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PubMed2000

Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice.

Alterations in the expression and activity of the matrix metalloproteinases (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been implicated in tissue remodeling in a number of disease states. One of the better characterized TIMPs, TIMP-1, has been shown to bind to active MMPs and to regulate the MMP activational process. The goal of this study was to determine whether deletion of the TIMP-1 gene in mice, which in turn would remove TIMP-1 expression in LV myocardium, would produce time-dependent effects on LV geometry and function. Age-matched sibling mice (129Sv) deficient in the TIMP-1 gene (TIMP-1 knock-out (TIMP-1 KO), n=10) and wild-type mice (n=10) underwent comparative echocardiographic studies at 1 and 4 months of age. LV catheterization studies were performed at 4 months and the LV harvested for histomorphometric studies. LV end-diastolic volume and mass increased (18+/-4 and 38+/-3%, respectively, P<0.05) at 4 months in the TIMP-1 KO group; a significant increase compared to wild-type controls (P<0.05). At 4 months, LV and end-diastolic wall stress was increased by over two-fold in the TIMP-1 KO compared to wild type (P<0.05). However, LV systolic pressure and ejection performance were unchanged in the two groups of mice. LV myocyte cross-sectional area was unchanged in the TIMP-1 KO mice compared to controls, but myocardial fibrillar collagen content was reduced. Changes in LV geometry occurred in TIMP-1 deficient mice and these results suggest that constitutive TIMP-1 expression participates in the maintenance of normal LV myocardial structure.

Animals↗
PubMed1999

A system for low field imaging of laser-polarized noble gas.

We describe a device for performing MRI with laser-polarized noble gas at low magnetic fields (<50 G). The system is robust, portable, inexpensive, and provides gas-phase imaging resolution comparable to that of high field clinical instruments. At 20.6 G, we have imaged laser-polarized (3)He (Larmor frequency of 67 kHz) in both sealed glass cells and excised rat lungs, using approximately 0.1 G/cm gradients to achieve approximately 1 mm(2) resolution. In addition, we measured (3)He T(2)(*) times greater than 100 ms in excised rat lungs, which is roughly 20 times longer than typical values observed at high ( approximately 2 T) fields. We include a discussion of the practical considerations for working at low magnetic fields and conclude with evidence of radiation damping in this system.

Animals↗
PubMed2000

Mechanisms of blood pressure alterations in response to the Valsalva maneuver in postural tachycardia syndrome.

The postural tachycardia syndrome (POTS) is characterized clinically by orthostatic lightheadedness and tachycardia. When these patients perform a Valsalva maneuver, there is an excessive blood pressure increment after cessation of the maneuver (phase IV) that is sometimes associated with headaches. It is not known whether excessive phase IV is due to excessive peripheral vascular tone (an alpha-adrenergic mechanism) or is a manifestation of increased beta-adrenergic tone (hyperadrenergic state). The authors undertook a pharmacologic study evaluating the effect of intravenous phentolamine (alpha-adrenergic antagonist) and propranolol (beta-adrenergic antagonist) on the different phases of the Valsalva maneuver in a group of patients with POTS and age-matched normal control subjects. Patients with POTS had mean phases, when compared with controls, that were characterized by more negative II_E (p = 0.07), smaller II_L (p = 0.04), and significantly larger phase IV (p = 0.001). The effect of phentolamine was qualitatively and quantitatively different in POTS when compared with controls. Ten mg phentolamine in controls resulted in a significant accentuation of phase II_E (p = 0.001), attenuation of phase II_L (p = 0.002), and increase of phase IV (57.6 vs 30.7 mm Hg; p = 0.025). These changes resembled those of patients with POTS at baseline. In patients with POTS, the phase II abnormalities, already present, were further accentuated (p <0.001), and phase IV became smaller (50.6 vs 73.8 mm Hg; p = 0.09). Propranolol had no significant effect on phases II_E and II_L, but significantly reduced phase IV in both controls (p <0.05) and in patients with POTS (p <0.001) and improved the headache symptoms, when present, during and after phase IV. The authors conclude that phase IV is mainly under beta-adrenergic regulation and that the exaggerated phase IV in POTS is a result of a hyperadrenergic state.

Adrenergic alpha-Antagonists↗
PubMed2000

Hemodynamic and symptomatic effects of acute interventions on tilt in patients with postural tachycardia syndrome.

A variety of approaches have been used to alleviate symptoms in postural tachycardia syndrome (POTS). Drugs reported to be of benefit include midodrine, propranolol, clonidine, and phenobarbital. Other measures used include volume expansion and physical countermaneuvers. These treatments may influence pathophysiologic mechanisms of POTS such as alpha-receptor dysfunction, beta-receptor supersensitivity, venous pooling, and brainstem center dysfunction. The authors prospectively studied hemodynamic indices and symptom scores in patients with POTS who were acutely treated with a variety of interventions. Twenty-one subjects who met the criteria for POTS were studied (20 women, 1 man; mean age, 28.7 +/- 6.8 y; age range, 14-39 y). Patients were studied with a 5-minute head-up tilt protocol, ECG monitoring, and noninvasive beat-to-beat blood pressure monitoring, all before and after the administration of an intervention (intravenous saline, midodrine, propranolol, clonidine, or phenobarbital). The hemodynamic indices studied were heart rate (ECG) and systolic, mean, and diastolic blood pressure. Patients used a balanced verbal scale to record any change in their symptoms between the tilts. Symptom scores improved significantly after the patients received midodrine and saline. Midodrine and propranolol reduced the resting heart rate response to tilt (p <0.005) and the immediate and 5-minute heart rate responses to tilt (p <0.002). Clonidine accentuated the immediate decrease in blood pressure on tilt up (p <0.05). It was concluded that midodrine and intravenous saline are effective in decreasing symptoms on tilt in patients with POTS when given acutely. Effects of treatments on heart rate and blood pressure responses generally reflected the known pharmacologic mechanisms of the agents.

Adolescent↗
PubMed2003

Flexor bias of joint position in humans during spaceflight.

The ability to estimate ankle and elbow joint position was tested before, during, and after a 17-day spaceflight. Subjects estimated targeted joint angles during isovelocity (IsoV) joint movements with agonist muscle groups either active or relaxed. These movements included elbow extension (EE) and elbow flexion (EF), and plantarflexion (PF) and dorsiflexion (DF) of the ankle. Subjects also estimated these joint positions while moving the dynamometer at their chosen (variable) velocity (VarV) during EE and PF. For IsoV tests, no differences were observed between active and passive movements for either the ankle or elbow. Compared with those of pre-flight test days, estimates of targeted elbow joint angles were approximately 5 degrees to 15 degrees more flexed in-flight, and returned toward the pre-flight values during recovery. The spaceflight effects for the ankle were inconsistent and less prevalent than those for the elbow. The VarV PF test condition for the 120 degrees target angle at the ankle exhibited approximately 5 degrees to 7 degrees more DF target angle estimates in-flight compared with those pre- or post-flight. In contrast, during IsoV PF there was a tendency for ankle estimates to be approximately 2 degrees to 3 degrees more PF after 2-3 days exposure to spaceflight. These data indicate that during spaceflight the perception of elbow extension is greater than actuality, and are consistent with the interpretation that microgravity induced a flexor bias in the estimation of the actual elbow joint position. Moreover, these effects in joint proprioception during spaceflight were observed in individual isolated single-joint movements during tasks in which vestibular function in maintaining posture were minimal.

Adult↗
PubMed2000

Human orientation and movement control in weightless and artificial gravity environments.

Our goal is to summarize what has been learned from studies of human movement and orientation control in weightless conditions. An understanding of the physics of weightlessness is essential to appreciate the dramatic consequences of the absence of continuous contact forces on orientation and posture. Eye, head, arm, leg, and whole body movements are discussed, but only experiments whose results seem relatively incontrovertible are included. Emphasis is placed on distinguishing between virtually immediate adaptive compensations to weightlessness and those with longer time courses. The limitations and difficulties of performing experiments in weightless conditions are highlighted. We stress that when astronauts and cosmonauts return from extended space flight they do so with both physical "plant" and neural "controller" structurally and functionally altered. Recent developments in adapting humans to artificial gravity conditions are discussed as a way of maintaining sensory-motor and structural integrity in extended missions involving transitions between different force environments.

Humans↗
PubMed1999

Effect of viewing distance on the generation of vertical eye movements during locomotion.

Vertical head and eye coordination was studied as a function of viewing distance during locomotion. Vertical head translation and pitch movements were measured using a video motion analysis system (Optotrak 3020). Vertical eye movements were recorded using a video-based pupil tracker (Iscan). Subjects (five) walked on a linear treadmill at a speed of 1.67 m/s (6 km/h) while viewing a target screen placed at distances ranging from 0.25 to 2.0 m at 0. 25-m intervals. The predominant frequency of vertical head movement was 2 Hz. In accordance with previous studies, there was a small head pitch rotation, which was compensatory for vertical head translation. The magnitude of the vertical head movements and the phase relationship between head translation and pitch were little affected by viewing distance, and tended to orient the naso-occipital axis of the head at a point approximately 1 m in front of the subject (the head fixation distance or HFD). In contrast, eye velocity was significantly affected by viewing distance. When viewing a far (2-m) target, vertical eye velocity was 180 degrees out of phase with head pitch velocity, with a gain of 0. 8. This indicated that the angular vestibulo-ocular reflex (aVOR) was generating the eye movement response. The major finding was that, at a close viewing distance (0.25 m), eye velocity was in phase with head pitch and compensatory for vertical head translation, suggesting that activation of the linear vestibulo-ocular reflex (lVOR) was contributing to the eye movement response. There was also a threefold increase in the magnitude of eye velocity when viewing near targets, which was consistent with the goal of maintaining gaze on target. The required vertical lVOR sensitivity to cancel an unmodified aVOR response and generate the observed eye velocity magnitude for near targets was almost 3 times that previously measured. Supplementary experiments were performed utilizing body-fixed active head pitch rotations at 1 and 2 Hz while viewing a head-fixed target. Results indicated that the interaction of smooth pursuit and the aVOR during visual suppression could modify both the gain and phase characteristics of the aVOR at frequencies encountered during locomotion. When walking, targets located closer than the HFD (1.0 m) would appear to move in the same direction as the head pitch, resulting in suppression of the aVOR. The results of the head-fixed target experiment suggest that phase modification of the aVOR during visual suppression could play a role in generating eye movements consistent with the goal of maintaining gaze on targets closer than the HFD, which would augment the lVOR response.

Adolescent↗
PubMed2000

Influence of central set on anticipatory and triggered grip-force adjustments.

The effects of predictability of load magnitude on anticipatory and triggered grip-force adjustments were studied as nine normal subjects used a precision grip to lift, hold, and replace an instrumented test object. Experience with a predictable stimulus has been shown to enhance magnitude scaling of triggered postural responses to different amplitudes of perturbations. However, this phenomenon, known as a central-set effect, has not been tested systematically for grip-force responses in the hand. In our study, predictability was manipulated by applying load perturbations of different magnitudes to the test object under conditions in which the upcoming load magnitude was presented repeatedly or under conditions in which the load magnitudes were presented randomly, each with two different pre-load grip conditions (unconstrained and constrained). In constrained conditions, initial grip forces were maintained near the minimum level necessary to prevent pre-loaded object slippage, while in unconstrained conditions, no initial grip force restrictions were imposed. The effect of predictable (blocked) and unpredictable (random) load presentations on scaling of anticipatory and triggered grip responses was tested by comparing the slopes of linear regressions between the imposed load and grip response magnitude. Anticipatory and triggered grip force responses were scaled to load magnitude in all conditions. However, regardless of pre-load grip force constraint, the gains (slopes) of grip responses relative to load magnitudes were greater when the magnitude of the upcoming load was predictable than when the load increase was unpredictable. In addition, a central-set effect was evidenced by the fewer number of drop trials in the predictable relative to unpredictable load conditions. Pre-load grip forces showed the greatest set effects. However, grip responses showed larger set effects, based on prediction, when pre-load grip force was constrained to lower levels. These results suggest that anticipatory processes pertaining to load magnitude permit the response gain of both voluntary and triggered rapid grip force adjustments to be set, at least partially, prior to perturbation onset. Comparison of anticipatory set effects for reactive torque and lower extremity EMG postural responses triggered by surface translation perturbations suggests a more general rule governing anticipatory processes.

Adult↗
PubMed2000

Dynamics of airborne fungal populations in a large office building.

The increasing concern with bioaerosols in large office buildings prompted this prospective study of airborne fungal concentrations in a newly constructed building on the Gulf coast. We collected volumetric culture plate air samples on 14 occasions over the 18-month period immediately following building occupancy. On each sampling occasion, we collected duplicate samples from three sites on three floors of this six-story building, and an outdoor sample. Fungal concentrations indoors were consistently below those outdoors, and no sample clearly indicated fungal contamination in the building, although visible growth appeared in the ventilation system during the course of the study. We conclude that modern mechanically ventilated buildings prevent the intrusion of most of the outdoor fungal aerosol, and that even relatively extensive air sampling protocols may not sufficiently document the microbial status of buildings.

Air Conditioning↗
PubMed2000

Vascular mechanics of the coronary artery.

UNLABELLED: This paper describes our research into the vascular mechanics of the coronary artery and plaque. The three sections describe the determination of arterial mechanical properties using intravascular ultrasound (IVUS), a constitutive relation for the arterial wall, and finite element method (FEM) models of the arterial wall and atheroma. METHODS: Inflation testing of porcine left anterior descending coronary arteries was conducted. The changes in the vessel geometry were monitored using IVUS, and intracoronary pressure was recorded using a pressure transducer. The creep and quasistatic stress/strain responses were determined. A Standard Linear Solid (SLS) was modified to reproduce the non-linear elastic behavior of the arterial wall. This Standard Non-linear Solid (SNS) was implemented into an axisymetric thick-walled cylinder numerical model. Finite element analysis models were created for five age groups and four levels of stenosis using the Pathobiological Determinants of Atherosclerosis Youth (PDAY) database. RESULTS: The arteries exhibited non-linear elastic behavior. The total tissue creep strain was epsilon creep = 0.082 +/- 0.018 mm/mm. The numerical model could reproduce both the non-linearity of the porcine data and time dependent behavior of the arterial wall found in the literature with a correlation coefficient of 0.985. Increasing age had a strong positive correlation with the shoulder stress level, (r = 0.95). The 30% stenosis had the highest shoulder stress due to the combination of a fully formed lipid pool and a thin cap. CONCLUSIONS: Studying the solid mechanics of the arterial wall and the atheroma provide important insights into the mechanisms involved in plaque rupture.

Animals↗
PubMed2000

Postural control model interpretation of stabilogram diffusion analysis.

Collins and De Luca [Collins JJ. De Luca CJ (1993) Exp Brain Res 95: 308-318] introduced a new method known as stabilogram diffusion analysis that provides a quantitative statistical measure of the apparently random variations of center-of-pressure (COP) trajectories recorded during quiet upright stance in humans. This analysis generates a stabilogram diffusion function (SDF) that summarizes the mean square COP displacement as a function of the time interval between COP comparisons. SDFs have a characteristic two-part form that suggests the presence of two different control regimes: a short-term open-loop control behavior and a longer-term closed-loop behavior. This paper demonstrates that a very simple closed-loop control model of upright stance can generate realistic SDFs. The model consists of an inverted pendulum body with torque applied at the ankle joint. This torque includes a random disturbance torque and a control torque. The control torque is a function of the deviation (error signal) between the desired upright body position and the actual body position, and is generated in proportion to the error signal, the derivative of the error signal, and the integral of the error signal [i.e. a proportional, integral and derivative (PID) neural controller]. The control torque is applied with a time delay representing conduction, processing, and muscle activation delays. Variations in the PID parameters and the time delay generate variations in SDFs that mimic real experimental SDFs. This model analysis allows one to interpret experimentally observed changes in SDFs in terms of variations in neural controller and time delay parameters rather than in terms of open-loop versus closed-loop behavior.

Computer Simulation↗
PubMed2004

Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function.

Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity.

Amphetamine↗
PubMed2004

The ALTEA/ALTEINO projects: studying functional effects of microgravity and cosmic radiation.

The ALTEA project investigates the risks of functional brain damage induced by particle radiation in space. A modular facility (the ALTEA facility) is being implemented and will be operated in the International Space Station (ISS) to record electrophysiological and behavioral descriptors of brain function and to monitor their time dynamics and correlation with particles and space environment. The focus of the program will be on abnormal visual perceptions (often reported as "light flashes" by astronauts) and the impact on retinal and brain visual structures of particle in microgravity conditions. The facility will be made available to the international scientific community for human neurophysiological, electrophysiological and psychophysics experiments, studies on particle fluxes, and dosimetry. A precursor of ALTEA (the 'Alteino' project) helps set the experimental baseline for the ALTEA experiments, while providing novel information on the radiation environment onboard the ISS and on the brain electrophysiology of the astronauts during orbital flights. Alteino was flown to the ISS on the Soyuz TM34 as part of mission Marco Polo. Controlled ground experiments using mice and accelerator beams complete the experimental strategy of ALTEA. We present here the status of progress of the ALTEA project and preliminary results of the Alteino study on brain dynamics, particle fluxes and abnormal visual perceptions.

Brain↗
PubMed2004

The effects of proton exposure on neurochemistry and behavior.

Future space missions will involve long-term travel beyond the magnetic field of the Earth, where astronauts will be exposed to radiation hazards such as those that arise from galactic cosmic rays. Galactic cosmic rays are composed of protons, alpha particles, and particles of high energy and charge (HZE particles). Research by our group has shown that exposure to HZE particles, primarily 600 MeV/n and 1 GeV/n 56Fe, can produce significant alterations in brain neurochemistry and behavior. However, given that protons can make up a significant portion of the radiation spectrum, it is important to study their effects on neural functioning and on related performance. Therefore, these studies examined the effects of exposure to proton irradiation on neurochemical and behavioral endpoints, including dopaminergic functioning, amphetamine-induced conditioned taste aversion learning, and spatial learning and memory as measured by the Morris water maze. Male Sprague-Dawley rats received a dose of 0, 1.5, 3.0 or 4.0 Gy of 250 MeV protons at Loma Linda University and were tested in the different behavioral tests at various times following exposure. Results showed that there was no effect of proton irradiation at any dose on any of the endpoints measured. Therefore, there is a contrast between the insignificant effects of high dose proton exposure and the dramatic effectiveness of low dose (<0.1 Gy) exposures to 56Fe particles on both neurochemical and behavioral endpoints.

Animals↗
PubMed2004

Effects of heavy ions on visual function and electrophysiology of rodents: the ALTEA-MICE project.

ALTEA-MICE will supplement the ALTEA project on astronauts and provide information on the functional visual impairment possibly induced by heavy ions during prolonged operations in microgravity. Goals of ALTEA-MICE are: (1) to investigate the effects of heavy ions on the visual system of normal and mutant mice with retinal defects; (2) to define reliable experimental conditions for space research; and (3) to develop animal models to study the physiological consequences of space travels on humans. Remotely controlled mouse setup, applied electrophysiological recording methods, remote particle monitoring, and experimental procedures were developed and tested. The project has proved feasible under laboratory-controlled conditions comparable in important aspects to those of astronauts' exposure to particle in space. Experiments are performed at the Brookhaven National Laboratories [BNL] (Upton, NY, USA) and the Gesellschaft für Schwerionenforschung mbH [GSI]/Biophysik (Darmstadt, FRG) to identify possible electrophysiological changes and/or activation of protective mechanisms in response to pulsed radiation. Offline data analyses are in progress and observations are still anecdotal. Electrophysiological changes after pulsed radiation are within the limits of spontaneous variability under anesthesia, with only indirect evidence of possible retinal/cortical responses. Immunostaining showed changes (e.g. increased expression of FGF2 protein in the outer nuclear layer) suggesting a retinal stress reaction to high-energy particles of potential relevance in space.

Animals↗
PubMed2004

The effects of heavy particle irradiation on exploration and response to environmental change.

Free radicals produced by exposure to heavy particles have been found to produce motor and cognitive behavioral toxicity effects in rats similar to those found during aging. The present research was designed to investigate the effects of exposure to 56Fe particles on the ability of male Sprague-Dawley rats to detect novel arrangements in a given environment. Using a test of spatial memory previously demonstrated to be sensitive to aging, open field activity and reaction to spatial and non-spatial changes were measured in a group that received a dose of 1.5 Gy (n=10) of 56Fe heavy particle radiation or in non-radiated controls (n=10). Animals irradiated with 1.5 Gy of 56Fe particles exhibited some age-like effects in rats tested, even though they were, for the most part, subtle. Animals took longer to enter, visited less and spent significantly less time in the middle and the center portions of the open field, independently of total frequency and duration of activity of both groups. Likewise, irradiated subjects spend significantly more time exploring novel objects placed in the open field than did controls. However, irradiated subjects did not vary from controls in their exploration patterns when objects in the open field were spatially rearranged. Thus, irradiation with a dose of 1.5 Gy of 56Fe high-energy particle radiation elicited age-like effects in general open field exploratory behavior, but did not elicit age-like effects during the spatial and non-spatial rearrangement tasks.

Aging↗
PubMed2004

Distributed interactive communication in simulated space-dwelling groups.

This report describes the development and preliminary application of an experimental test bed for modeling human behavior in the context of a computer generated environment to analyze the effects of variations in communication modalities, incentives and stressful conditions. In addition to detailing the methodological development of a simulated task environment that provides for electronic monitoring and recording of individual and group behavior, the initial substantive findings from an experimental analysis of distributed interactive communication in simulated space dwelling groups are described. Crews of three members each (male and female) participated in simulated "planetary missions" based upon a synthetic scenario task that required identification, collection, and analysis of geologic specimens with a range of grade values. The results of these preliminary studies showed clearly that cooperative and productive interactions were maintained between individually isolated and distributed individuals communicating and problem-solving effectively in a computer-generated "planetary" environment over extended time intervals without benefit of one another's physical presence. Studies on communication channel constraints confirmed the functional interchangeability between available modalities with the highest degree of interchangeability occurring between Audio and Text modes of communication. The effects of task-related incentives were determined by the conditions under which they were available with Positive Incentives effectively attenuating decrements in performance under stressful time pressure.

Adaptation, Psychological↗