Silvio Cavalcanti

Altered excitability of motor neurons in a transgenic mouse model of familial amyotrophic lateral sclerosis

Various evidence suggests that amyotrophic lateral sclerosis (ALS) selectively affects motor neuron functioning, but electrophysiological alterations of single motor neurons in ALS remains to be documented. In the present work, the excitability of motor neurons has been tested in a transgenic mouse model of a familial form of ALS, associated with a mutation in Cu,Zn superoxide dismutase (Gly(93)-->Ala). Patch-clamp recordings of membrane potential in transgenic mice motor neurons showed that they fire with increased frequency and shorter duration compared to motor neurons from control mice. The passive membrane properties of these neurons were equivalent however. Such results suggest that an altered motor neuron excitability accompanies an ALS associated mutation and that may contribute to the pathogenesis of the disease.

Modeling of cardiovascular variability using a differential delay equation

The influence of time delay in the baroreflex control of the heart activity is analyzed by using a simple mathematical model of the short-term pressure regulation. The mean arterial pressure in a Windkessel model is controlled by a nonlinear feedback driving a nonpulsatile model of the cardiac pump in accordance with the steady-state characteristics of the arterial baroreceptor reflex. A pure time delay is placed in the feedback branch to simulate the latent period of the baroreceptor regulation. Because of system nonlinearity model dynamics is found to be highly sensitive to time delay and changes of this parameter within a physiological range cause the model to exhibit different patterns of behavior. For low values of time delay (shorter than 0.5 s) the model remains in a steady state. When time delay is longer than 0.5 s, a Hopf bifurcation is crossed and spontaneous oscillations occur with frequencies in the high-frequency (HF) band. Further increases of time delay above 1.2 s cause the oscillations to become more complex, and following the typical Feigenbaum cascade, the system becomes chaotic. In this condition heart rate, pressure, and how show evident variability. The heart rate power spectrum exhibits a peak whose frequency moves from the HF to LF band depending on whether simulated time delay is as short as the vagal-mediated control or long as the sympathetic one.

Hemodynamics of an artery with mild stenosis

In this study the hemodynamics in the early stages of the atherosclerotic process--when a neointimal hyperplasia or an intimal fibrocellular hypertrophy takes place--is theoretically investigated. A local, slight increase in the wall thickness of a canine femoral artery is simulated using an original two-dimensional mathematical model of arterial hemodynamics and the effects induced on the velocity field by the simulated mild stenosis--only 2% of area reduction--are analysed. The model incorporates: fluid non-linear inertial forces, viscoelastic wall motion, anatomical taper, unsteady flow, pressure propagation and reflections on both the proximal and distal vessel ends. Two different physiological pulsatile flows are considered: a basal flow condition and a light vasodilation state inducing in the vessel segment a limited increase in mean flow (50%). The distribution along the vessel during the cardiac cycle of both the velocity profile and wall shear stress, are shown. The shape of velocity distributions is strongly perturbed by the stenosis and disturbances are clearly evident whatever instant of the cardiac cycle is considered. After vasodilatation, during the phase of systolic deceleration, a vortex circulation appears in the post-stenotic region. The vortex persists for the whole diastolic phase, causing a very strong stress at the arterial wall: wall shear stress in the distal part of the simulated mild stenosis is at least five times the basal value. The reported results provide a coherent explanation of the critical role that hemodynamic factors may play in the early stages of atherogenic process.

α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptors in spinal cord motor neurons are altered in transgenic mice overexpressing human Cu,Zn superoxide dismutase (Gly93→Ala) mutation

There are many evidences implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). This neurodegenerative disorder is characterized by the progressive loss of motor neurons, whose pathogenesis is thought to involve Ca(2+) influx mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptors (AMPARs). In the present study we report alterations in the AMPARs function in a transgenic mouse-model of the human SOD1(G93A) familial ALS. Compared with those expressed in motor neurons carrying the human wild type gene, AMPAR-gated channels expressed in motor neurons carrying the human mutant gene exhibited modified permeability, altered agonist cooperativity between the sites involved in the process of channel opening and were responsible for slower spontaneous synaptic events. These observations demonstrate that the SOD1(G93A) mutation induces changes in AMPAR functions which may underlie the increased vulnerability of motor neurons to glutamatergic excitotoxicity in ALS.

Theoretical analysis of pressure pulse propagation in arterial vessels

An original mathematical model of viscous fluid motion in a tapered and distensible tube is presented. The model equations are deduced by assuming a two-dimensional flow and taking into account the nonlinear terms in the fluid motion equations, as well as the nonlinear deformation of the tube wall. One distinctive feature of the model is the formal integration with respect to the radial coordinate of the Navier-Stokes equations by power series expansion. The consequent computational frame allows an easy, accurate evaluation of the effects produced by changing the values of all physical and geometrical tube parameters. The model is employed to study the propagation along an arterial vessel of a pressure pulse produced by a single flow pulse applied at the proximal vessel extremity. In particular, the effects of the natural taper angle of the arterial wall on pulse propagation are investigated. The simulation results show that tapering considerably influences wave attenuation but not wave velocity. The substantially different behavior of pulse propagation, depending upon whether it travels towards the distal extremity or in the opposite direction, is observed: natural tapering causes a continuous increase in the pulse amplitude as it moves towards the distal extremity; on the contrary, the reflected pulse, running in the opposite direction, is greatly damped. For a vessel with physical and geometrical properties similar to those of a canine femoral artery and 0.1 degree taper angle, the forward amplification is about 0.9 m-1 and the backward attenuation is 1.4 m-1, so that the overall tapering effect gives a remarkably damped pressure response. For a natural taper angle of 0.14 degrees the perturbation is almost extinct when the pulse wave returns to the proximal extremity.

A new nonlinear two-dimensional model of blood motion in tapered and elastic vessels

An original mathematical model for the local study of blood motion in tapered and distensible arteries was developed. The theory takes into account the nonlinear terms of the Navier-Stokes equations, as well as wall motion and instantaneous taper angle, and allows the calculation of axial and radial velocity profiles with low computational complexity. The relationship between instantaneous flow and the pressure gradient in steady and dynamic conditions is evaluated by means of the mathematical model. The results obtained by simulation agree with experimental evidence and also indicate that the anatomic tapering of arteries and pulsatile changes in diameter highly influence blood motion.

Electrophysiological response to dialysis: the role of dialysate potassium content and profiling.

UNLABELLED The task of dialysis therapy is, amongst other things, to remove excess potassium (K+) from the body. The need to achieve an adequate K+ removal with the risk of cardiac arrhythmias due to sudden intra-extracellular K+ gradient advises the distribution of the removal throughout the dialysis session instead of just in the first half. The aim of the study was to investigate the electrical behavior of two different K+ removal rates on myocardial cells (risk of arrhythmia and ECG alterations). Constant acetate-free biofiltration (AFB) and profiled K+ (decreasing during the treatment) AFB (AFBK) were used in a patient sample to understand, first of all, the effect on premature ventricular contraction (PVC) and on repolarization indices [QT dispersion (QTd) and principal component analysis (PCA)]. The study was divided into two phases: phase 1 was a pilot study to evaluate K+ kinetics and to test the effect on the electrophysiological response of the two procedures. The second phase was set up as an extended cross-over multicenter trial in patient subsets prone to arrhythmias during dialysis. Phase 1: PVC increased during both AFB and AFBK but less in the latter in the middle of dialysis (298 in AFB vs. 200 in AFBK). The PVC/h in a subset of arrhythmic patients was 404 +/- 145 in AFB and 309 +/- 116 in AFBK (p = 0.0028). QT interval (QTc) prolongation was less pronounced in AFBK than in AFB. Phase 2: The PVC again increased in both AFB and AFBK but less in the latter mid-way through dialysis (79 +/- 19 AFB vs. 53 +/- 13 AFBK). Moreover, in the most arrhythmic patients the benefit accruing from the smooth K+ removal rate was more pronounced (103 +/- 19 in AFB vs. 78 +/- 13 in AFBK). CONCLUSION It is not the K+ dialysis removal alone that can be destabilizing from an electrophysiological standpoint, but rather its removal dynamics. This is all the more evident in patients with arrhythmias who benefit from the K+ profiling during their dialysis treatment.

Chaotic oscillations in microvessel arterial networks

A mathematical model of a multibranched microvascular network was used to study the mechanisms underlying irregular oscillations (vasomotion) observed in arteriolar microvessels. The networks layout included three distinct terminal arteriolar branches originating from a common parent arteriole. The biomechanical model of the single microvessel was constructed to reproduce the time pattern of the passive and active (myogenic) response of arterioles in the hamster cheek pouch to a step-wise arterial pressure change. Simulation results indicate that, as a consequence of the myogenic reflex, each arteriole may behave as an autonomous oscillator, provided its intraluminal pressure lies within a specific range. In the simulated network, the interaction among the various oscillators gave rise to a complex behavior with many different oscillatory patterns. Analysis of model bifurcations, performed with respect to the arterial pressure level, indicated that modest changes in this parameter caused the network to shift between periodic, quasiperiodic, and chaotic behavior. When arterial pressure was changed from approximately 60–150 mm Hg, the model exhibited a classic route toward chaos, as in the Ruelle-Takens scenario. This work reveals that the nonlinear myogenic mechanism is able to produce the multitude of different oscillatory patterns observedin vivo in microvascular beds, and that irregular microvascular fluctuations may be regarded as a form of deterministic chaos.

Arterial baroreflex influence on heart rate variability: a mathematical model-based analysis.

The influence of the arterial baroreflex on the heart rate variability is analysed by using a mathematical model of heart rate baroreceptor control. The basic mechanisms of the model, sufficient to elicit heart rate variability include: systemic circulation, a non-pulsatile cardiac pump and nonlinear negative feedback simulating arterial baroreflex closed-loop control of the heart rate (−3bpm/mmHg as maximum reflex sensitivity). The latter reproduces, through two distinct delayed branches (0.8 and 2.8 s), the short-term autonomic control effected respectively by sympathetic and parasympathetic divisions on the sinus node. By means of this model, two distinct self-sustained oscillatory components with incommensurate frequencies (0.1 and 0.26 Hz) are reproduced. Frequencies of these two oscillatory components closely agree with the main heart rate rhythms in humans (0.09±0.01 Hz and 0.26±0.01 Hz). When sympathetic-mediated regulation prevails over parasympathetic activity, simulated heart rate oscillation is characterised by a low frequency (∼0.1 Hz). On the other hand, a high-frequency oscillatory component (∼0.26 Hz) appears when enhanced vagal activation or partial inhibition of the sympathetic control is simulated. When both autonomic divisions are operative, both low- and high-frequency components are present and the heart rate oscillates quasi-periodically. This variability in heart rate at different frequencies is reproduced without including outside perturbations and is due to the nonlinear delayed structure of the closed-loop control. Bifurcation theory of nonlinear system is used to explain the high sensitivity of the heart rate oscillatory pattern to model parameter changes.

Electrocardiographic Changes during Hemodiafiltration with Different Potassium Removal Rates

Background/Aims: Sudden K removal is thought to be implicated in ECG alterations observed during hemodialysis (HD). The effects of the K removal rate on ECG-derived parameters have been investigated. Methods: Two different hemodiafiltration (HDF) schedules were used for 10 HD patients: the dialysate K concentration was kept constant in HDFst, while in HDFK it was decreased during the session in order to maintain a uniform plasma-dialysate K gradient. A 12-lead Holter monitor was used to acquire the ECG in the course of the treatments. Classical ECG parameters and overall indices for quantifying ventricular repolarization abnormalities were evaluated. Results: Several ECG parameters were affected by both HD therapies (ST depression, QRS amplitude and QT dispersion), but only indices of the homogeneity of repolarization (PCA-T, E1-T) were significantly affected by the K removal rate. Conclusion: The present study confirms the large impact of HD therapy on ECG. The analysis of the spatial T wave complexity points out the intrinsic arrhythmogenic implications of the K removal rate.