Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “dynamics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,567 records · Page 87Linked to original sources
PubMed2006

Prostate cancer localization with dynamic contrast-enhanced MR imaging and proton MR spectroscopic imaging.

PURPOSE: To prospectively determine the accuracies of T2-weighted magnetic resonance (MR) imaging, dynamic contrast material-enhanced MR imaging, and quantitative three-dimensional (3D) proton MR spectroscopic imaging of the entire prostate for prostate cancer localization, with whole-mount histopathologic section findings as the reference standard. MATERIALS AND METHODS: This study was approved by the institutional review board, and informed consent was obtained from all patients. Thirty-four consecutive men with a mean age of 60 years and a mean prostate-specific antigen level of 8 ng/mL were examined. The median biopsy Gleason score was 6. T2-weighted MR imaging, dynamic contrast-enhanced MR imaging, and 3D MR spectroscopic imaging were performed, and on the basis of the image data, two readers with different levels of experience recorded the location of the suspicious peripheral zone and central gland tumor nodules on each of 14 standardized regions of interest (ROIs) in the prostate. The degree of diagnostic confidence for each ROI was recorded on a five-point scale. Localization accuracy and ROI-based receiver operating characteristic (ROC) curves were calculated. RESULTS: For both readers, areas under the ROC curve for T2-weighted MR, dynamic contrast-enhanced MR, and 3D MR spectroscopic imaging were 0.68, 0.91, and 0.80, respectively. Reader accuracy in tumor localization with dynamic contrast-enhanced imaging was significantly better than that with quantitative spectroscopic imaging (P < .01). Reader accuracy in tumor localization with both dynamic contrast-enhanced imaging and spectroscopic imaging was significantly better than that with T2-weighted imaging (P < .01). CONCLUSION: Compared with use of T2-weighted MR imaging, use of dynamic contrast-enhanced MR imaging and 3D MR spectroscopic imaging facilitated significantly improved accuracy in prostate cancer localization.

Aged↗
PubMed1993

Normal uterus and FIGO stage I endometrial carcinoma: dynamic gadolinium-enhanced MR imaging.

Dynamic magnetic resonance (MR) imaging was performed on a 1.5-T superconducting unit for evaluation of 26 stage I endometrial carcinomas. To establish the appearance of the normal uterus, 27 normal uteri were also evaluated. After rapid injection of gadopentetate dimeglumine, dynamic images were obtained every 30 seconds with the spin-echo technique in the sagittal plane. On dynamic studies of endometrial carcinoma, the tumor-myometrial contrast was marked at 120 seconds after administration of gadopentetate dimeglumine (contrast-to-noise ratio [C/N], 26.0). The tumor-myometrial contrast on the dynamic study was more marked than that on postcontrast T1-weighted images (C/N, 10.0) and on T2-weighted images (C/N, 2.14). Dynamic and postcontrast MR images were superior in enabling differentiation of viable tumors from necrosis or residual secretion in the endometrial cavity. In the evaluation of presence of tumor and myometrial invasion, the accuracy of T2-weighted imaging and dynamic imaging was 67.9% and 84.9%, respectively.

Adult↗
PubMed1993

Small hepatocellular carcinomas: two-phase dynamic incremental CT in detection and evaluation.

PURPOSE: To compare dynamic incremental computed tomography (CT) with other techniques in detecting and evaluating small hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: Two-phase (early vascular and parenchymal) dynamic incremental CT of the entire liver and ultrasonography (US) were performed in 184 patients with chronic liver disease. Thirty patients had 36 small HCCs (less than 30 mm in diameter); 27 of these 30 patients also underwent CT after intraarterial injection of iodized oil, and the results were compared. RESULTS: The HCC detection rate was 92% with dynamic incremental CT, 69% with US, and 81% with iodized oil-enhanced CT. Of six well-differentiated HCCs, two were detected with the first dynamic incremental CT series and two with iodized oil-enhanced CT, whereas all were detected with the second dynamic incremental CT series and five with US. CONCLUSION: Two-phase dynamic incremental CT was superior to the other techniques and is a useful and easy procedure for routine follow-up of patients with chronic liver disease.

Carcinoma, Hepatocellular↗
PubMed1997

Differentiation between recurrent tumor and benign conditions after treatment of gynecologic pelvic carcinoma: value of dynamic contrast-enhanced subtraction MR imaging.

PURPOSE: To compare dynamic contrast material-enhanced subtraction and T2-weighted spin-echo (SE) magnetic resonance (MR) imaging in the differentiation of fibrosis from tumor recurrence during the follow-up of treated gynecologic pelvic malignancy. MATERIALS AND METHODS: Thirty-four patients (aged 24-82 years) with 18 benign and 35 malignant lesions confirmed by means of surgery (n = 18), biopsy (n = 25), or 18-month follow-up examination (n = 10) underwent dynamic contrast-enhanced subtraction and T2-weighted SE MR imaging. Contrast material enhancement of an abnormal pelvic structure within the first 90 seconds on dynamic contrast-enhanced subtraction images or high signal intensity on T2-weighted SE images was considered indicative of malignancy. RESULTS: The sensitivity, specificity, accuracy, and positive and negative predictive values were 91%, 67%, 83%, 86%, and 86%, respectively, for dynamic contrast-enhanced subtraction imaging and 91%, 22%, 68%, 70%, and 57%, respectively, for T2-weighted SE imaging. More lesions were correctly classified with dynamic contrast-enhanced subtraction imaging than with T2-weighted SE imaging (P < .01). CONCLUSION: Dynamic contrast-enhanced subtraction imaging is more accurate than T2-weighted SE imaging for differentiating fibrosis from tumor recurrence during the follow-up of treated gynecologic pelvic malignancy. However, use of both sequences is recommended.

Adult↗
PubMed2006

Chondrocyte intracellular calcium, cytoskeletal organization, and gene expression responses to dynamic osmotic loading.

While chondrocytes in articular cartilage experience dynamic stimuli from joint loading activities, few studies have examined the effects of dynamic osmotic loading on their signaling and biosynthetic activities. We hypothesize that dynamic osmotic loading modulates chondrocyte signaling and gene expression differently than static osmotic loading. With the use of a novel microfluidic device developed in our laboratory, dynamic hypotonic loading (-200 mosM) was applied up to 0.1 Hz and chondrocyte calcium signaling, cytoskeleton organization, and gene expression responses were examined. Chondrocytes exhibited decreasing volume and calcium responses with increasing loading frequency. Phalloidin staining showed osmotic loading-induced changes to the actin cytoskeleton in chondrocytes. Real-time PCR analysis revealed a stimulatory effect of dynamic osmotic loading compared with static osmotic loading. These studies illustrate the utility of the microfluidic device in cell signaling investigations, and their potential role in helping to elucidate mechanisms that mediate chondrocyte mechanotransduction to dynamic stimuli.

Actins↗
PubMed1980

Interpretation by theoretical model of dynamic and steady components in frog gustatory response.

The behavior of dynamic component (slow component) and steady component of the frog glossopharyngeal nerve response to CaCl2, measured in number of impulses firing per second, was examined under various conditions. 1) The magnitude of the dynamic component increased with the flow rate below about 0.3 ml/s, whereas that of the steady component was independent of the flow rate. 2) The magnitude of the dynamic component increased with a rise of temperature between 2.5 and 20 degrees C, whereas that of the steady component was practically independent of temperature. Removal of Ca2+ from the receptor membrane yielded a large dynamic component even at 2.5 degrees C. 3) The treatment of the tongue with procaine led to a large reduction in the magnitude of the dynamic component, whereas the effect of procaine on the steady component was not pronounced. 4) The magnitude of the dynamic component varied with the pH of the stimulating solution, whereas that of steady component was practically independent of a pH between 4.5 and 7.5. The above results were well interpreted by the following reaction scheme: S (stimulus + A (receptor domain) in equilibrium (SA)active in equilibrium (SA) inactive where (SA) active and (SA) inactive are active and inactive complexes.

Action Potentials↗
PubMed2003

"Step" vs. "dynamic" autoregulation: implications for susceptibility to hypertensive injury.

Renal autoregulatory (AR) mechanisms provide the primary protection against transmission of systemic pressures, and their impairment is believed to be responsible for the enhanced susceptibility to hypertensive renal damage in renal mass reduction (RMR) models. Assessment of AR capacity by the "step" change methodology under anesthesia was compared with that by "dynamic" methods in separate conscious control Sprague-Dawley rats and after uninephrectomy (UNX) and (3/4) RMR (RK-NX) (n = 7-10/group). Substantially less AR capacity was seen by the dynamic vs. the step methodology in control rats. Moreover, dynamic AR capacity did not differ among controls, UNX, and RK-NX rats (fractional gain in admittance approximately 0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). By contrast, significant impairment of step AR was seen in RK-NX vs. control or UNX rats (AR indexes 0.7 +/- 0.1 vs. 0.1 +/- 0.02 and 0.2 +/- 0.04, respectively, P < 0.01). We propose that the step and dynamic methods evaluate the renal AR responses to different components of blood pressure (BP) power with the step AR assessing the ability to buffer large changes in average BP (DC power), whereas the present "dynamic" methods assess the AR ability to buffer slow BP fluctuations (<0.25 Hz) superimposed on the average BP (AC power), a substantially smaller component of total BP power. We further suggest that step but not dynamic AR methods as presently performed provide a valid index of the underlying susceptibility to hypertensive glomerular damage after RMR.

Animals↗
PubMed1977

Influence of lung parenchyma on dynamic bronchial collapsibility of excised dog lungs.

The main bronchi of excised dog lobes were obstructed 5-6 cm from their origin with beads, so that they did not communicate with the peripheral air spaces. With the lobe held at constant transpulmonary pressure, bronchial pressure-volume curves were recorded during both static and dynamic bronchial deflations. This was done both before and after dissecting the obstructed bronchus free of parenchymal attachments. The parenchymal contribution on dynamic deflation was much larger than the airway contribution: dynamic bronchial compliances in intact bronchi were 58 +- 8% and 65 +- 8% of the static at dynamic rates of bronchial deflation of 14 and 8 ml/s, respectively, whereas in dissected bronchi they were 72 +- 9% and 78 +- 9%. These relationships were not influenced by changes of transpulmonary pressure applied to the lobar parenchyma. The parenchymal effect on dynamic bronchial compliance was analyzed in terms of parenchymal interdependence and bronchial stress adaptation. We concluded that the presence of lung parenchymal attachments significantly reduced dynamic bronchial collapsibility as compared to static collapsibility.

Adaptation, Physiological↗
PubMed2004

Fast force-generation dynamics of human articulatory muscles.

To explore the mechanisms of speech articulation, which is one of the most sophisticated human motor skills controlled by the central nervous system, we investigated the force-generation dynamics of the human speech articulator muscles [orbicularis oris superior (OOS) and inferior (OOI) muscles of the lips]. Short-pulse electrical stimulation (300 micros) with approximately three or four times the sensation threshold intensity of each subject induced the muscle response. The responses of these muscles were modeled as second-order dynamics with a time delay (TD), and the model parameters [natural frequency (NF), damping ratio (DR), and TD] were identified with a nonlinear least mean squares method. The OOS (NF: 6.1 Hz, DR: 0.71, TD: 14.5 ms) and OOI (NF: 6.1 Hz, DR: 0.68, TD: 15.6 ms) showed roughly similar characteristics in eight subjects. The dynamics in the tongue (generated by combined muscles) also showed similar characteristics (NF: 6.1 Hz, DR: 0.68, TD: 17.4 ms) in two subjects. The NF was higher, and the DR was lower than results measured for arm muscles (NF: 4.25 Hz, DR: 1.05, TD: 23.8 ms for triceps long head), indicating that articulatory organs adapt for more rapid movement. In contrast, slower response dynamics was estimated when muscle force data by voluntarily contraction task were used for force-generation dynamics modeling. We discuss methodological problems in estimating muscle dynamics when different kinds of muscle contraction methods are used.

Electric Stimulation↗
PubMed2003

Different mechanisms involved in adaptation to stable and unstable dynamics.

Recently, we demonstrated that humans can learn to make accurate movements in an unstable environment by controlling magnitude, shape, and orientation of the endpoint impedance. Although previous studies of human motor learning suggest that the brain acquires an inverse dynamics model of the novel environment, it is not known whether this control mechanism is operative in unstable environments. We compared learning of multijoint arm movements in a "velocity-dependent force field" (VF), which interacted with the arm in a stable manner, and learning in a "divergent force field" (DF), where the interaction was unstable. The characteristics of error evolution were markedly different in the 2 fields. The direction of trajectory error in the DF alternated to the left and right during the early stage of learning; that is, signed error was inconsistent from movement to movement and could not have guided learning of an inverse dynamics model. This contrasted sharply with trajectory error in the VF, which was initially biased and decayed in a manner that was consistent with rapid feedback error learning. EMG recorded before and after learning in the DF and VF are also consistent with different learning and control mechanisms for adapting to stable and unstable dynamics, that is, inverse dynamics model formation and impedance control. We also investigated adaptation to a rotated DF to examine the interplay between inverse dynamics model formation and impedance control. Our results suggest that an inverse dynamics model can function in parallel with an impedance controller to compensate for consistent perturbing force in unstable environments.

Adaptation, Physiological↗
PubMed1994

Dynamic exercise stimulates group III muscle afferents.

1. In decerebrate cats, we investigated the responses of group III muscle afferents to dynamic exercise. The cats performed low intensity dynamic exercise on a treadmill. Group III afferent activity from the dynamically exercising triceps surae muscles was recorded from L7-S1 dorsal root filaments. 2. Single-unit recordings were obtained from 15 group III afferent fibers whose receptive fields were in the triceps surae muscles and from one group III afferent whose receptive field was in the flexor digitorum longus muscle. Conduction velocities for the 16 group III afferents ranged from 3.0 to 27.9 m/s (15.6 +/- 1.9 m/s, mean +/- SE). 3. Ten of 16 group III muscle afferents were stimulated by dynamic exercise. Of the 10, 7 were strongly responsive and 3 were mildly responsive to dynamic exercise. Each of the 10 afferents displayed at least some activity that was synchronized to the contraction phase of the step cycle. The mean developed tensions for strongly responsive afferents, mildly responsive afferents, and afferents that did not respond were 0.8 +/- 0.3, 1.3 +/- 0.5, and 0.7 +/- 0.3 Kg, respectively (P > 0.05). Thus differences in the responsiveness of the afferents to exercise were not attributable to differences in developed tensions. 4. The group III afferents that were strongly responsive to dynamic exercise were also mechanically sensitive. Each strongly responsive afferent (n = 7) was stimulated by nonnoxious pressure applied to its receptive field. Most strongly responsive afferents (n = 5) were stimulated by stretch of the triceps surae muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1995

Afferent synaptic drive of rat medial nucleus tractus solitarius neurons: dynamic simulation of graded vesicular mobilization, release, and non-NMDA receptor kinetics.

1. We have developed a comprehensive mathematical model of an afferent synaptic connection to the soma of a medial nucleus tractus solitarius (mNTS) neuron. Model development is based on numerical fits to quantitative data recorded in our laboratory. This work is part of a continuing collaborative effort aimed at identifying and characterizing the mechanisms responsible for the non-linear integrative properties of this first synapse in the baroreceptor reflex. 2. The complete model consists of three major parts: 1) a Hodgkin-Huxley (HH)-type membrane model of the prejunctional sensory terminal bouton; 2) a multistage model describing vesicular storage, adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca(2+)-dependent mobilization, release and recycling; and 3) a HH-type membrane model of the postjunctional mNTS cell that includes descriptions for a desensitizing non-N-methyl-D-aspartate (NMDA) ionic current that is responsible for the fast excitatory postsynaptic potentials (EPSPs) observed in mNTS cells. The membrane models for both the terminal bouton and the mNTS neuron are coupled to separate lumped fluid compartment models describing intracellular Ca2+ ion concentration dynamics. 3. Our modeling strategy is twofold. The first is to validate model performance by reproducing a wide variety of experimental data both from our laboratory and from the literature. The second is to explore the functional aspects of the model in order to gain a greater appreciation for the balance between presynaptic mechanisms (e.g., terminal membrane properties and vesicular dynamics) and postsynaptic mechanisms (e.g., non-NMDA receptor kinetics and neuronal dynamics) that underlie the afferent synaptic drive of mNTS neurons. 4. The model accurately reproduces EPSP dynamics recorded with the use of a wide range of stimulus protocols. The model can also mirror the unique pattern of graded frequency- and use-dependent reduction in peak EPSP magnitude observed experimentally through 60 s of constant, suprathreshold synaptic activation. We demonstrate how vesicular mobilization, recycling, and receptor kinetics can function synergistically in establishing synaptic transfer. Furthermore, we show that by allowing the aggregate rate of vesicle mobilization to respond in a use-dependent manner, it is possible to compensate for the attenuating affects of desensitization at elevated rates of stimulation. 5. Our simulations indicate that the low-frequency characteristics of this synapse are dominated by vesicular dynamics, whereas the high-frequency properties arise from a combination of Ca(2+)-dependent vesicular mobilization and the kinetics of the non-NMDA receptor. Desensitization can influence the peak magnitude and decay time of the EPSP, thereby affecting synaptic throughput. However, we demonstrate that, as the time course of neurotransmitter in the synaptic cleft decreases, the influence of desensitization should be somewhat diminished. As a result, the effective bandwidth of the synapse increases and becomes limited by the gating characteristics of the non-NMDA channel. 6. The model also includes a neuromodulatory aspect in that the frequency response of the synapse can be modulated by an adenylate cyclase-mediated regulatory mechanism. Although our simulations indicate the behavior of a limited number of possible neuromodulatory agents, the results demonstrate the pivotal role such agents could play in modifying synaptic transfer characteristics presynaptically. 7. Both continuous and burst-mode tract stimulation evoke patterns of action potentials in spontaneously active mNTS neurons that are mimicked very well by our model. Our simulations demonstrate that, as the rate of stimulation increases beyond approximately 20-30 Hz, the inherent low-pass frequency-response characteristics of the synapse limit the overall dynamic range of the mNTS neuron, causing the postsynaptic cell to "entrain" at frequencies within its normal operating range.

Afferent Pathways↗
PubMed1997

Analysis of primate IBN spike trains using system identification techniques. I. Relationship To eye movement dynamics during head-fixed saccades.

The dynamic behavior of primate (Macaca fascicularis) inhibitory burst neurons (IBNs) during head-fixed saccades was analyzed by using system identification techniques. Neurons were categorized as IBNs on the basis of their anatomic location as well as by their activity during horizontal head-fixed saccadic and smooth pursuit eye movements and vestibular nystagmus. Each IBN's latency or "dynamic lead time" (td) was determined by shifting the unit discharge in time until an optimal fit to the firing rate frequency B(t) profile was obtained by using the simple model based on eye movement dynamics,B(t) = r + b1(t); where is eye velocity. For the population of IBNs, the dynamic estimate of lead time provided a significantly lower value than a method that used the onset of the first spike. We then compared the relative abilities of different eye movement-based models to predict B(t) by using objective optimization algorithms. The most important terms for predicting B(t) were eye velocity gain (b1) and bias terms (r) mentioned above. The contributions of higher-order velocity, acceleration, and/or eye position terms to model fits were found to be negligible. The addition of a pole term [the time derivative of B(t)] in conjunction with an acceleration term significantly improved model fits to IBN spike trains, particularly when the firing rates at the beginning of each saccade [initial conditions (ICs)] were estimated as parameters. Such a model fit the data well (a fit comparable to a linear regression analysis with a R2 value of 0.5, or equivalently, a correlation coefficient of 0.74). A simplified version of this model [B(t) = rk + b1(t)], which did not contain a pole term, but in which the bias term (rk) was estimated separately for each saccade, provided nearly equivalent fits of the data. However, models in which ICs or rks were estimated separately for each saccade contained too many parameters to be considered as useful models of IBN discharges. We discovered that estimated ICs and rks were correlated with saccade amplitude for the majority of short-lead IBNs (SLIBNs; 56%) and many long-lead IBNs (LLIBNs; 42%). This observation led us to construct a more simple model that included a term that was inversely related to the amplitude of the saccade, in addition to eye velocity and constant bias terms. Such a model better described neuron discharges than more complex models based on a third-order nonlinear function of eye velocity. Given the small number of parameters required by this model (only 3) and its ability to fit the data, we suggest that it provides the most valuable description of IBN discharges. This model emphasizes that the IBN discharges are dependent on saccade amplitude and implies further that a mechanism must exist, at the motoneuron (MN) level, to offset the effect of the bias and amplitude-dependent terms. In addition, we did not find a significant difference in the variance accounted for by any of the downstream models tested for SLIBNs versus LLIBNs. Therefore we conclude that the eye movement signals encoded dynamically by SLIBNs and LLIBNs are similar in nature. Put another way, SLIBNs are not closer, dynamically, to MNs than LLIBNs.

Action Potentials↗
PubMed1994

Renal blood flow regulation and arterial pressure fluctuations: a case study in nonlinear dynamics.

The arterial blood pressure, a physiological variable on which all renal excretory processes depend, fluctuates over a wide range of amplitudes and frequencies. Much of this variation originates in nonrenal vascular beds to support nonrenal tasks, and the fluctuations provide a noisy environment in which the kidney is obliged to operate. Were it not for renal blood flow autoregulation, it would be difficult to regulate renal excretory processes so as to maintain whole body variables within narrow bounds. Autoregulation is the noise filter on which other renal processes depend for maintaining a relatively noise-free environment in which to work. Because of the time-varying nature of the blood pressure, we have concentrated in this review on the now substantial body of work on the dynamics of renal blood flow regulation and the underlying mechanisms. Renal vascular control mechanisms are not simply reactive but have their own spontaneous dynamics. Both TGF and the myogenic mechanism oscillate autonomously. The TGF oscillation is the better understood of the two. There is an oscillation of tubular pressure, proximal tubular flow, early distal Cl- concentration, and efferent arteriolar blood flow at approximately 35 mHz; all these variables are synchronized when the measurements are made in a single tubule. The autonomous nature of the oscillation is supported by simulations of the nephron and its vasculature, which show that for a reasonable representation of the dynamics of these structures and of the parameters that govern their behavior, the solutions of the equation set are periodic at the frequency of the observed oscillation, and with the same phase relationships among its variables. The simulations also show that the critical variables for the development of the oscillation are the open-loop gain of the feedback system, and the various delays in the system of which convective transport in the axis of the thick ascending limb and signal transmission between the macula densa and the afferent arteriole are the most important. The oscillation in TGF is an example of nonlinear dynamical behavior and is yet another in a long list of oscillations and related dynamics arising in the inherently nonlinear properties of living systems. Some nonlinear systems can bifurcate to states known collectively as deterministic chaos, and TGF is a clear example of such a system. Rats with two different and unrelated forms of experimental hypertension provide tubular pressure records that pass statistical tests for ordered structure and sensitive dependence on initial conditions in the reconstructed state space, two of the hallmarks of deterministic chaos. These records also pass recent more stringent tests for chaos. The significance of deterministic chaos in the context of renal blood flow regulation is that the system regulating blood flow undergoes a physical change to a different dynamical state, and because the change is deterministic, there is every expectation that the critical change will yield itself to experimental discovery.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells.

Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells. Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et al., Clin. Cancer Res., 6: 1978-1987, 2000). To understand their synergy, we examined the effects of the two drugs singly and in combination in A549 cells and found that, surprisingly, their antiproliferative synergy is related to their ability to synergistically inhibit microtubule dynamic instability and mitosis. The combination of discodermolide and paclitaxel at their antiproliferative IC(50)s (7 nm for discodermolide and 2 nm for paclitaxel) altered all of the parameters of dynamic instability synergistically except the time-based rescue frequency. For example, together the drugs inhibited overall microtubule dynamicity by 71%, but each drug individually inhibited dynamicity by only 24%, giving a combination index (CI) of 0.23. Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G(2)-M (41, 9.6, and 16% for both drugs together, for discodermolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85). Microtubules are unique receptors for drugs. The results suggest that ligands that bind to large numbers of binding sites on an individual microtubule can interact in a poorly understood manner to synergistically suppress microtubule dynamic instability and inhibit both mitosis and cell proliferation, with important consequences for combination clinical therapy with microtubule-targeted drugs.

Alkanes↗
PubMed2005

Antiangiogenic concentrations of paclitaxel induce an increase in microtubule dynamics in endothelial cells but not in cancer cells.

Microtubule-targeted drugs such as paclitaxel exhibit potent antiangiogenic activity at very low concentrations, but the mechanism underlying such an effect remains unknown. To understand the involvement of microtubules in angiogenesis, we analyzed the dynamic instability behavior of microtubules in living endothelial cells [human microvascular endothelial cells (HMEC-1) and human umbilical vascular endothelial cells (HUVEC)] following 4 hours of paclitaxel treatment. Unexpectedly, antiangiogenic concentrations of paclitaxel (0.1-5 nmol/L) strongly increased microtubule overall dynamicity in both HMEC-1 (86-193%) and HUVEC (54-83%). This increase was associated with increased microtubule growth and shortening rates and extents and decreased mean duration of pauses. The enhancement of microtubule dynamics by paclitaxel seemed to be specific to antiangiogenic concentrations and to endothelial cells. Indeed, cytotoxic concentration (100 nmol/L) of paclitaxel suppressed microtubule dynamics by 40% and 54% in HMEC-1 and HUVECs, respectively, as observed for all tested concentrations in A549 tumor cells. After 4 hours of drug incubation, antiangiogenic concentrations of paclitaxel that inhibited endothelial cell proliferation without apoptosis (1-5 nmol/L) induced a slight decrease in anaphase/metaphase ratio, which was more pronounced and associated with increased mitotic index after 24 hours of incubation. Interestingly, the in vitro antiangiogenic effect also occurred at 0.1 nmol/L paclitaxel, a concentration that did not alter mitotic progression and endothelial cell proliferation but was sufficient to increase interphase microtubule dynamics. Altogether, our results show that paclitaxel mediates antiangiogenesis by an increase in microtubule dynamics in living endothelial cells and suggest that the impairment of interphase microtubule functions is responsible for the inhibition of angiogenesis.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Knee extension strength is a significant determinant of static and dynamic balance as well as quality of life in older community-dwelling women with osteoporosis.

BACKGROUND: Determinants of balance have not been well studied in women with osteoporosis yet falls are the major cause of fracture in this population. OBJECTIVE: To describe the associations among knee extension strength, medication history, medical history, physical activity and both static and dynamic balance in women diagnosed with osteoporosis. METHODS: We assessed health history, current medication and quality of life by questionnaire in 97 community-dwelling women with osteoporosis. Static balance was measured by computerized dynamic posturography (Equitest), dynamic balance by timed figure-eight run, and knee extension strength by dynamometry. RESULTS: The 97 participants (mean (SD) age 69 (3.2) years) had a mean lumbar spine BMD of T = -3.3 (0.7) and total hip BMD of -2.9 (0.4). In stepwise linear regression, the significant determinants of static balance that explained 18% of total variance were knee extension strength (10%, p < 0.001), age (5%, p < 0.01) and tobacco use (3%, p < 0.05). The significant predictors of dynamic balance were knee extension strength (26%, p < 0.001), medications (6%, p < 0.05), age (4%, p < 0.05), height (4%, p < 0.001), as well as years of estrogen use (2%), tobacco use (2%) and weight (2%) (all p < 0.05). Knee extension strength was also associated with quality of life (r(2) = 0.12, p < 0.001). Based on these models, a 1 kg/cm ( approximately 3%) increase in mean knee extension strength was associated with 1.2, 2.4 and 3.4% greater static balance, dynamic balance and quality of life, respectively. CONCLUSIONS: Knee extension strength is a significant determinant of performance on static and dynamic balance tests in 65- to 75-year-old women with osteoporosis. In this cross-sectional study, knee extension strength explained a greater proportion of the variance in balance tests than did age. Investigation into the effect of intervention to improve knee extension strength in older women with osteoporosis is warranted.

Accidental Falls↗
PubMed2003

Serial changes in static and dynamic cerebral autoregulation after acute ischaemic stroke.

BACKGROUND: The longitudinal changes in static and dynamic cerebral autoregulation (CA) following acute ischaemic stroke are unknown and were assessed in this study. METHODS: Fifty-four ischaemic stroke patients were studied within 96 h of ischaemic stroke and again 7-14 days later, using transcranial Doppler techniques to measure CA. Results were compared to an age-, sex- and blood pressure (BP)-matched control group. Static BP pressor stimulus was produced by thigh cuff inflation and dynamic stimulus by rapid thigh cuff release. RESULTS: Dynamic, but not static, CA was globally impaired at initial (mean dynamic CA index 3.9 +/- 3.1 vs. 6.2 +/- 2.3, p < 0.005) and follow-up studies (dynamic CA 3.9 +/- 2.8 vs. 6.2 +/- 2.3, p < 0.01) in stroke patients compared to controls. Static CA was similar in stroke patients and controls and was unchanged during follow-up. CONCLUSIONS: Dynamic, but not static, CA is impaired after acute ischaemic stroke and remains abnormal for at least 1-2 weeks post ictus. These changes are present in both the affected and non-affected hemispheres and are unrelated to previous antihypertensive treatment, baseline BP levels or BP changes after stroke, age or stroke type.

Acute Disease↗