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PubMed2005

Long-term denervation of the humerus in turkeys as an experimental model for osteopenia.

The aim of this study was to evaluate the influence of long-term denervation on volumetric bone mineral density, and geometrical and mechanical properties of the humerus in turkeys. The experiment was conducted from d 22 after hatching until wk 17 of life. All experimental birds (male turkeys) were randomly divided into 2 weight-matched groups. The first group of turkeys served as the control group and underwent a sham operation on the right wing, and the second group was subjected to surgical denervation of the right humerus. The denervation was performed by neurectomy of the radialis and the mediano-ulnaris nerves in the region of the proximal epiphysis of the humerus. All the left wings within both groups were surgically untouched. The left humerus served as the control bone to the right humerus in both investigated groups. Effect of denervation of humerus was determined in terms of geometrical and mechanical properties and quantitative computed tomography. The denervation of the humerus in turkeys significantly decreased volumetric bone mineral density, and geometrical and mechanical properties of this bone, when compared with the results obtained in humerus from the sham-operated or surgically untouched wings. However, no significant differences between right and left humerus were observed when analyzing all of the investigated parameters in the sham-operated group of turkeys. It is concluded that long-term denervation of humerus in turkeys induces osteopenia and may serve as a new experimental model for investigating factors that affect skeletal homeostasis in poultry and other vertebrates.

Animals↗

PubMed1997

Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis.

Voriconazole, a new azole antifungal agent, showed potent activity against clinical isolates of Aspergillus spp. in vitro. For A. fumigatus, the MIC range was < 0.03 to 0.5 microgram/ml and the MIC at which 90% of isolates are inhibited was 0.25 microgram/ml. In an experimental model of invasive pulmonary aspergillosis which mimics infection in humans, oral voriconazole at dosages of 30 mg/kg of body weight per day significantly delayed or prevented mortality.

Amphotericin B↗

PubMed1988

Experimental models for the investigation of water and solute transport in man. Implications for oral rehydration solutions.

For patients suffering from mild to moderate dehydration, oral rehydration therapy has proved a simple and efficacious treatment. There remains, however, a need to develop improved oral rehydration solutions (ORS), and suitable experimental models are required to develop and assess new formulations. The ideal model for such investigations would take into account rates of gastric emptying, influx and efflux of water and solutes in the intestine, and the consequent changes in body composition. As no such definitive model is currently available, a variety of techniques are used to examine parts of the process of intestinal absorption. Clinical studies which assess the recovery of dehydrated patients during therapy using different ORS will ultimately evaluate the efficacy of treatment. However, ethical considerations, the relative insensitivity of this technique and the exacting nature of such studies make this approach unsuitable for the development of specific ORS. Gastric emptying of solutions can be determined by a variety of techniques, among which the radioactive tracer method offers the advantage of having no direct effect on the emptying rate, giving almost continuous measurement and allowing the use of relatively small volumes of fluids. Perfusion techniques allow measurement of the net flux of water and solute in predetermined sections of the intact human intestine. Measurement of the rate of accumulation in the circulation of orally ingested tracer molecules for water and solutes can estimate unidirectional flux. This method allows for the rates of gastric emptying and intestinal absorption of the test substance, but the rate of efflux of the tracer from the vascular space must be known to calculate net uptake. Each of these models has limitations, and care must be taken in interpreting the results in a clinical context. However, their use in the development of improved formulations is well established.

Fluid Therapy↗

PubMed2002

The immunosuppressive activity of proinflammatory cytokines in experimental models: potential for therapeutic intervention in autoimmunity.

The role of cytokines in the pathogenesis of T cell-mediated diseases, and in particular autoimmune responses, has been the subject of intense investigation in the past few years. Transgenic strains of mice have been generated, each expressing individual cytokines in organs targeted by autoimmunity. These animal models provide the most advanced tool available for analyzing the relationship between cytokines and T-dependent autoimmune responses. On the one hand, these experiments confirm that the local expression of proinflammatory cytokines is pivotal in initiating and maintaining pathogenic responses to self. On the other hand, and somewhat unexpectedly, these models have also revealed that cytokine factors controlling autoimmunity can act both as potentiating and inhibitory agents, depending upon the site and timing of exposure. As a result, one major concept emerging from different experimental models, including those originally established in our laboratory, is that proinflammatory cytokines may ameliorate autoimmunity. In this review, we analyze the mechanisms whereby cytokines that are considered as proinflammatory may in contrast suppress immune responses to self antigens. Besides emphasizing that the proinflammatory/immunogenic properties of a given cytokine may not be an intrinsic property, we review evidence that the regulation imposed by the cytokine network on autoimmunity is a finely tuned balance between activation and downmodulation of an individual autoreactive T cell repertoire. By emphasizing that factors such as the duration of cytokine exposure and the type of cell population involved strongly influence that balance, we underline the potential therapeutic implications of cytokine-mediated modulation of autoimmunity.

Animals↗

PubMed1997

Angiotensin receptor antagonists in experimental models of chronic renal failure.

The efficacy of angiotensin converting enzyme inhibitors (ACEI) in slowing the advancement of chronic renal disease attests to the importance of angiotensin II (Ang II) in the pathophysiological mechanisms underlying disease progression. It is apparent from studies of the effects of orally-active AT1 receptor antagonists (AT1RA) in experimental models of chronic progressive renal disease, that AT1RA have broadly similar effects to those of ACEI, implying that the favorable effects of ACEI on systemic and renal hemodynamics and indices of glomerular injury are mediated, in large part, by reducing the action of Ang II at AT1 receptors. The possibility remains, however, that differences in the modes of action of ACEI and AT1RA are significant in terms of renal protection and that the two classes of drugs are not therapeutically equivalent. Thus far, however, virtually all experimental studies comparing the renal protective effects of ACEI versus AT1RA have failed to show any convincing differences between the two classes of drug that cannot be attributed to discrepancies in the levels of blood pressure control achieved. As many rodent studies have adopted protocols originally designed to distinguish between the effects of treatment versus no treatment, however, it may be premature to conclude that ACEI and AT1RA are, essentially, therapeutically equivalent. Since both classes of drug have such potent renoprotective effects, the extent of injury that develops in treated rats may be so slight as to compromise the sensitivity of the experimental comparison. Fresh experimental approaches may be required to overcome this issue and resolve any outstanding questions concerning the therapeutic equivalence of AT1RA and ACEI in slowing the progression of renal disease.

Angiotensin II↗

PubMedDate not supplied

Experimental model of cardiovascular post-resuscitation syndrome--no effect of platelet activating factor antagonism.

The cardiovascular instability seen in the reperfusion phase after resuscitation from cardiac arrest may contribute to secondary brain injury. The aim of the present study was to characterise post-resuscitation cardiovascular instability in an experimental model of cardiac arrest and to test if cardiovascular stability could be improved by pre-treatment with the platelet activating factor (PAF) antagonist BN52021. Ten anaesthetised pigs received pre-treatment with BN52021 before induction of ventricular fibrillation (arrest/BN52021 group), while ten animals received only the vehicle (arrest/vehicle group). After a non-intervention interval of 9 min, resuscitation was attempted. Resuscitated animals were observed for 5 h and compared to a sham arrest group of seven animals. The haemodynamic situation after resuscitation was characterised by a low cardiac output that was inadequate in relation to the oxygen demand, as reflected by a low mixed venous oxygen saturation. The arterial blood pressure was to some extent reduced and the filling pressures in both the right and left heart were increased, but urinary output was not reduced. The severe haemodynamic compromise was not adequately reflected by standard monitoring variables such as arterial blood pressure and urinary output. Pre-treatment with BN52021 was unable to improve any aspect of short-term survival or haemodynamic stability.

Acid-Base Equilibrium↗

PubMed1983

Monocusp aortic valve replacement in dogs: an experimental model.

Aortic valve replacement using human allograft valves is a well established procedure, following which histological evidence of a host-graft interaction is seen. This varies in intensity, depending on the types of sterilizing and storage agents to which the allograft is exposed prior to insertion. A canine experimental model which enables study of these tissue ingrowth patterns in variously treated allografts has been devised. The technique is described in detail.

Animals↗

PubMed1994

Fetal heart block: a new experimental model to assess fetal pacing.

Epicardial fetal pacing via thoracotomy has the potential of being a safer and more reliable procedure to treat congenital complete heart block (CHB) associated with fetal hydrops refractory to medical therapy. To assess the acute electrophysiological characteristics of two ventricular epicardial leads, a new experimental model of fetal heart block induced by cryosurgical ablation of the AV node without the need for fetal cardiac bypass was performed in 12 pregnant ewes at 110-115 days gestation. A modified screw-in lead (1 1/2 turns) was used in six fetal lambs and a stitch-on lead in the other six lambs. CHB was achieved in 100% of the fetal lambs, with no ventricular escape rate noticed in any of the lambs. The acute stimulation thresholds were consistently low for both leads, with lower values for the screw-in lead at pulse duration below 0.9 msec (P < 0.03). Current measured at voltage threshold with pulse width below 0.5 msec was lower for the screw-in lead (P < 0.048). Stimulation resistance, measured during constant-voltage pacing, was not statistically different between the two leads (441.8 +/- 13.7 omega for the screw-in lead vs 480.2 +/- 59.2 omega for the stitch-on lead). No significant differences (P > 0.20) were found in R wave amplitude between the two electrodes. Slew rates were significantly higher in the screw-in group than in the stitch-on group (1.40 +/- 0.2 vs 0.62 +/- 0.2 V/sec, P = 0.04). This model of CHB is a simple and reproducible method to assess fetal pacing. We find the screw-in electrode to be a better option when fetal pacing is indicated.

Animals↗

PubMed1986

Efficacy of right ventricular unloading during right coronary artery occlusion in an experimental model.

This investigation examined the efficacy of right atrial-pulmonary artery bypass (RA-PA) during acute ischemia of the right ventricle. The right coronary artery (RCA) was ligated in 25 open chest, open pericardium sheep. Control animals (n = 15) were resuscitated with only intravenous fluids. In the experimental animals (n = 10) RA-PA bypass was initiated 5 minutes after right coronary occlusion. Sixty percent (9/15) of the control animals died within 90 minutes of RCA occlusion from refractory ventricular arrhythmia or right ventricular failure. Four of 10 RA-PA animals died within 2 hours of RCA occlusion from severe pulmonary hemorrhage and arterial oxygen desaturation when high flow rates (2.5 to 3.5 L/min) were initially instituted. In these animals, lung histologic findings demonstrated extensive hemorrhage into the alveolar spaces. After 6 hours of RCA occlusion in the six surviving control animals, there were significant increases in central venous pressure and right ventricular end-diastolic cord length (relative ventricular volume change measured by ultrasonic crystal analysis), and a significant decrease in the cardiac output. In contrast, during RCA occlusion in the six surviving animals on RA-PA bypass, cardiac output was well maintained, and there was a significant decrease in central venous pressure and end-diastolic length. The percent of change from baseline in end-diastolic length correlated inversely with the percent of change from baseline in cardiac output (r = -0.81, p less than 0.01). By crystal violet and triphenyltetrazolium chloride dye techniques, the mean percentage area of necrosis to area of risk was significantly less for the RA-PA group compared with the control group (5.6% versus 67.1%, p less than 0.0001). In this experimental model, RA-PA bypass effectively unloaded the acutely ischemic right ventricle, maintained systemic cardiac output, and significantly reduced right ventricular infarction size. Further investigations with this ventricular support modality are needed to determine its effects on pulmonary pathophysiology.

Animals↗

PubMed2005

Use of the transforming growth factor-beta1 inhibitor peptide in periprosthetic capsular fibrosis: experimental model with tetraglycerol dipalmitate.

BACKGROUND: Capsular contracture is the most common specific complication associated with silicone prostheses. It is thought to be caused by the gradual retraction of the fibrous scar tissue that forms around the prosthesis. Molecular biology has made it possible to determine the role of transforming growth factor beta (TGF-beta) in the scar physiopathology of any fibrotic process, including periprosthetic capsular fibrosis. The effects on the inhibition of TGF-beta have also been demonstrated in experimental models of scar formation and fibrosis, which opens the way for new therapeutic alternatives in the treatment of capsular contracture. METHODS: Three experimental groups of 10 rats each were formed to evaluate periprosthetic fibrosis after its modulation with a newly synthesized TGF-beta1 peptide inhibitor in a tetraglycerol dipalmitate matrix. In the first group, subcutaneously and submuscularly placed, smooth, solid silicone prostheses were left untreated; in the second group, the prostheses were left after being immersed in a solution of tetraglycerol dipalmitate; and in the third group, following the same protocol as in the second group, the solution contained tetra-glycerol dipalmitate mixed with the inhibitor peptide of TGF-beta1. The animals were euthanized 8 weeks after implantation, and the capsules were assessed both macroscopically and histologically. RESULTS: Inhibition of capsular thickness and cellularity was significantly more effective in the group of animals treated with the inhibitor peptide of TGF-beta1. CONCLUSIONS: The TGF-beta1 inhibitor peptide applied in a matrix with tetraglycerol dipalmitate is significantly effective in achieving a reduction in periprosthetic fibrosis after placement of silicone implants, either subcutaneously or submuscularly. This result suggests new therapeutic approaches.

Animals↗

PubMed2005

Lavage enhances the production of proinflammatory mediators by peritoneal mesothelial cells in an experimental model.

PURPOSE: There is a lack of clinical evidence supporting the use of lavage in patients with peritonitis. It is known that fluids such as normal saline cause temporary damage to the peritoneum and that increased production of proinflammatory mediators is associated with a poor outcome. This study used an experimental model to evaluate the effect of lavage on the peritoneal mesothelium and the ability of peritoneal mesothelial cells to produce a battery of proinflammatory mediators (TNFalpha, IL-1beta, GROalpha, and ICAM-I.). METHODS: Wistar rats were allocated into four groups (control, peritonitis, lavage, peritonitis plus lavage). Peritonitis was induced by exposure to zymosan and saline was used for lavage. After 18, 24, and 43 hours, mesothelial imprints were taken from the peritoneum for histology, semiquantitative reverse transcription-polymerase chain reaction, Western blot analyses, and immunocytochemistry. RESULTS: Both peritonitis and lavage caused peritoneal damage at 18 and 24 hours, and this effect was additive. At varying times, peritoneal mesothelial cells from animals undergoing lavage had greater up-regulation (P < 0.05) of mRNA expression for TNFalpha, IL-1beta, GROalpha, and ICAM-I and greater production (P < 0.05) of TNFalpha, IL-1RII, GROalpha, and ICAM-I. The latter was heavily concentrated at the cell membrane. CONCLUSIONS: Lavage causes self-limiting peritoneal damage and this is associated with an up-regulation of proinflammatory mediators in animals with peritonitis.

Animals↗

PubMed1999

Altered mechanics of cartilage with osteoarthritis: human osteoarthritis and an experimental model of joint degeneration.

OBJECTIVE: Studies of cartilage mechanics seek to determine the fundamental relationships between mechanical behavior and the composition and structure of healthy cartilage and to determine mechanisms for changes associated with degeneration. METHOD: The mechanics of normal and osteoarthritic (OA) human articular cartilage are reviewed. Studies of the initiation and pathogenesis of cartilage degeneration in the anterior cruciate ligament transection (ACLT) model of joint instability are also presented. RESULTS: In human cartilage with OA, tensile, compressive and shear behaviors are dramatically altered. These changes present as decreases in the modulus or stiffness of OA cartilage in tension, compression and shear loading, and increases in the propensity to swell as compared to healthy cartilage. In the ACL transection model of OA, similar changes in the mechanics of cartilage have been observed. In addition, changes in structure, composition, and as metabolism consistent with human OA have been found. Deterioration of the collagen-proteoglycan solid network, which appears to be focused at the articular surface, has been the earliest cartilage changes in the model. It remains to be determined if the initial disruption of the cartilage surface is a direct result of mechanical forces or a product of altered chondrocyte activity. CONCLUSIONS: These data and continued research using experimental models of OA provide a basis for our understanding of the pathogenesis and the time course of events in OA and will lead to the development of better procedures for disease intervention and treatment.

Animals↗

PubMed1987

Antiulcerogenic activity of zinc acexamate in different experimental models.

The antiulcerogenic activity of zinc acexamate (ZAC; Laboratorios Viñas, S.A.) has been tested in several models of gastric injury induced by acid hypersecretion, prostaglandin blockade and disruption of the gastric barrier. Lowest doses which have demonstrated to significantly prevent gastric damage ranged from 10 to 100 mg/kg depending on the experimental model used. The benefit obtained with this compound was always dose-dependent. These findings would support the hypothesis that ZAC acts by a complex inhibition of several of the mechanisms involved in the development of peptic diseases.

Aminocaproates↗

PubMed2006

An experimental model of peripheral neuropathy induced in rats by Karwinskia humboldtiana (buckthorn) fruit.

Intoxication by Karwinskia humboldtiana (buckthorn) fruit presents a neurological picture similar to that of Guillain-Barré syndrome. In this report, we describe an experimental animal model of peripheral neuropathy induced by buckthorn fruit. Four groups of Wistar rats received one oral dose of 1.5 g/kg followed by oral doses of 0.5 g/kg at days 3, 7, 10, and 14 of dried and ground buckthorn fruit in aqueous suspension. Rats were sacrificed at 24, 48, 58, and 112 days after initial dose. Treated animals developed progressive paralysis through 58 days, then completely recovered by 112 days. Sciatic nerves showed segmental demyelination and cellular infiltrates until 58 days after exposure and then remyelinating changes at 112 days. This experimental model for peripheral neuropathy is reproducible and easy to handle. Its manipulation is relatively innocuous and allows us to study reversible peripheral nerve damage. This model can be developed in other animal species and may be useful to test new therapies for peripheral neuropathy.

Animals↗

PubMed1984

An experimental model to study thermogenesis in the neonatal surgical patient.

The nonshivering thermogenic response of the newborn to cold exposure and the potentially detrimental effects of the resultant hypermetabolic state have been documented by numerous animal and clinical studies. It is standard practice to protect the newborn infant from cold stress by controlling environmental temperature and preventing heat loss. Although these measures are well accepted, little attention has been paid to the effect of surgical factors, such as operative trauma, anesthetic agents, and muscle relaxants on nonshivering thermogenesis. The purpose of this investigation is to develop an experimental model to study the effect of surgical factors on the neonatal thermogenic response. Newborn rabbits were chosen as the experimental subject because these animals rely solely on nonshivering thermogenesis. One-hundred-eleven animals were studied. In the newborn rabbit, there was an inverse relationship between age and the percentage of brown fat. Body weight doubled in the first week of life, while the quantity of brown fat fell from a maximum of 2.9% of body weight in the first day of life to 1.56% at 7 days of age. It was possible to maintain the newborn rabbit in a warm environment for periods of up to 2 hours without changes in blood flow to the brown fat or oxygen consumption. The thermogenic response to cold did not appear to be altered in terms of oxygen consumption when the animals were lightly anesthetized with pentobarbital or paralyzed with metocurine and locally anesthetized. The rise in oxygen consumption was similar in awake, intact animals and those that received pentobarbital or metocurine and xylocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗

PubMed1999

Basal ganglia calcification induced by excitotoxicity: an experimental model characterised by electron microscopy and X-ray microanalysis.

Activation of glutamate receptors induces an excitotoxic neurodegenerative process characterised in some brain areas by the formation of calcium precipitates. To examine the pathogenesis of basal ganglia calcification (BGC), an improved procedure of X-ray microanalysis was used to study experimental excitotoxic calcification in the rat. Three weeks after injection of ibotenic acid (IBO) in the rat basal forebrain, calcified inclusions within hypertrophied astrocytes were characterised. They appeared to form part of a filamentous structure localised in the cytoplasm in association with normal mitochondria and other organelles. Larger inclusions were surrounded by reactive microglia. The main inorganic components in these deposits were Ca and P, frequently accompanied by S. Al, Si and K. The shape and Ca/P molar ratio of the large deposits (>10 microm) indicate that they may be biological apatites. Aluminosilicates were detected as small deposits (<4 microm) free of other mineral constituents. To our knowledge this is the first report showing that IBO lesion induces brain accumulation of aluminosilicates similar to that described in Alzheimer's or Fahr's patients. Our data indicate that precipitation of Ca and Al may reduce their IBO-induced increased concentration. In conclusion, the experimental model and the improved efficiency of X-ray analysis described may help us to understand the pathogenesis of BGC.

Aluminum Silicates↗

PubMed2005

An experimental model to demonstrate the carcinogenic action of oral chronic traumatic ulcer.

BACKGROUND: Oral chronic traumatic ulcer (CTU) is caused by constant irritation by dental edges or restorations and could behave as a pre-malignant lesion in a field initiated by carcinogens such as tobacco or alcohol. METHODS: We developed an experimental model in the hamster cheek pouch, combining the chemical carcinogen 7,12-dimethyl-benzanthracene (DMBA) with CTU. RESULTS: The successive or simultaneous action of both agents induced a significantly larger number of endophytic carcinomas than larger doses of DMBA alone. CTU alone failed to induce tumor development. Ploidy analysis revealed significantly higher malignancy indices in endophytic than in exophytic carcinomas. 5-Bromo-2-deoxyuridine labeling evidenced greater proliferation around the ulcers in chemically cancerized epithelium than around ulcers in healthy epithelium. CONCLUSIONS: The results show that CTU acts as a tumor promoter in this model. This finding is clinically relevant in that CTU may increase the risk of malignant transformation in patients with subclinical tumor initiation.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2000

[Analysis and improvement consideration of the current human experimental models of humoral regulation in microgravity].

The main differences between physiological effects of microgravity in spaceflight and simulated microgravity on humans appeared in the circulation of the low pressure side, in humoral and electrolyte metabolism. For a further understanding of the physiological effects of microgravity, some improvement of the current human experimental models are needed. It is possible to choose more adequate models closer to the situation in microgravity through measuring cardiovascular parameters, fluid regulation and renal excretion variables under head-up tilt (HUT) plus lower body positive pressure condition, or under head-down tilt (HDT) plus upper body negative pressure in various angles and pressure levels.

Adaptation, Physiological↗