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PubMed1999

Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds.

The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely beta-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (r = 0.90, P < 0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.

Age Factors↗
PubMedDate not supplied

Alpha-tocopherol derivatives and wound healing in an experimental model of filtering surgery.

OBJECTIVE: To describe the effect of alpha-tocopherol derivatives (acetate and acid-succinate) on the histopathological characteristics of the surgical fistula in an experimental model of filtering surgery. MATERIALS AND METHODS: Thirty pigmented rabbits were divided into 3 groups. Twenty-four hours before surgery the animals were injected subconjunctivally with 0.5 mL of solution that depended on the group of treatment: Group 1 (n = 10) 0.75% ethanol in balanced salt solution (BSS); Group 2 (n = 10) 100 microg alph-tocopherol-acetate in 0.75% ethanol in BSS; Group 3 (n = 10) 100 microg alpha-tocopheryl-acid-succinate in 0.75% ethanol in BSS. Histological findings were evaluated 30 days after surgery. RESULTS: The groups treated with alpha-tocopherol derivatives showed a higher percentage of persistence of the fistula and better intraocular pressure (IOP) control. CONCLUSIONS: Alpha-tocopherol derivatives showed antiproliferative properties in this experimental model of filtering surgery.

Animals↗
PubMed2002

[Morphologic study of the intestine in an experimental model of amnioinfusion in fetal rabbits with gastroschisis].

An experimental model of serial amnioinfusion has been developed in fetal rabbits with gastroschisis, using an intraamniotic catheter connected to a subcutaneous port. Fetuses of 4 groups were compared 7 days after surgery: group A: gastroschisis and daily amnioinfusion through an implanted catheter; group C: gastroschisis and blind amniotic catheter; group G: gastroschisis without catheter; group O: nonoperated fetuses. Survival rate, fetal body weight, lung weight, intestinal weight and length were determined. Computer aided morphometric analysis was performed, in which intestinal diameter, thickness and villi length were measured. Amniotic fluid samples were recovered along the experimental period. Intestinal length was significantly shorter and had a significantly thicker wall than nonoperated fetuses; we found no other morphometric differences between gastroschisis treated with amnioinfusion (group A) and the other gastroschisis groups (C and G). Amnioinfusion did not affect fetal survival rate; the amniotic catheter alone did not cause pulmonary hypoplasia due to significant amniotic leak. The physiological decrease in amniotic volume towards the end of gestation has not been modified by this regime of amnioinfusion.

Amniotic Fluid↗
PubMed1996

[Continuous hemofiltration. Development of an experimental model].

OBJECTIVE: Continuous hemofiltration is an extracorporeal technique used to eliminate water and solutes by convective transport through a hemofilter. The aim of this study was to develop an experimental model of arterio-venous and veno-venous continuous hemofiltration in order to gain experience before its clinical application in human neonates. MATERIALS AND METHODS: Twelve white New Zealand adult rabbits were anesthetized, tracheotomized and connected to a continuous flow neonatal ventilator. Continuous arterio-venous hemofiltration (n = 6) was performed via catheters placed in the carotid artery and jugular vein and veno-venous hemofiltration (n = 6) by a double-lumen catheter located in the inferior vena cava. Heart rate, arterial pressure, pH and blood gases, and the volume of ultra-filtrate were monitored and recorded for a three hour period. RESULTS: In both groups a high rate of ultrafiltration was achieved. The volume of ultrafiltration decreased somewhat during the second hour and remained stable thereafter. No hemodynamic changes were detected. CONCLUSIONS: The development of an experimental model for continuous arterio-venous and veno-venous hemofiltration in rabbits, facilitated the implantation of these techniques in human neonates. The model may be used to train the staff of the Neonatal Intensive Care Unit and to eliminate difficulties with vascular access and the care of extracorporeal lines.

Acute Disease↗
PubMed2001

Eosinophil-induced liver injury: an experimental model using IL-5 transgenic mice.

BACKGROUND/AIMS: In certain liver diseases, activated eosinophils are considered to be important effector cells in addition to T-cell-mediated cytotoxicity. No experimental model, however, has been developed for in vivo analysis of the cytotoxic mechanisms. METHODS: Interleukin-5 (IL-5) transgenic mice (C3H/HeN-TgN(IL-5)Imeg), which exhibit marked eosinophilia without liver injury, were injected once with 25 microg of lipopolysaccharide (LPS) intraperitoneally. The mice were sacrificed weekly and eosinophilic injuries were assessed microscopically. To clarify the role of Kupffer cells and tumor necrosis factor-alpha (TNF-alpha) in the liver injury, gadolinium chloride (GdCl3) and anti-TNF-alpha neutralizing antibody were administrated before the LPS injection. RESULTS: Two weeks after injection, transgenic mice exhibited marked infiltration of eosinophils and extensive lobular necrosis. Transmigration of eosinophils through vascular endothelium and degranulation of eosinophil cytotoxic granules in inflamed areas were observed. These eosinophilic injuries were transient, but liver-specific. Pre-administration of GdCl3 and anti-TNF-alpha markedly reduced the hepatic inflammation, suggesting that LPS-activated Kupffer cells play a key role in producing the cytotoxicity of eosinophils by releasing TNF-alpha. CONCLUSIONS: We have established an experimental model of eosinophil-induced liver injury using IL-5 transgenic mice. Since this model is simple and highly reproducible, it will be useful for analysis of in vivo cytotoxic mechanisms of eosinophils.

Animals↗
PubMed1995

Effects of tetraprenylacetone on pancreatic exocrine secretion and acute pancreatitis in two experimental models in rats.

The effects of tetraprenylacetone (TPN), an acyclic polyisoprenoid with antiulcer actions, on pancreatic exocrine secretion, and its preventive and therapeutic effects on acute pancreatitis in two experimental models were studied in rats. Intraduodenal administration of TPN (0, 100, 200, and 400 mg/kg/h) caused dose-dependent increases in pancreatic juice and bicarbonate output without increasing protein output and plasma cholecystokinin (CCK) concentrations. TPN-stimulated pancreatic exocrine secretion was completely abolished by antisecretin serum but it was not by CCK receptor antagonist loxiglumide (50 mg/kg/h). In acute pancreatitis induced by four subcutaneous injections of 20 micrograms/kg cerulein at hourly intervals over, 3 h, TPN (400 mg/kg) given by an oral route either 1 h before the first cerulein injection or immediately after the last injection significantly reduced the increases in serum amylase and lipase activities and pancreatic wet wt. Pretreatment with TPN caused histologic improvements, whereas posttreatment failed to ameliorate histologic alterations. In severe type of acute pancreatitis induced by retrograde intraductal injection of 1.0 mL/kg of 4% sodium taurocholate, TPN exerted no apparent beneficial effects on biochemical and histologic alterations of acute pancreatitis. It is concluded that TPN given by an oral route stimulates pancreatic exocrine secretion through an increase in endogenous secretin release and causes beneficial effects on the experimental model of mild acute pancreatitis in rats.

Acute Disease↗
PubMed2000

A comparison of bolus versus continuous cardiac output in an experimental model of heart failure.

OBJECTIVE: The majority of studies examining cardiac output measurement have been done in physiologically stable models with low thermal background noise. Research comparing continuous cardiac output (CCO) with bolus thermodilution cardiac output (COTD) measures in human and animal models have reported high correlations, negligible bias, but large limits of agreement. The purpose of this project was to compare CCO with COTD measures in an experimental model of heart failure where the cardiac output values were low and the range was narrow. DESIGN: A one-group experimental design with preintervention control measures and repeated CCO and COTD measures across nine time points. SETTING: Cardiovascular research laboratory. SUBJECTS: Thirty dogs. MEASURES AND MAIN RESULTS: Univariate and multivariate versions of repeated-measures analysis were used to assess the influences of temperature, weight, and stage of the experimental protocol on CCO, COTD, and the differences between them. The two measures CCO and COTD were assessed for agreement by using methods proposed by Bland and Altman. Two hundred and fifty pairs of measurements were obtained during sinus rhythm. The range for COTD measures was 0.5-4.67 L/min and for CCO measures 1.0-5.40 L/min. Of the 250 cardiac outputs estimated by the continuous method, 73.4% of the values were within +/-15% of that estimated by the repetitive, single thermodilution method. The mean bias for the entire protocol was 0.01 (SD = 0.51) with a range of 4.33 L/min. CONCLUSION: Agreement between the two measures may be the function of biological variability, responses to anesthesia, and technique. Bland and Altman evaluation demonstrated low bias and precision and similar levels of agreement when compared with previous studies in an experimental model where the cardiac output was low and the range was narrow.

Animals↗
PubMed1992

The ICT in situ experimental model in dental research.

The intra-oral cariogenicity test (ICT) in situ experimental model was introduced in 1964 for the study of caries on sample enamel in the human mouth. Slabs of human or bovine enamel are mounted with a Dacron gauze cover in the acrylic flanges of prosthetic appliances. The extent of enamel demineralization or remineralization of lesions is assessed from surface microhardness measurements and microradiography of the enamel sections. The ICT model offers the potential of studying various parameters related to caries. This publication presents a typical ICT study comparing the cariogenicity of 10% sucrose solutions containing 1, 3, 10, and 30 ppm F with that of the control solution, 10% sucrose (without fluoride). The treatments were applied to the ICT as 10-minute extra-oral immersions. The results indicate: (1) a strong effect of F in decreasing demineralization of sound enamel and increasing remineralization of pre-softened enamel in the ICT; (2) pronounced resistance to a subsequent in vitro acid test; (3) pronounced F incorporation into pre-softened enamel; and (4) a characteristic acid-resistant zone, as seen in microradiographs, associated with exposure to F. This in situ model enables one to study experimental caries with repeated testing of enamel that follows the development and/or the regression of subsurface enamel lesions, F incorporation, increased acid resistance, cariogenicity of substrates, and other parameters of caries that can be assessed under standard conditions of tooth substrate and microbial sheltering.

Animals↗
PubMed2000

Experimental models for the study of cardiovascular function and disease.

In the study of cardiovascular biology, both under conditions of health and disease, the investigator enjoys the availability of a vast range of experimental models ranging from man to a single molecule and beyond. There is also a vast spectrum of measurable indices of function and injury. This is particularly so in the case of myocardial ischemia, a disease which still contributes to the majority of deaths in the Western Hemisphere. Each experimental model, each species and each end-point has its own inherent advantages and disadvantages and appreciating these will help the investigator select the most appropriate study system for the particular question under investigation. This article endeavours to identify some of these strengths and weaknesses and reveals the frequently encountered paradox that the greater the amount and reproducibility of data the further removed is the model from clinical reality. Fortunately, however, an appreciation of this 'weakness' can often be exploited for the advancement of knowledge.

Animals↗
PubMed1976

The hemodynamic effects of intrauterine hypoxia: an experimental model in newborn lambs.

An experimental animal model of intrauterine hypoxia and respiratory distress in newborn lambs was produced by inducing maternal hypotension. Serial hemodynamic data indicated that the oxygenation defect in the lambs was due to right-to-left shunting of blood through fetal channels rather than within the lungs. Shunting was mainly across the foramen ovale, but, in severely distressed animals, significant right-to-left shunt also occurred through the ductus arteriosus. Left-to-right shunts across the ductus arteriosus were found in lambs with milder respiratory distress. The implications of perinatal hypoxia as it affects the pulmonary vascular bed in human neonates with the respiratory distress syndrome (hyaline membrane disease) and persistence of the fetal circulation are discussed. It is speculated that the early pulmonary vascular esponses in the two diseases may be identical.

Animals↗
PubMed2003

An experimental model to study the in vivo survival of von Willebrand factor. Basic aspects and application to the R1205H mutation.

To explore the molecular basis of von Willebrand factor (VWF) clearance, an experimental model employing VWF-deficient mice was developed. Biodistribution was examined by the injection of radiolabeled VWF, which was primarily directed to the liver with minor amounts in other organs. Disappearance of VWF from plasma was characterized by a rapid initial phase (t((1/2))alpha = 13 min) and a slow secondary phase (t((1/2))beta = 3 h), with a mean residence time (MRT) of 2.8 h. A similar clearance was observed for VWF consisting of only high or low molecular weight multimers, indicating that, in our experimental model, clearance is independent of multimeric distribution. This allowed us to compare the survival of full-length VWF to truncated variants. Deletion of both the amino-terminal D'-D3 and carboxyl-terminal D4-CK domains resulted in a fragment with a similar clearance to wild-type VWF. Deletion of only the D'-D3 region was associated with an almost 2-fold lower recovery and increased clearance (MRT = 1.6 h), whereas deletion of only the D4-CK region resulted in a significantly reduced clearance (MRT = 4.5 h, p < 0.02). These results point to a role of the D'-D3 region in preventing clearance of VWF. Furthermore, replacement of D3 domain residue Arg-1205 by His resulted in a markedly increased clearance (MRT = 0.3 h; p = 0.004). Therefore, this mutation seems to abrogate the protective effect of the D'-D3 region. In vitro analysis of this mutant also revealed a 2-fold reduced affinity for VWF propeptide at low pH, showing that mutation of Arg-1205 results not only in an increased clearance rate but is also associated with an impaired pH-dependent interaction with VWF propeptide.

Animals↗
PubMed1998

Streptococcal and staphylococcal superantigen-induced lymphocytic arteritis in a local type experimental model: comparison with acute vasculitis in the Arthus reaction.

Many pathogenic bacteria produce superantigenic exotoxins. To study their pathogenetic role, in particular to test whether these toxins are able to induce vasculitis, we developed a local-type experimental model in rabbits. Toxins were injected along the intermediate auricular artery of the ear. The histology of ear skin, including the artery, was examined after single or repeated injections. Repeated injections of streptococcal erythrogenic toxins produced chronic-type arteritis characteristic of lymphocytic infiltration, whereas single injection induced no acute-type vasculitis. Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 also induced the same type of arteritis, although weaker in degree. In human patients these lesions are similar to those of Kawasaki disease, a systemic vasculitis with unknown etiology. The Arthus reaction to human serum albumin in immunized rabbits included acute-type vasculitis similar to polyarteritis nodosa when examined in this model. Microvasculitis lesions similar to leukoclastic vasculitis were combined in the Arthus reaction but not in the superantigen-induced lesions. Our experimental model described here is widely applicable to the study of the etiology and pathogenesis of human diseases involving vasculitis lesions.

Animals↗
PubMed2006

An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study.

BACKGROUND: Acute exacerbations of COPD are a major cause of morbidity, mortality and hospitalisation. Respiratory viruses are associated with the majority of exacerbations but a causal relationship has not been demonstrated and the mechanisms of virus-induced exacerbations are poorly understood. Development of a human experimental model would provide evidence of causation and would greatly facilitate understanding mechanisms, but no such model exists. METHODS: We aimed to evaluate the feasibility of developing an experimental model of rhinovirus induced COPD exacerbations and to assess safety of rhinovirus infection in COPD patients. We carried out a pilot virus dose escalating study to assess the minimum dose of rhinovirus 16 required to induce experimental rhinovirus infection in subjects with COPD (GOLD stage II). Outcomes were assessed by monitoring of upper and lower respiratory tract symptoms, lung function, and virus replication and inflammatory responses in nasal lavage. RESULTS: All 4 subjects developed symptomatic colds with the lowest dose of virus tested, associated with evidence of viral replication and increased pro-inflammatory cytokines in nasal lavage. These were accompanied by significant increases in lower respiratory tract symptoms and reductions in PEF and FEV1. There were no severe exacerbations or other adverse events. CONCLUSION: Low dose experimental rhinovirus infection in patients with COPD induces symptoms and lung function changes typical of an acute exacerbation of COPD, appears safe, and provides preliminary evidence of causation.

Adult↗
PubMed1991

Experimental models for drug teratogenicity.

Teratogenicity a specific manifestation of embryotoxicity, is explored in the course of the preclinical phase of drug testing. The official routine rat-rabbit procedures employ an integral experimental model--the whole animal with its species-specific metabolism. Although it has been widely accepted that pharmaco-kinetics of drugs represents the most important source of interspecies differences in teratology, the official procedure is still considered satisfactory. The reason why a new thalidomide affair has not occurred can be explained by the extremely low expression of teratogenic potential at the human population level--a condition inherent in the principles of teratogenesis. On the other hand, many partial experimental models have been developed that use mainly suborganismic objects (i.e. isolated morphogenetic systems, explanted tissues and cell populations). These objects possess many limitations disgracing their use as candidates for replacing the whole-animal experiments. Nevertheless, some of the partial models can be used and must be used in deeper analysis of the teratogenic potential of drugs with the aim of improving the predictive power of embryotoxicity risk assessment. (Fig. 1, Ref. 7.)

Animals↗
PubMed1984

Variability in isolate recovery rates from multiple and single breeds of outbred pigmented rabbits in an experimental model of Candida keratitis.

We evaluated variability of isolate recovery rates in an experimental model of Candida keratitis for both heterogeneous, pigmented, outbred rabbits and homogeneous Dutch-belted rabbits. Our purpose was to achieve more precise evaluation of topical antifungal agents in our model by substantially reducing the component of variance due to inter-rabbit differences. For the homogeneous Dutch-belted rabbits, the overall variance was reduced by a factor of 2.34 (p = 0.18) vis a vis the heterogenous outbred rabbits. The greatest reduction, a factor of 3.5, was achieved for the inter-rabbit component of variance. The upper bound for the hereditability measure was reduced from 29% to 18%. These data suggest that (1) researchers using animal models should perform a components of variance analysis to identify the factors influencing experimental precision, and (2) for our model, additional reduction in variability must come from refinement of experimental technique.

Analysis of Variance↗
PubMed1981

Inguinal hernia repair: an experimental model in the rat to evaluate technical factors.

An experimental model in the rat has been developed that we believe simulates the situation in inguinal hernia. Using this model, the bursting strength of wounds made by approximating uninjured fascia were compared with wounds made by apposing either incised fascia or the raw edges left after excising fascia. The strongest healing resulted when raw edges were apposed and when continuous sutures were used. We believe that these studies give support the use of Shouldice's hernia repair.

Animals↗
PubMed1980

Experimental model of haemophilic arthropathy with high pressure haemarthrosis.

An experimental model of haemophilic arthropathy was developed in 12 growing dogs by anastomosing the popliteal artery to the joint cavity of the knee to produce haemarthrosis under considerable pressure. The dogs were sacrificed at intervals of one to eight weeks and the morphological and radiological changes found in the specimens mimicked those occurring in haemophilic arthropathy. In some of the animals total destruction of the articular cartilage and subchondral bone occurred. The significance of a high pressure haemarthrosis is discussed in relation to the development of changes found in haemophilic arthropathy.

Animals↗
PubMed1994

Regeneration of mesenteric lymphatic vessels in a new experimental model of orthotopic intestinal transplantation in rats.

A new experimental model of orthotopic intestinal transplantation was performed using microsurgical techniques in rats; the physiological flow of blood, lymph, and food was reconstructed. Regeneration of mesenteric lymphatic vessels, which plays an extremely important role in lipid absorption of the transplanted intestine, was studied by mesenteric lymphangiography. Regeneration of mesenteric lymphatic vessels was first confirmed on the seventh postoperative day by mesenteric lymphangiography, and favorable regenerative patterns, without obstruction, were observed on the 32nd, 58th, and 93rd postoperative days.

Animals↗