Left-ventricular pressure gradients: a computer-model simulation

Both invasive left-ventricular pressure measurements and non-invasive colour M-mode echographic measurements have shown the existence of intraventricular pressure gradients (IVPGs) during early filling. The mechanisms responsible for these IVPG cannot be completely explained by the experiments. Therefore a one-dimensional numerical model is developed and validated. The model describes filling (both velocities and pressures) along a left ventricular (LV) base-apex axis. Blood-wall interaction in the left ventricle with moving boundaries is taken into account. The computational results for a canine heart indicate that the observed IVPGs during filling are the consequence of a complex interaction between, on the one hand, pressure waves travelling in the LV and, on the other hand, LV geometry, relaxation and compliance. The computational results indicate the pressure dependency of wavespeed (0.77-1.90 m-1 s) for different mean intraventricular pressures (0.88-5.00 mmHg) and IVPGs up to 2 mmHg, independent of the ratio of end systolic volume and equilibrium volume. Increasing relaxation rate not only decreases minimum basal pressure (2.8 instead of 3.6 mmHg) but also has a strong influence on the time delay between the minimum basal and apical pressures (14 ms instead of 49 ms). The results sustain the hypothesis that pressure-wave propagation determines IVPGs and that IVPGs are no proof of elastic recoil.     

Altered mitochondrial oxidative phosphorylation in hippocampal slices of kainate-treated rats

Mitochondria provide the main neuronal energy supply and are important organelles for the sequestration of intracellular Ca2+. This indicates a possible important role for mitochondria in modulating neuronal excitability in normal function as well as in disease. Therefore, we have investigated mitochondrial oxidative phosphorylation in the kainate model of epilepsy. We measured the oxygen consumption of single 400-micron rat hippocampal slices applying high resolution respirometry and determined mitochondrial NAD(P)H autofluorescence signal changes in single slices by laser-excited fluorescence spectroscopy. We observed an about 2-fold higher (p<0.001) basal glucose oxidation rate in slices from kainate-treated animals. This increased endogenous energy consumption was found to be unrelated to spontaneous activity since it was not sensitive to the inhibitors of the sodium-potassium ATPase ouabain and of the mitochondrial adenine nucleotide translocator atractyloside. This finding suggested an increased mitochondrial energy turnover in kainate-induced epilepsy. Furthermore, the uncoupler-stimulated oxygen consumption of the slices was approximately 1.3-fold higher (p<0.01) in the kainate model. In accordance with the respirometric data, fluorescence spectroscopy showed decreased reduction levels of the mitochondrial NAD-system in glucose oxidizing slices from kainate-treated rats. The preincubation of epileptic hippocampal slices with either BAPTA AM, ruthenium red or TPP+ increased the atractyloside sensitivity of glucose oxidation to about 1.4-fold (p<0.01). These observations indicate that the increased mitochondrial energy turnover in hippocampal slices from kainate-treated rats is most possibly caused by futile Ca2+-cycling.     

Inositol reduces depressive-like behaviors in two different animal models of depression

  Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP₃). Clinical studies have reported that inositol is effective in relieving symptoms of depression. Objective: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. Methods and results: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. Conclusions: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action. Received: 31 August 1998 / Final version: 18 November 1998     

The effect of separate red blood cells on capillary tissue oxygenation calculated with a numerical model

Author to whom correspondence should be addressed In simplified models that describe large quantities of capillariesthe capillary content is considered to be homogeneous for oxygentransport; but, in reality, the capillaries contain discretered blood cells (RBCs), and this discreteness will affect oxygentransport from the capillary to the tissue. This was previouslyinvestigated with an analytical model, where RBCs were modelledas point-like sources. A numerical approach is used in thisinvestigation, and the results are compared with the analyticalmodel. In both models the effect of the particulate nature ofblood depends on the haematocrit and on the RBC velocity. Thereis only a minor difference between the two models. For rat hearts,the correction factor used in this study, the extraction pressure,can be up to 3 kPa (23 mmHg).     

A prospective study to evaluate the efficacy of modified swim-up preparation for male sex selection

A previously published study reporting the use of a modifiedswim-up technique for sperm preparation prior to inseminationwhich resulted in a high percentage of male births has beencriticized for its lack of controls. The present prospectivestudy was initiated to investigate further the efficacy of modifiedswim-up preparation for male sex-selection when applied in aproperly defined control group. Our results showed that theproportion of males born in singleton pregnancies was 50% inthe group inseminated following sperm preparation with Percolland in the control group with no sperm preparation comparedwith 88.5% in the group treated with the modified method ofswim-up sperm preparation prior to insemination. This high rateof males in the group treated with modified swim-up was alsoobserved in singleton pregnancies of women taking ovulationinducing drugs (primarily clomiphene citrate). This contrastswith previous publications in which a higher rate of femaleswas found in clomiphene citrate patients using the albumin separationtechnique. How the mechanism of the swim-up procedure may resultin a high male birth rate remains unclear. A high percentageof y enriched semen was found using fluorochrome quinacrinemustard staining but this procedure may falsely stain autosomalchromosomes. If analysis using sensitive DNA probes fails toconfirm the y enrichment of the spermatozoa, one must hypothesizethat the modified swim-up procedure damages the x-spermatozoa.     

How do normal subjects learn a simple adaptative task: How and why do paranoid schizophrenic patients fail?

Summary The authors studied the behavior of normal subjects and paranoid schizophrenic patients in a simple problem-solving situation. The schizophrenics were divided into two sample groups, one of individuals under treatment and the other of individuals not under treatment.The learning process involved in this problem-solving situation is very similar to an instrumental conditioning, and can be understood by means of the following assumptions: (1) the subjects use decision functions in reacting to the stimuli, although they may be not fully aware of this; (2) learning is the result of successive transformations of these decisions in the course of time; (3) the changes have specific probabilities and are related to (a) those responses which are made to the latest stimuli, and (b) a differential probability for decision functions which were effective, or only interrupted painful reinforcement, or were completely ineffective.In schizophrenics further factors of importance were (1) an inertia factor and (2) the rigidly continued use of unsuccessful or only partially successful decision criteria.The authors used a systems theory based on Galois field theory and a calculus of operators specifying three groups of subjects. A computer program based on these hypotheses was tested in a simulation experiment.The statistical evaluation of the results showed a congruence between the theoretical approach and the experimental data.This work was carried out with financial support from the Institute de Alta Cultura, Lisbon, between 1970 and 1974     

Kinetics of d-tubocurarine disposition and pharmacologic response in rats

After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of³H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses 0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range 0.15 mg/kg.This work was presented at the First Japanese-American Symposium on Pharmacokinetics and Biopharmaceutics, Tokyo, July 1981, which was held in memory of Dr. Sidney Riegelman.     

Functional imaging and localization of electromagnetic brain activity

Functional imaging of electric brain activity requires specific models to transform the signals recorded at the surface of the human head into an image. Two categories of model are available: single-time-point and spatio-temporal methods. The instantaneous methods rely only on the few voltage differences measured at one sampling point. To create a spatial image from this limited information, they require strict assumptions that rarely conform with the underlying physiology. Spatio-temporal models create two kinds of images: first, a spatial image of discrete equivalent multiple dipoles or regional sources, and second, an image of source current waveforms that reflect the temporal dynamics of the brain activity in circumscribed areas. The accuracy of the spatial image is model dependent and limited, but it can be validated from the spatio-temporal data by the "regional source imaging" technique, introduced here. The source waveforms are linear combinations of the scalp waveforms, and thus, specific derivations which image local brain activities at a macroscopic level. Brain source imaging of somatosensory evoked potentials revealed temporally overlapping activities from the brainstem, thalamus and from multiple sources in the region of the contralateral somatosensory projection areas.     

Photodynamic therapy in the bladder: Can the light dose be easily quantified?

The shape of the bladder and the optical characteristics of the tissue within the wall can be shown to play an important role in the amount of light actually received at the wall. The use of estimated doses even assuming spherical geometry, cannot therefore be relied upon. This paper describes some experimental work carried out on a glass model that was used to simulate the bladder. A specially constructed dual detector was used which consisted of an isotropic probe and semiconductor detector. This enabled measurements of irradiance and space irradiance (light energy fluence rate) to be made simultaneously. By changing the optical characteristics of the wall a four-fold increase in space irradiance was measured. Contamination of the water contained within the model by blood was also investigated and has shown that with concentrations as low as 0.5% the delivered light dose reaching the wall can be reduced by up to 50% at a wavelength of 510 nm. Some in vivo measurements are also presented together with some comments on the difficulties that have been encountered when transferring measurements from the model to the patient.     

Terbutaline aerosol from a metered dose inhaler via a 750 ml spacer

Summary The effect on large and small airways of a pressurized terbutaline aerosol delivered via a 750 ml spacer, or via an ordinary actuator, was investigated in a double-blind study of 15 patients with reversible obstructive airflow disease. There was significant bronchodilatation with both devices as measured byRaw, FEV_1.0, PEFR, MEF₇₅, MEF₅₀, and MEF₂₅.Raw showed, a significant difference in favour of the 750 ml spacer. Measurement of Closing Volume (CV) revealed a significant decrease with the spacer, but with the ordinary actuator there was a slight increase in CV; the difference between the devices was significant. The quotient Closing Volume/Vital Capacity (CV/VC%) was significantly decreased with the 750 ml spacer but not with the ordinary actuator. The decrease in volume of isoflow (Viso ) was more pronounced with the spacer but not significantly so. The results suggest that use of a 750 ml spacer may promote more extensive peripheral deposition of the drug in the bronchial tract.