the first year of life. MATERIALS AND METHODS: We identified all renal and abdominal ultrasound examinations that were performed between March 1994 and October 1997 in full-term infants under age 1 year during which (1) both renal lengths were measured and (2) both kidneys appeared anatomically normal. Using three different computerized algorithms based on published standards for sonographic renal length in relation to age, we calculated z-scores for the renal lengths and compared the results of the three methods: in method A the standards at birth, 1 week, 4 months, 8 months, and 1 year were all used; in method B the 1-week standard was omitted; in method C the standards at 1 week, 4 months, and 8 months were omitted. RESULTS: We evaluated 1,234 renal measurements in 617 patients (293 boys, 324 girls; mean age 0.24 year). Compared with method A, z-scores were significantly increased when either method B or C was used (P < 0. 0001). The mean increment in z-score was + 0.433 for method B and + 1.135 for method C. The prevalence of "nephromegaly" (z > + 2) was significantly increased when subannual standards were omitted (P < 0. 0001): using method A, 20 (1.6 %) kidneys were large for age compared with 74 (6.0 %) using method B, and 214 (17.3 %) using method C. All kidneys that were large for age based on method A were also large for age using both methods B and C. The rate of false-positive diagnosis of nephromegaly was 73 % (54/74 kidneys) with method B and 91 % (194/214 kidneys) with method C. CONCLUSIONS: Although the use of multiple subannual standards for renal length in infants less than 1 year of age is time consuming and mathematically more complicated, omission of these standards results in a statistically significant increase in the frequency of "spurious" nephromegaly. LEARNING OBJECTIVES: Precise application of published standards is important in the interpretation of sonographic measurements of renal length. Omission of the subannual standards for renal length in children who are less than 1 year of age can result in an incorrect impression of nephromegaly.

Female↗

PubMed2003

Field-dependent proton relaxation in aqueous solutions of some manganese(II) complexes: a new interpretation.

Field-dependent measurements of the paramagnetic relaxation enhancement for water protons in the presence of Mn(II) complexes ( S=5/2), reported recently, are re-interpreted using theoretical models that take into consideration the fact that the relaxation of the electron spin for S>1 is multiexponential (even in the Redfield limit) and that are valid for an arbitrary relation between the electronic Zeeman interaction and the zero-field splitting in the complex.

Algorithms↗

PubMed2005

Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology.

(1) The specifically regulated restrictive permeability barrier to cells and molecules is the most important feature of the blood-brain barrier (BBB). The aim of this review was to summarize permeability data obtained on in vitro BBB models by measurement of transendothelial electrical resistance and by calculation of permeability coefficients for paracellular or transendothelial tracers. (2) Results from primary cultures of cerebral microvascular endothelial cells or immortalized cell lines from bovine, human, porcine, and rodent origin are presented. Effects of coculture with astroglia, neurons, mesenchymal cells, blood cells, and conditioned media, as well as physiological influence of serum components, hormones, growth factors, lipids, and lipoproteins on the barrier function are discussed. (3) BBB permeability results gained on in vitro models of pathological conditions including hypoxia and reoxygenation, neurodegenerative diseases, or bacterial and viral infections have been reviewed. Effects of cytokines, vasoactive mediators, and other pathogenic factors on barrier integrity are also detailed. (4) Pharmacological treatments modulating intracellular cyclic nucleotide or calcium levels, and activity of protein kinases, protein tyrosine phosphatases, phospholipases, cyclooxygenases, or lipoxygenases able to change BBB integrity are outlined. Barrier regulation by drugs involved in the metabolism of nitric oxide and reactive oxygen species, as well as influence of miscellaneous treatments are also listed and evaluated. (5) Though recent advances resulted in development of improved in vitro BBB model systems to investigate disease modeling, drug screening, and testing vectors targeting the brain, there is a need for checking validity of permeability models and cautious interpretation of data.

Animals↗

PubMed2006

Molecular mobility in glass forming fananserine: a dielectric, NMR, and TMDSC investigation.

PURPOSE: This study was conducted to characterize the molecular mobility of supercooled fananserine and derive from this analysis the non-Arrhenius and nonexponential properties of the primary alpha-relaxation. METHODS: The use of three investigation techniques of the molecular mobility, namely, dielectric relaxation, modulated differential scanning calorimetry, and proton nuclear magnetic resonance, allowed us to describe the dynamic properties of supercooled fananserine on a wide range of frequencies and temperatures, ranging from the melting temperature T(m) = 372 K down to the glass transition temperature T(g) = 292 K. RESULTS: We emphasized the capacity of these three techniques to give a coherent set of information. We used the coupling-model theory to interpret the dielectric results. It allowed us to identify two relaxation processes (alpha and beta), corresponding to different molecular motions. The temperature evolution of the alpha-relaxation indicates that fananserine is a fragile glass former, as reflected by the steepness index value, m = 77. The temperature T(o) where the relaxation times diverge was also determined. CONCLUSIONS: The description of the dielectric relaxation data in terms of the Kohlrausch-Williams-Watt relaxation function has shown the existence of an additional low-amplitude relaxation process assigned to the so-called Johari-Goldstein process. Mainly concerned by the primary alpha-process directly involved in the glass formation, we derived from this analysis the characteristic features of this process and showed that supercooled fananserine is characterized by a strongly non-Arrhenius and nonexponential behavior.

Air Pressure↗

PubMed1994

The relationship between truck accidents and geometric design of road sections: Poisson versus negative binomial regressions.

This paper evaluates the performance of Poisson and negative binomial (NB) regression models in establishing the relationship between truck accidents and geometric design of road sections. Three types of models are considered: Poisson regression, zero-inflated Poisson (ZIP) regression, and NB regression. Maximum likelihood (ML) method is used to estimate the unknown parameters of these models. Two other feasible estimators for estimating the dispersion parameter in the NB regression model are also examined: a moment estimator and a regression-based estimator. These models and estimators are evaluated based on their (i) estimated regression parameters, (ii) overall goodness-of-fit, (iii) estimated relative frequency of truck accident involvements across road sections, (iv) sensitivity to the inclusion of short road sections, and (v) estimated total number of truck accident involvements. Data from the Highway Safety Information System are employed to examine the performance of these models in developing such relationships. The evaluation results suggest that the NB regression model estimated using the moment and regression-based methods should be used with caution. Also, under the ML method, the estimated regression parameters from all three models are quite consistent and no particular model outperforms the other two models in terms of the estimated relative frequencies of truck accident involvements across road sections. It is recommended that the Poisson regression model be used as an initial model for developing the relationship. If the overdispersion of accident data is found to be moderate or high, both the NB and ZIP regression models could be explored. Overall, the ZIP regression model appears to be a serious candidate model when data exhibit excess zeros, e.g. due to underreporting. However, the interpretation of the ZIP model can be difficult.

Accidents, Traffic↗

PubMed1978

Myocardial imaging with thallium-201: a multicenter study in patients with angina pectoris or acute myocardial infarction.

A multicenter study of rest and exercise thallium-201 myocardial imaging in 190 patients from five centers was performed. Exercise images were obtained after graded treadmill or bicycle stress with use of five different gamma camera models and were interpreted by the originating investigator without knowledge of other clinical data. Of 42 patients with less than 50 percent coronary stenosis, 4 (10 percent) had a resting image defect, 1 (2 percent) a new exercise defect and 5 (12 percent) either a resting or an exercise image defect, or both. Of 148 patients with coronary stenosis of 50 percent or greater, 64, (45 percent) had an image defect in the study at rest, 90 (61 percent) had new or increased defects after exercise, and 115 (78 percent) had resting or exercise defects, or both. New exercise image defects were more common than exercise S-T depression (90 of 148 [61 percent] versus 62 of 148[42 percent]; P less than 0.01). In a second group of 111 patients with acute myocardial infarction studied at three centers, 90 patients (81 percent) had image defects compared with 71 (64 percent) two had new electrocardiographic Q waves (P less than 0.01). Smaller infractions, as assessed with serum enzyme values, and diaphragmatic infarctions were less commonly detected than larger or anterior infarctions. These findings suggest that myocardial imaging complements the electrocardiographic identification of acute myocardial infarction of exericse-induced myocardial ischemia.

Acute Disease↗

PubMed1988

A new mathematical model of the spine and its relationship to spinal loading in the workplace.

A knowledge of the loads imposed on the spine during manual work and of the postures in which the spine is least stressed while performing a particular task are of considerable importance for the design of a safe and comfortable working environment. Spinal loads are intrinsically very difficult to measure and so are generally calculated from mathematical models of the spine. These models are based on assumptions of how the spine functions mechanically, and the forces calculated are dependent on the particular model used. A new model, which assumes that the spine functions in a similar way to an arch, is discussed. This model shows that spinal stresses are not as great as previously calculated using the traditional cantilever model and that, even when no external loads are being carried, the stress is strongly dependent on posture. The arch model re-interprets the role of intra-abdominal pressure and shows that it acts together with the lumbar lordosis to strengthen the spine. Maintaining a lumbar lordosis is then important when lifting heavy loads.

Journal Article↗

PubMed1990

Probing the yeast 5 S RNA-protein complex by fluorescence and controlled proteolytic digestion.

The nature of the interaction between the RNA and the protein component in the yeast 5 S rRNA-L1a complex was assessed using fluorescence and controlled proteolytic and RNase digestion. (a) Influence of L1a on the RNA conformation was monitored by ethidium fluorescence and controlled RNase T1 digestion. The complex was digested with alpha-chymotrypsin, Staphylococcus aureus protease V8, subtilisin, or trypsin. Both termini of L1a in the complex were readily accessible to proteases. Proteolytic digestion of the complex resulted in a reduction in fluorescence intensity if ethidium was added after proteolysis. No change was observed when ethidium was allowed to react with the complex prior to proteolysis. Neither the rate of proteolysis nor the resultant peptide pattern was affected by the presence of ethidium. T1 digestion of intact RNP and trypsin-treated RNP produced different oligonucleotide patterns. Both the fluorescence and the T1 digestion data suggest that the conformation of the RNA moiety was influenced by the protein. (b) Influence of the RNA molecule on L1a conformation in the complex was monitored by limited proteolysis. Whereas the protein in the complex was relatively sensitive to proteases, free protein was completely resistant to digestion under identical conditions. The trypsin sensitivity of L1a in complexes containing different truncated 5 S RNA molecules was studied also. Upon removal of residues 31-49 of the 5 S RNA molecule, L1a in the complex became resistant to proteolysis. These results are interpreted in a model in which specific regions of both the RNA and the protein are involved in the interaction.

Chymotrypsin↗

PubMed1985

The effect of mono- and divalent salts on the rise and decay kinetics of EPR signal II in Photosystem II preparations from spinach.

The rise and decay kinetics of EPR signal II have been used to probe the organization of the donor side of Photosystem II (PS II) before and after extraction of PS II preparations with high concentrations of salt. 800 mM NaCl or 500-800 mM NaBr substantially depletes the preparations of the 16 and 24 kDa proteins and decreases the steady-state rate of O2-evolution by 70-80% from control rates. These treatments do not largely alter the decay kinetics of Signal II; the rise kinetics remain in the instrument limited time range (2 microseconds or less) during the first 8-12 flashes. Treating PS II preparations with 800 mM CaCl2 removes the 16, 24 and 33 kDa proteins with at least 95% inhibition of the steady-state rates of O2 evolution. The additional removal of the 33 kDa polypeptide decreases the rates of oxidation and rereduction of Z, the species responsible for Signal II. Preparations treated with either mono- or divalent salts show a steady-state light-induced increase in Signal II similar to that seen in Tris-washed samples. Such a steady-state increase indicates that the rate of electron transport from water to Z is greatly decreased or blocked. The data are interpreted within a model in which there is an intermediate electron carrier between the O2 evolving complex and Z.

Calcium Chloride↗

PubMed1992

Properties of oligomycin-induced occlusion of Na+ by detergent-solubilized Na,K-ATPase from pig kidney or shark rectal gland.

Oligomycin induces occlusion of Na+ in membrane-bound Na,K-ATPase. Here it is shown that Na,K-ATPase from pig kidney or shark rectal gland solubilized in the nonionic detergent C12E8 is capable of occluding Na+ in the presence of oligomycin. The apparent affinity for Na+ is reduced for both enzymes upon solubilization, and there is an increase in the sigmoidicity of binding curves, which indicates a change in the cooperativity between the occluded ions. A high detergent/protein ratio leads to a decreased occlusion capacity. De-occlusion of Na+ by addition of K+ is slow for solubilized Na,K-ATPase, with a rate constant of about 0.1 s-1 at 6 degrees C. Stopped-flow fluorescence experiments with 6-carboxyeosin, which can be used to monitor the E1Na-form in detergent solution, show that the K(+)-induced de-occlusion of Na+ correlates well with the fluorescence decrease which follows the transition from the E1Na-form to the E2-form. There is a marked increase in the rate of fluorescence change at high detergent/protein ratios, indicating that the properties of solubilized enzyme are subject to modification by detergent in other respects than mere solubilization of the membrane-bound enzyme. The temperature dependence of the rate of de-occlusion in the range 2 degrees C to 12 degrees C is changed slightly upon solubilization, with activation energies in the range 20-23 kcal/mol for membrane-bound enzyme, increasing to 26-30 kcal/mol for solubilized enzyme. Titrations of the rate of transition from E1Na to E2K with oligomycin can be interpreted in a model with oligomycin having an apparent dissociation constant of about 2.5 microM for C12E8-solubilized shark Na,K-ATPase and 0.2 microM for solubilized pig kidney Na,K-ATPase.

Animals↗

PubMed1992

Effect of bovine prothrombin fragment 1 on the translational diffusion of phospholipids in Langmuir-Blodgett monolayers.

Previous work has shown that bovine prothrombin fragment 1 binds to supported planar membranes composed of phosphatidylcholine and phosphatidylserine in a Ca(2+)-specific manner (Tendian et al. (1991) Biochemistry 30, 10991; Pearce et al. (1992) Biochemistry 31, 5983-5995). In the present work, fluorescence pattern photobleaching recovery has been used to examine the effect of membrane-bound fragment 1 on the translational diffusion coefficients of two fluorescent phospholipids in fluid-like phosphatidylserine/phosphatidylcholine Langmuir-Blodgett monolayers. The results show that saturating concentrations of fragment 1, in the presence of Ca2+, reduce the diffusion coefficient of nitrobenzoxadiazolyl-conjugated phosphatidylserine (NBD-PS) and nitrobenzoxadiazolyl-conjugated phosphatidylcholine (NBD-PC) by factors of approximately four and two, respectively. Ca2+ or fragment 1 alone do not have a statistically significant effect on NBD-PS or NBD-PC diffusion. In addition, a nonspecific protein (ovalbumin) does not change the diffusion coefficients of the fluorescent phospholipids either in the absence or presence of Ca2+. The fractions of the fluorescent phospholipids that are laterally mobile are approximately 0.9 for all samples. These results are interpreted with several models for possible mechanisms by which extrinsically bound proteins might retard phospholipid diffusion in membranes.

4-Chloro-7-nitrobenzofurazan↗