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This compendium organizes and summarizes the scientific literature dealing with the study of hypokinetic and hypodynamic animal studies. It includes both American and foreign research papers.
BACKGROUND: For evaluating patients with aortic regurgitation (AR), regurgitant volumes, left ventricular (LV) stroke volumes (SV), and absolute LV volumes are valuable indices. AIM: The aim of this study was to validate the combination of real-time 3-dimensional echocardiography (3DE) and semiautomated digital color Doppler cardiac flow measurement (ACM) for quantifying absolute LV volumes, LVSV, and AR volumes using an animal model of chronic AR and to investigate its clinical applicability. METHODS: In 8 sheep, a total of 26 hemodynamic states were obtained pharmacologically 20 weeks after the aortic valve noncoronary (n = 4) or right coronary (n = 4) leaflet was incised to produce AR. Reference standard LVSV and AR volume were determined using the electromagnetic flow method (EM). Simultaneous epicardial real-time 3DE studies were performed to obtain LV end-diastolic volumes (LVEDV), end-systolic volumes (LVESV), and LVSV by subtracting LVESV from LVEDV. Simultaneous ACM was performed to obtain LVSV and transmitral flows; AR volume was calculated by subtracting transmitral flow volume from LVSV. In a total of 19 patients with AR, real-time 3DE and ACM were used to obtain LVSVs and these were compared with each other. RESULTS: A strong relationship was found between LVSV derived from EM and those from the real-time 3DE (r = 0.93, P <.001, mean difference (3D - EM) = -1.0 +/- 9.8 mL). A good relationship between LVSV and AR volumes derived from EM and those by ACM was found (r = 0.88, P <.001). A good relationship between LVSV derived from real-time 3DE and that from ACM was observed (r = 0.73, P <.01, mean difference = 2.5 +/- 7.9 mL). In patients, a good relationship between LVSV obtained by real-time 3DE and ACM was found (r = 0.90, P <.001, mean difference = 0.6 +/- 9.8 mL). CONCLUSION: The combination of ACM and real-time 3DE for quantifying LV volumes, LVSV, and AR volumes was validated by the chronic animal study and was shown to be clinically applicable.
Two squirrel monkeys and 24 rats were flown on Spacelab-3 to provide hands-on maintenance of animals in a laboratory environment. With few exceptions, the animals grew and behaved normally, were free of chronic stress, and differed from ground controls only for gravity-dependent parameters. One of the monkeys exhibited symptoms of space sickness similar to those observed in humans, which suggests squirrel monkeys may be good models for studying the space-adaptation syndrome. Among parameters measured in the rats, most notable is the dramatic loss of muscle mass and increased fragility of long bones. Other rat findings include suppressed interferon production by spleen cells, defective release of growth hormone by somatrophs, possible dissociation of circadian pacemakers, changes in hepatic lipid and carbohydrate metabolism, and hypersensitivity of marrow cells to erythropoietin.
BACKGROUND: Pitfalls of the flow convergence (FC) method, including 2-dimensional imaging of the 3-dimensional (3D) geometry of the FC surface, can lead to erroneous quantification of mitral regurgitation (MR). This limitation may be mitigated by the use of real-time 3D color Doppler echocardiography (CE). Our objective was to validate a real-time 3D navigation method for MR quantification. METHODS: In 12 sheep with surgically induced chronic MR, 37 different hemodynamic conditions were studied with real-time 3DCE. Using real-time 3D navigation, the radius of the largest hemispherical FC zone was located and measured. MR volume was quantified according to the FC method after observing the shape of FC in 3D space. Aortic and mitral electromagnetic flow probes and meters were balanced against each other to determine reference MR volume. As an initial clinical application study, 22 patients with chronic MR were also studied with this real-time 3DCE-FC method. Left ventricular (LV) outflow tract automated cardiac flow measurement (Toshiba Corp, Tokyo, Japan) and real-time 3D LV stroke volume were used to quantify the reference MR volume (MR volume = 3DLV stroke volume - automated cardiac flow measurement). RESULTS: In the sheep model, a good correlation and agreement was seen between MR volume by real-time 3DCE and electromagnetic (y = 0.77x + 1.48, r = 0.87, P <.001, delta = -0.91 +/- 2.65 mL). In patients, real-time 3DCE-derived MR volume also showed a good correlation and agreement with the reference method (y = 0.89x - 0.38, r = 0.93, P <.001, delta = -4.8 +/- 7.6 mL). CONCLUSIONS: real-time 3DCE can capture the entire FC image, permitting geometrical recognition of the FC zone geometry and reliable MR quantification.
The flight of two squirrel monkeys and 24 rats on Spacelab-3 was the first mission to provide hands-on maintenance on animals in a laboratory environment. With few exceptions, the animals grew and behaved normally, were free of chronic stress, and differed from ground controls only for gravity dependent parameters. One of the monkeys exhibited symptoms of space sickness similar to those observed in humans, which suggests squirrel monkeys may be good models for studying the space adaptation syndrome. Among the wide variety of parameters measured in the rats, most notable was the dramatic loss of muscle mass and increased fragility of long bones. Other interesting rat findings were those of suppressed interferom production by spleen cells, defective release of growth hormone by somatrophs, possible dissociation of circadian pacemakers, changes in hepatic lipid and carbohydrate metabolism, and hypersensitivity of marrow cells to erythropoietin. These results portend a strong role for animals in identifying and elucidating the physiological and anatomical responses of mammals to microgravity.
The flight of two squirrel monkeys and 24 rates on Spacelab-3 was the first mission to provide hand-on maintenance on animals in a laboratory environment. With few exceptions, the animals grew and behaved normally, were free of chronic stress, and differed from ground controls only for gravity-dependent parameters. One of the monkeys exhibited symptoms of space sickness similar to those observed in humans, which suggests squirrel monkeys may be good models for studying the space-adaptation syndrome. Among the wide variety of parameters measured in the rats, most notable was the dramatic loss of muscle mass and increased fragility of long bones. Other interesting rat findings were those of suppressed interferon production by spleen cells, defective release of growth hormone by somatotrophs, possible dissociation of circadian pacemakers, changes in hepatic lipid and carbohydrate metabolism, and hypersensitivity of marrow cells to erythopoietin. These results portend a strong role for animals in identifying and elucidating the physiological and anatomical responses of mammals to microgravity.
BACKGROUND: Temporary shunt placement can quickly restore perfusion after extremity arterial injury. This study examined the adequacy of limb blood flow with shunt use, non-heparin-bonded shunt patency over prolonged periods, and the safety of this technique. METHODS: Common iliac arteries were divided and 4.0-mm Silastic Sundt shunts placed in 16 anesthetized pigs. Eight (group I) had shunts placed immediately; eight others (group II) were shunted after an hour of limb ischemia and hemorrhagic shock. Physiologic parameters and femoral artery blood flow in both hindlimbs were continuously monitored. Limb lactic acid generation, oxygen utilization, and hematologic and metabolic effects were serially evaluated for 24 hours. RESULTS: Shunts remained patent in 13 of 16 pigs. Shunts thrombosed in two group I animals because of technical errors, but functioned well after thrombectomy and repositioning. Patency could not be maintained in one animal that died from shock. Flow in group I shunted limbs was 57 (+/-11 SD) % of control. For group II animals in shock, shunted limb flow initially averaged 46 +/- 15% of control, but 4 hours after shunt placement, the mean limb blood flow was the same as in group I. Increased oxygen extraction compensated for the lower flow. Lactic acid production was not increased in comparison to control limbs. CONCLUSION: Shunts provided adequate flow in this model of extremity trauma. Correctly placed shunts stayed patent for 24 hours, without anticoagulation, if shunt placement followed resuscitation.
University studies on human & animal impact - automobile accidents
Mankind's exploration and colonization of the frontier of space will ultimately depend on men's and women's ability to live, work, and reproduce in the space environment. This paper reviews animal studies, from microorganisms to mammals, done in space or under space-simulated conditions, which identify some of the key areas which might interfere with human reproductive physiology and/or embryonic development. Those space environmental factors which impacted almost all species included: microgravity, artificial gravity, radiation, and closed life support systems. These factors may act independently and in combination to produce their effects. To date, there have been no studies which have looked at the entire process of reproduction in any animal species. This type of investigation will be critical in understanding and preventing the problems which will affect human reproduction. Part II will discuss these problems directly as they relate to human physiology.
OBJECTIVE: The purpose of this study was to develop a technique to investigate the regeneration of utricular hair cells in the adult pigeon (Columba livia) following complete hair cell loss through administration of streptomycin. STUDY DESIGN: Experimental animal study. METHODS: Animals were divided into four groups. Group 1 received 10 to 15 days of systemic streptomycin injections. Animals in Groups 2 and 3 received a single direct placement of a 1-, 2-, 4-, or 8-mg streptomycin dose into the perilymphatic space. Animals in Groups 1 and 2 were analyzed within 1 week from injection to investigate hair cell destruction, whereas Group 3 was investigated at later dates to study hair cell recovery. Group 4 animals received a control injection of saline into the perilymphatic space. Damage and recovery were quantified by counting hair cells in isolated utricles using scanning electron microscopy. RESULTS: Although systemic injections failed to reliably achieve complete utricular hair cell destruction, a single direct placement of a 2-, 4-, or 8-mg streptomycin dose caused complete destruction within the first week. Incomplete hair cell loss was observed with the 1-mg dose. Over the long term, regeneration of the hair cells was seen with the 2-mg dose but not the 8-mg dose. Control injections of saline into the perilymphatic space caused no measurable hair cell loss. CONCLUSIONS: Direct placement of streptomycin into the perilymph is an effective, reliable method for complete destruction of utricular hair cells while preserving the regenerative potential of the neuroepithelium.
Weight control is dependent on energy balance. Reduced energy expenditure (EE) associated with decreased physical activity is suggested to be a major underlying cause in the increasing prevalence of weight gain and obesity. Therefore, a better understanding of the biological determinants involved in the regulation of physical activity is essential. To facilitate interpretation in humans, it is helpful to consider the evidence from animal studies. This review focuses on animal studies examining the biological determinants influencing activity and potential implications to human. It appears that physical activity is influenced by a number of parameters. However, regardless of the parameter involved, body weight appears to play an underlying role in the regulation of activity. Furthermore, the regulation of activity associated with body weight appears to occur only after the animal achieves a critical weight. This suggests that activity levels are a consequence rather than a contributor to weight control. However, the existence of an inverse weight-activity relationship remains inconclusive. Confounding the results are the multifactorial nature of physical activity and the lack of appropriate measuring devices. Furthermore, many determinants of body weight are closely interlocked, making it difficult to determine whether a single, combination, or interaction of factors is important for the regulation of activity. For example, diet-induced obesity, aging, lesions to the ventral medial hypothalamus, and genetics all produce hypoactivity. Providing a better understanding of the biological determinants involved in the regulation of activity has important implications for the development of strategies for the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population.
Weight control is dependent on energy balance. Reduced energy expenditure (EE) associated with decreased physical activity is suggested to be a major underlying cause in the increasing prevalence of weight gain and obesity. Therefore, a better understanding of the biological determinants involved in the regulation of physical activity is essential. To facilitate interpretation in humans, it is helpful to consider the evidence from animal studies. This review focuses on animal studies examining the biological determinants influencing activity and potential implications to human. It appears that physical activity is influenced by a number of parameters. However, regardless of the parameter involved, body weight appears to play all underlying role in the regulation of activity. Furthermore, the regulation of activity associated with body weight appears to occur only after the animal achieves a critical weight. This suggests that activity levels are a consequence rather than a contributor to weight control. However, the existence of an inverse weight-activity relationship remains inconclusive. Confounding the results are the multi-factorial nature of physical activity and the lack of appropriate measuring devices. Furthermore, many determinants of body weight are closely interlocked making it difficult to determine whether a single, combination or interaction of factors is important for the regulation of activity. For example, diet-induced obesity, aging, lesions to tile ventral medial hypothalamus and genetics all produce hypoactivity. Providing a better understanding of the biological determinants involved in the regulation of activity has important implications for the development of strategies for the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population.
Research on radiation detectors for absorptiometry; analysis of errors affective single photon absorptiometry and development of instrumentation; analysis of errors affecting dual photon absorptiometry and development of instrumentation; comparison of skeletal measurements with other techniques; cooperation with NASA projects for skeletal evaluation in spaceflight (Experiment MO-78) and in laboratory studies with immobilized animals; studies of postmenopausal osteoporosis; organization of scientific meetings and workshops on absorptiometric measurement; and development of instrumentation for measurement of fluid shifts in the human body were performed. Instrumentation was developed that allows accurate and precise (2% error) measurements of mineral content in compact and trabecular bone and of the total skeleton. Instrumentation was also developed to measure fluid shifts in the extremities. Radiation exposure with those procedures is low (2-10 MREM). One hundred seventy three technical reports and one hundred and four published papers of studies from the University of Wisconsin Bone Mineral Lab are listed.
Recent evidence has shown that a subtle alternation in the surface ECG (electrical alternans) may be correlated with the susceptibility to ventricular fibrillation. In the present work, the author presents evidence that a mechanical alternation in the heartbeat (mechanical alternans) generally accompanies electrical alternans. A simple finite-element computer model which emulates both the electrical and the mechanical activity of the heart is presented. A pilot animal study is also reported. The computer model and the animal study both found that (1) there exists a regime of combined electrical-mechanical alternans during the transition from a normal rhythm towards a fibrillatory rhythm, (2) the detected degree of alternation is correlated with the relative instability of the rhythm, and (3) the electrical and mechanical alternans may result from a dispersion in local electrical properties leading to a spatial-temporal alternation in the electrical conduction process.
It was demonstrated that up to 8ml of blood can be drawn from donar rats without significantly increasing volume and stress sensitive hormones, and thus can be used for volume expansion studies. Infusion of whole blood allows more physiological changes that can be seen with volume expansion by saline or other ionic solutions. The infusion of whole blood to induce hypervolemia may provide an improved model to study the fluid balance and control mechanisms operative in weightlessness. Blood samples were drawn as quickly as possible from femoral artery catheters chronically implanted in Sprague Dawley rats and analyzed for hematocrit, plasma sodium, potassium, osmolality, corticosterone, epinepherine, norepinephrine, and vasopressin. The levels were found to be comparable to those of normal rats.
The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.
Radiation and gravitational effect on wasps and shrimp - animal study
The perchlorate anion (ClO4) is typically manufactured as the ammonium salt. The most common use of ammonium perchlorate is in the aerospace program as a component of solid rocket fuel. The perchlorate anion is exceedingly stable under environmental conditions and has been found in ground and surface waters in CA, NV, UT, AZ, TX, AK, NY, MD, WV and FL. The National Center for Environmental Assessment (NCEA) of the U.S. Environmental Protection Agency (US EPA) is in the process of developing an oral reference dose (RfD) for perchlorate. An oral RfD is a body-weight-adjusted dose that can be consumed daily over an entire lifetime with the expectation of no adverse health effects. Once developed, the new RfD will be used by US EPA as the basis of a safe-drinking-water level (SDWL) guideline. US EPA and regional regulatory agencies will then jointly or separately propose clean-up action levels for ground and surface waters at contaminated sites. The toxicological database on CIO4- as of March 1997 was determined by an expert peer-review panel to be inadequate for the purpose of deriving an oral RfD. For example, little or no experimental data existed on the subchronic, reproductive, or developmental toxicity of perchlorate. To fill gaps in the toxicological database, eight animal studies were designed by a government-industry consortium that included US EPA and AFRL. These studies were performed in 1997-1998. It has been known for many years that in the thyroid, high doses of perchlorate block the function of iodide by competing for iodide binding sites. Perchlorate was used in the 1950s-60s as a treatment for Graves' disease (a hyperthyroid condition). Because of what was already known about the pharmacological mode of action of perchlorate, specific concerns addressed in the design of the recent animal studies included the potential for developmental toxicity, notably neurological development. Upon review of complete study reports from four of the studies and incomplete data from the other two, US EPA/NCEA issued a document in December 1998 stating that the critical effects were hormone and histology data from the neurodevelopmental/behavioral toxicity study that had been performed in rats; an RfD was proposed based upon the observation of thyroid-follicular-cell hypertrophy in the 5-day-old pups (PND) of dams given perchlorate in drinking water at 0.1 mg/kg-day (the lowest dose tested) in this study. US EPA/NCEA also focused attention on a nonsignificant increase in motor activity observed in 14-day-old male pups in the same study at the same dose. In February 1999, a public workshop was convened at which an external peer-review panel determined that there was still insufficient data to support the development of a RfD. Additional studies were recommended. Since that time a clinical study revealed significant depression of thyroidal uptake of iodide in volunteers receiving potassium perchlorate at 10 mg/day for 14 days. Follow-up studies currently underway include a pathology working-group review of histology slides from the all of the previous studies, a motor activity study similar to the first behavioral study, an additional immunotoxicity study, male and female rat kinetic studies, a hormone interlaboratory study, and an effects study for thyroid and brain in developing rats. These studies are expected to be complete by mid-2000. A clinical study is planned to determine inhibition of iodide uptake and kinetic parameters in humans following 14-day perchlorate ingestion. The kinetics studies will provide data for developing physiologically based pharmacokinetic (PBPK) models for rats and humans needed to establish the RfD.