Biomedical subjects

J Mizrahi

Publications and source records attributed to J Mizrahi.

At least 19 recordsLinked to original sources

PubMed2006

Muscle enhancement using closed-loop electrical stimulation: volitional versus induced torque.

In cases of partial deficiency of muscle activation capacity, force augmentation can be achieved by hybrid activation, i.e., by combining electrical stimulation (ES) with volitional activation. In this activation modality the shares of the volitional and induced torques within the overall hybrid torque are unknown. The purpose of this study was to suggest a computational approach to parcel out the volitional and stimulation induced components of joint torque generated during combined voluntary and electrical activation of the Tibialis Anterior muscle (TA). For this purpose, isometric contraction of the TA was studied on 5 healthy subjects, using an activation protocol involving ES alone, volitional activation alone and hybrid activation. Ankle torque and TA EMG were measured. A computational algorithm was developed to dissociate the volitional from the overall torque, based on EMG filtering and on pre-measured calibration curves of volitional torque versus EMG. The results indicated that for a certain hybrid torque there is a linear decaying relationship between the induced torque and the volitional torque shares. Moreover, based on a defined enhancement ratio, the results indicate that within the range of stimulation intensities, there exist regions of increased facilitation, in which the stimulation efficiency is higher under combined compared to isolated conditions.

Adult↗

PubMed2005

Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT(2C) receptor agonists.

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.

Animals↗

PubMed2005

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

Animals↗

PubMed2001

Fatigue-induced changes in decline running.

OBJECTIVE: Study the relation between muscle fatigue during eccentric muscle contractions and kinematics of the legs in downhill running. DESIGN: Decline running on a treadmill was used to acquire data on shock accelerations, muscle activity and kinematics, for comparison with level running. BACKGROUND: In downhill running, local muscle fatigue is the cause of morphological muscle damage which leads to reduced attenuation of shock accelerations. METHODS: Fourteen subjects ran on a treadmill above level-running anaerobic threshold speed for 30 min, in level and -4 degrees decline running. The following were monitored: metabolic fatigue by means of respiratory parameters; muscle fatigue of the quadriceps by means of elevation in myoelectric activity; and kinematic parameters including knee and ankle angles and hip vertical excursion by means of computerized videography. Data on shock transmission reported in previous studies were also used. RESULTS: Quadriceps fatigue develops in parallel to an increasing vertical excursion of the hip in the stance phase of running, enabled by larger dorsi flexion of the ankle rather than by increased flexion of the knee. CONCLUSIONS: The decrease in shock attenuation can be attributed to quadriceps muscle fatigue in parallel to increased vertical excursion of the hips.

Adult↗

PubMed2001

Interaction of array of finite electrodes with layered biological tissue: effect of electrode size and configuration.

A hybrid scheme, combining image series and moment method has been utilized for the calculation of the intramuscular three-dimensional (3-D) current density (CD) distribution and potential field transcutaneously excited by an electrode array. The model permits one to study the effect of tissue electrical properties and electrode placement on the CD distribution. The isometric recruitment curve (IRC) of the muscle was used for parameter estimation and model verification, by comparison with experimentally obtained IRCs of functional electrical stimulation (FES)-activated quadriceps muscle of paraplegic subjects. Sensitivity of the calculated IRC to parameters such as tissue conductivity, electrode size, and configuration was verified. The resulting model demonstrated characteristic features that were similar to those of experimentally obtained data. The model IRCs were insensitive to the electrode size; however, the inclusion of the bone-fascia layer significantly increased the intramuscular CD and, consequently, increased the IRC slope. Of the different configurations studied, a four-electrode array proved advantageous because, in this case, the CD between the electrodes was more evenly distributed, providing better resistance to fatigue. However, due to the steeper linear portion of the IRC, this configuration suffered from a somewhat reduced controllability of the muscle.

Electric Conductivity↗

PubMed2001

Effects of anorexinogen agents on cloned voltage-gated K(+) channel hKv1.5.

Appetite suppressants have been associated with primary pulmonary hypertension (PPH), inhibition of voltage-gated potassium channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells. In cells taken from pulmonary arteries of primary pulmonary hypertensive patients, voltage-gated potassium channels appear to be dysfunctional and in particular, reduced hKv1.5 gene transcription and hKv1.5 mRNA instability have been shown. We have compared the effects of anorexinogen agents on hKv1.5 channels stably expressed in mammalian cell line. We found that aminorex, phentermine, dexfenfluramine, sibutramine, and fluoxetine cause a dose-dependent inhibition of hKv1.5 current. Aminorex, phentermine, and dexfenfluramine had a K(D) of inhibition greater than to 300 microM and are not potent inhibitors of hKv1.5. Sibutramine and fluoxetine inhibited hKv1.5 current with lower K(D) values of 41 and 21 microM, respectively. Block by both drugs increased rapidly between -20 and +10 mV, coincident with channel opening and suggested an open channel block mechanism. This was confirmed by a slower deactivation time course resulting in a "crossover" phenomenon when tail currents recorded under control conditions and in the presence of either drug were superimposed. Single channel experiments demonstrated that open probability and open duration of hKv1.5 were decreased by fluoxetine and sibutramine. These results indicate that among the anorexinogen agents tested, sibutramine and fluoxetine are the most potent toward hKv1.5 channel, which they preferentially block in the open state. Nevertheless, their inhibitory effects do not correlate with their ability to produce PPH neither with their previously reported therapeutic plasma concentrations.

Algorithms↗

PubMed2000

The increased swelling and instantaneous deformation of osteoarthritic cartilage is highly correlated with collagen degradation.

OBJECTIVE: To provide evidence for the hypothesis that the loss of tensile strength of osteoarthritic (OA) cartilage (resulting in swelling-the hallmark of OA) is due to an impaired collagen network and not to loss or degradation of proteoglycans. METHODS: The amount of degraded collagen molecules, the fixed charge density (FCD) on a dry-weight basis, the degree of swelling in saline, and the instantaneous deformation (ID; a test reflecting the tensile stiffness of the collagen network) were measured in full-depth OA femoral condyle samples. In addition, levels of the crosslink hydroxylysylpyridinoline (HP), the amount of degraded collagen molecules, and the degree of swelling were determined in the 3 zones (surface, middle, and deep) of OA cartilage. We also compared the ID of normal and OA cartilage. RESULTS: In full-depth OA cartilage, a close relationship was found between swelling and ID. Swelling and ID correlated strongly with the amount of degraded collagen molecules, and were not related to FCD. OA cartilage showed the same zonal pattern in HP levels as normal cartilage (i.e., an increase with depth). No relationship was found between collagen crosslinking and swelling of the surface, middle, and deep zones. In all 3 zones, swelling was proportional to the amount of degraded collagen molecules. Compared with that of normal cartilage, the change in ID of OA cartilage was most pronounced at the surface in a direction parallel to the direction of the collagen fibrils. CONCLUSION: The decreased stiffness of the OA collagen network (as measured by swelling and ID) is strongly related to the amount of degraded collagen molecules. The anisotropy in ID parallel and perpendicular to the direction of the fibrils revealed that the impairment of strength resides mainly in, and not between, the fibrils. Proteoglycans play only a minor role in the degeneration of the tensile stiffness of OA cartilage.

Aged↗

PubMed2000

The effect of gamma-interferon to inhibit macrophage-high density lipoprotein interactions is reversed by 15-deoxy-delta12,14-prostaglandin J2.

Macrophage activation has been recognized as playing a central role in chronic inflammatory diseases in general and, more specifically, in the vascular wall during the progression of atherosclerotic lesions. Macrophage-activating factors present within the atherosclerotic lesion include the colony-stimulating factors and gamma interferon (IFNgamma). In the present study, the effects of IFNgamma on macrophage binding and uptake of fluorochrome-labeled high density lipoprotein (HDL) were investigated by flow cytometry and by measuring the amount of the type B scavenger receptors CD36 and scavenger receptor type B (SR-BI) by Northern blot analysis. IFNgamma-, but not granulocyte macrophage colony-stimulating factor (GM-CSF)-treated murine peritoneal macrophages displayed a two- to threefold decrease in Dil-labeled HDL uptake. This effect was observed in the absence of a comparable decrease in SR-BI message and protein or CD36 message. This decrease in both HDL binding and uptake was reversed by the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, 15-deoxy-delta12,4-prostaglandin J2 (15d-PGJ2), which also inhibited the IFNgamma induction of the beta2 integrin CD11a. Furthermore, 15d-PGJ2 increased the expression of SR-BI and CD36 message and SR-BI protein which was reflected in an increase in HDL binding and uptake. These results suggest a role for PPARgamma agonists in modulating the IFNgamma-mediated macrophage effector functions relevant to atherosclerotic disease progression.

Animals↗

PubMed2000

Shock accelerations and attenuation in downhill and level running.

OBJECTIVE: A study was conducted to investigate the possible effects of fatigue on the heel strike-initiated shock accelerations and on attenuation of these shocks along the body during eccentric muscle contractions. DESIGN: Level and decline running on a treadmill were used to acquire the experimental data on the foot strike-initiated shock accelerations. BACKGROUND: Eccentric contractions of the lower limb muscles in combination with shock generation and propagation during downhill running and muscle fatigue may diminish their ability to dissipate and attenuate loading on the system. METHODS: Fourteen young healthy males ran on a treadmill at a speed exceeding their anaerobic threshold by 5% for 30 min, as follows: (a) level running and (b) downhill running with a decline angle of -4 degrees. The foot strike-induced shock accelerations were recorded every five minutes on the tibial tuberosity and sacrum. Fatigue was monitored by means of the respiratory parameters. RESULTS: The downhill running related with eccentric muscle contractions was associated with increased shock propagation from the tibial tuberosity to the sacrum levels, even though fatigue did not develop. CONCLUSIONS: Shock propagation from the tibial tuberosity to the sacrum is augmented due to the eccentric action of the muscles, without metabolic fatigue development. RELEVANCE: Eccentric muscle contraction in downhill running reduces the musculoskeletal ability to attenuate the heel strike-induced shock waves. Knowledge about the effect of fatigue on the shock propagation between the shank and the sacrum levels may help in understanding the mechanism of stress fractures and joint damage.

Acceleration↗

PubMed2000

Transcutaneous FES of the paralyzed quadriceps: is knee torque affected by unintended activation of the hamstrings?

This study addresses the question whether unintended response of the knee flexors (hamstrings) accompanies transcutaneous functional electrical stimulation (FES) of the quadriceps and whether the knee torque is hereby affected. Transcutaneous FES of the right quadriceps of two paraplegic subjects was applied and measurements were made of the net torque and of the myoelectric activities of the quadriceps and hamstrings muscles of the right leg. A low correlation was obtained between the peak-to-peak amplitudes of the M-waves of the two muscles. This correlation decreased further with the development of fatigue, which indicated that the electromyography (EMG) signals from the hamstrings were not the result of cross-talk between adjacent recording sites. The force profile of each muscle was determined from a developed model incorporating EMG-based activation, muscle anthropometry as obtained from in vivo magnetic resonance imaging of the thigh, and metabolic fatigue function, based on data acquired by 31P nuclear magnetic resonance spectroscopy. A sensitivity analysis revealed that the muscle specific tension and the muscle moment arms have a major influence on the resulting muscle forces and should therefore be accurately provided. The results show that during the unfatigued phase of contraction the estimated maximal force in the hamstrings was lower than 20% of that in the quadriceps and could be considered to be practically negligible. As fatigue progressed the hamstrings-to-quadriceps force ratio increased, reaching up to 45%, and the effect of co-activation on the torque partition between the two muscles was no longer negligible.

Adult↗

PubMed2000

Involvement of caspase 3- and 8-like proteases in ceramide-induced apoptosis of cardiomyocytes.

Ceramides are the metabolic products of sphingolipids of the eukaryotic cell membranes and are believed to function as signaling molecules in a variety of biological processes. Ceramide induces apoptosis in cultured cardiomyocytes. However, the molecular pathway underlying ceramide-induced apoptosis is not clear. In this study, we investigated the role of the cysteinyl aspartate-specific proteases (caspases) in cardiomyocyte apoptosis induced by ceramide. Treatment of in vitro cultured rat neonatal cardiomyocytes with ceramide results in robust cell death, of which the majority is apoptotic, as shown by positive staining for terminal deoxyribonuclease transferase-mediated deoxyuridine triphosphate nick end-labeling and the appearance of pyknotic nuclei with Hoechst staining. Caspase 3- and 8-like protease activities are induced in cardiomyocytes by ceramide treatment. Addition of the tetrapeptide inhibitors for caspases attenuated ceramide-induced apoptosis. The nonselective caspase inhibitor (B-D-FMK) and the caspase 3 (Z-DEVD-FMK) and caspase 8 (Z-IETD-FMK) inhibitors reduced ceramide-induced cardiomyocyte death and significantly inhibited the activation of caspase 3. However, the inhibitors specific for caspases 1, 2, 4, 6, and 9 have no significant effects on cardiomyocyte survival under the same conditions. These data suggest that caspases 3- and 8-related proteases are involved in ceramide-induced cardiomyocyte apoptosis.

Animals↗

PubMed2000

Current distribution in skeletal muscle activated by functional electrical stimulation: image-series formulation and isometric recruitment curve.

The present work develops an analytical model that allows one to estimate the current distribution within the whole muscle and the resulting isometric recruitment curve (IRC). The quasistatic current distribution, expressed as an image series, i.e., a collection of properly weighted and shifted point-source responses, outlines an extension for more than three layers of the classical image theory in conductive plane-stratified media. Evaluation of the current distribution via the image series expansions requires substantially less computational time than the standard integral representation. The expansions use a unique recursive representation for Green's function, that is a generic characteristic of the stratification. This approach permits one to verify which of the tissue electrical properties are responsible for the current density distribution within the muscle, and how significant their combinations are. In addition, the model permits one to study the effect of different electrode placement on the shape and the magnitude of the potential distribution. A simple IRC model was used for parameter estimation and model verification by comparison with experimentally obtained isometric recruitment curves. Sensitivity of the model to different parameters such as conductivity of the tissues and activation threshold was verified. The resulting model demonstrated characteristic features that were similar to those of experimentally obtained data. The model also quantitatively confirmed the differences existing between surface (transcutaneous) and implanted (percutaneous) electrode stimulation.

Biomedical Engineering↗

PubMed2000

Fatigue-related loading imbalance on the shank in running: a possible factor in stress fractures.

In previous reports we have shown that in long distance running the impact acceleration on the shank increases with progressing fatigue. The aim of the present study was to test whether, in parallel to this increase, an imbalance in the activities between the ankle plantar and dorsi flexor muscles develops. The tests were made on fourteen subjects during 30 min treadmill running above their anaerobic thresholds. Respiratory data were collected to determine the anaerobic threshold speed and to indicate the progressively developing metabolic fatigue. Surface electromyogram (EMG) was monitored to indicate the changing activity of the shank muscles. In the tibialis anterior the average integrated EMG (iEMG) and the mean power frequency (MPF) significantly decreased from the beginning to the end of running. In the gastrocnemius iEMG did not change, while MPF increased during the course of running. The impact acceleration, measured by means of an accelerometer attached to the tibial tuberosity, significantly increased during the course of running. It was concluded that, with developing fatigue, an imbalance in the contraction of the shank muscles develops in parallel to an increase in shank shock acceleration. The combination of these two changes may hamper the loading balance on the tibia since the bone becomes exposed to excessive bending stresses and to higher risk of stress injury.

Acceleration↗

PubMed2000

Biomechanical simulation of an amputated forearm with and without a prosthesis.

In this study a computer simulation was developed for analysing the performance of a below-elbow amputated forearm, with and without a prosthesis. The upper extremity was represented in terms of two rigid bodies, the arm and the forearm. Five muscles, three elbow flexors and two elbow extensors, were included in the model. The muscle model used was the five-component model, including the contractile, parallel, series and viscous elements and the muscle mass. Dynamic and static simulations were conducted, with and without prosthesis, to study parametrically the effects of stump length, tendon distal transfer, tendon or muscle shortening and muscle physiological cross-sectional area. The performance measures which were the most affected included flexion moment of the forearm about the elbow, muscle moment, force in the joint, flexion rate and mechanical energy. The simulation presented an interesting case when the amputation site is more proximal than the anatomical insertion point of a muscle, necessitating shortening of the muscle to avoid the situation where it exerts no force. It was also found that, of the changeable parameters, the most beneficial changes in the forearm parameters for improved dynamic performance were: (a) tendon distal transfer and (b) increase of the muscle cross-sectional area, the latter achievable by means of physical training.

Amputation, Surgical↗

PubMed1999

EMG and metabolite-based prediction of force in paralyzed quadriceps muscle under interrupted stimulation.

A major issue associated with functional electrical stimulation (FES) of a paralyzed limb is the decay with time of the muscle force as a result of fatigue. A possible means to reduce fatigue during FES is by using interrupted stimulation, in which fatigue and recovery occur in sequence. In this study, we present a model which enables us to evaluate the temporal force generation capacity within the electrically activated muscle during first stimulation fatigue, i.e., when the muscle is activated from unfatigued initial conditions, and during postrest stimulation, i.e., after different given rest durations. The force history of the muscle is determined by the activation as derived from actually measured electromyogram (EMG) data, and by the metabolic fatigue function expressing the temporal changes of muscle metabolites, from existing data acquired by in vivo 31P MR spectroscopy in terms of the inorganic phosphorus variables, Pi or H2PO4-, and by the intracellular pH. The model was solved for supra-maximal stimulation in isometric contractions separated by rest periods, and compared to experimentally obtained measurements. EMG data were fundamental for prediction of the ascending force during its posttetanic response. On the other hand, prediction of the decaying phase of the force was possible only by means of the metabolite-based fatigue function. The prediction capability of the model was assessed by means of the error between predicted and measured force profiles. The predicted force obtained from the model in first stimulation fatigue fits well with the experimental one. In postrest stimulation fatigue, the different metabolites provided different prediction capabilities of the force, depending on the duration of the rest period. Following rest duration of 1 min, Pi provided the best prediction of force; H2PO4- extended the prediction capacity of the model to up to 6 min and pH provided a reliable prediction for rest durations longer than 12 min. The results presented shed light on the roles of EMG and of metabolites in prediction of the force history of a paralyzed muscle under conditions where fatigue and recovery occur in sequence.

Algorithms↗

PubMed1998

Standing sway: iterative estimation of the kinematics and dynamics of the lower extremities from force-plate measurements.

In this study, a model for the estimation of the dynamics of the lower extremities in standing sway from force plate data only is presented. A three-dimensional, five-segment, four-joint model of the human body was used to describe postural standing sway dynamics. Force-plate data of the reactive forces and centers of pressure were measured bilaterally. By applying the equations of motion to these data, the transversal trajectory of the center of gravity (CG) of the body was resolved in the sagittal and coronal planes. An inverse kinematics algorithm was used to evaluate the kinematics of the body segments. The dynamics of the segments was then resolved by using the Newton-Euler equations, and the model's estimated dynamic quantities of the distal segments were compared with those actually measured. Differences between model and measured dynamics were calculated and minimized, using an iterative algorithm to re-estimate joint positioning and anthropometric properties. The above method was tested with a group of 11 able-bodied subjects, and the results indicated that the relative errors obtained in the final iteration were of the same order of magnitude as those reported for closed loop problems involved in direct kinematic measurements of human gait.

Algorithms↗

PubMed1998

Weight-bearing patterns on the knees of preterm infants.

In this study we present a method of monitoring the forces under the knees of preterm infants lying in the prone position. Dual force sensing resistor transducers, connected to optically-isolated amplifiers, were used to monitor the forces. A thermistor airflow sensor was used for the parallel monitoring of the respiratory signal. The measurements were made on ten preterm infants. The average forces were 0.51 and 0.50 N for the left and right knees, respectively. In the frequency domain, the basic harmonic of the force traces was 1.27 Hz approximately, corresponding to the respiratory rhythm. Additional, smaller harmonics, were detected in the force traces at 2.54 and 3.81 Hz. A rather notable power signal could also be seen around 0.1 Hz. The results obtained indicate that the system developed is highly sensitive for providing data on the amplitudes, periods and sequences of oscillations and symmetry of load bearing in preterm infants. Knowledge of the normal and abnormal reaction force patterns may assist in the early diagnosis of abnormal neurodevelopment.

Humans↗

PubMed1997

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion.

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.

Adult↗